Oncology, Solid Tumors
Conditions
Keywords
Palliative Radiotherapy, Advanced solid tumors, M3814, Avelumab
Brief summary
The main purpose of the study was to evaluate a safe, tolerable recommended Phase II dose (RP2D) and/or the maximum tolerated dose (MTD) of M3814 when given in combination with avelumab with and without radiotherapy in participants with selected advanced solid tumors.
Interventions
DRUGM3814
Participants received M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity.
DRUGAvelumab
Participants received avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity.
RADIATIONRadiotherapy
Participants received radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Part A and Part FE (M3814 + avelumab): Participants had histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide clinical benefit for their condition * Part B (M3814 + Radiotherapy \[RT\] + avelumab): histologically or cytologically proven advanced or metastatic solid tumors for which no standard therapy exists, standard therapy has failed, or participants are intolerant to or have rejected established therapy known to provide benefit for their condition and are amenable to receive RT * Part A, B and FE: Measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1) * Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at study entry * Part A, B and FE: Female participants of childbearing potential should be willing to use a highly effective contraceptive method * Part A, B and FE: Male participants should agree to refrain from donating sperm plus, either: abstain from any activity that allows for exposure to ejaculate * Use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy * Part A, B and FE: Be willing to provide informed consent for the trial * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Participants who had received prior chemotherapy, hormonal anticancer therapy with the exception of luteinizing hormone-releasing hormone analogs, biologic therapy, or any other anticancer therapy within 28 days of the first dose of study treatments (6 weeks for nitrosoureas or mitomycin C) * Participants who had undergone major surgery for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or has not fully recovered from the surgery within 4 weeks of the study intervention * Participants with evidence of active or history of autoimmune disease that might deteriorate when receiving an immune-stimulatory agent * Participants with brain metastases, except those meeting the following criteria: a) brain metastases that have been treated locally and are clinically stable for greater than or equal to (\>=) 4 weeks prior to randomization b) no ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) c) participants must be either off steroids or on a stable or decreasing dose of less than (\<) 10 milligrams (mg) daily prednisone (or equivalent) * Participants with severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year), psychiatric or substance abuse disorders; or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results * Participants requiring systemic immunosuppressive agents (such as steroids) for any reason who cannot be tapered off these drugs before start of study intervention, with the following exceptions: a) participants with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to less than or equal to (\<=) 10 mg prednisone daily b) participants requiring steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) is permitted c) participants with previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon planned to be completed in 14 days, or that the dose after 14 days will be equivalent to \<= 10 mg prednisone daily * Participants with a history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome, Hepatitis B virus or Hepatitis C and with history of infection must have a polymerase chain reaction (PCR) documentation that infection is cleared * Participants who had received a live vaccine within 30 days prior to the first dose of trial treatment * Participants with known prior severe hypersensitivity to any of the investigational products or any component in its formulations * Participants with evidence of additional malignancy within the last 5 years unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and participants were deemed to have been cured with no additional therapy required or anticipated to be required. Participants with treated nonmelanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate may participate * Participants pretreated with immunotherapy who have, any history of dose limiting toxicities (DLTs) with prior immunotherapy agents, including Grade 3/4 immune-related adverse events (irAEs); irreversible irAEs; Grade greater than or equals to (\>=) 3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant clinical sequelae * Participants with irAE requiring hormone replacement therapy (e.g., thyroxine, insulin, or physiologic dose of corticosteroid replacement therapy for adrenal or pituitary insufficiency) may participate as long as the endocrinopathy is well controlled and the participant is not otherwise symptomatic from hormone insufficiency * Physiologic corticosteroid dose is defined as \<= 10 mg daily of prednisone or equivalent * for Part B only: * Participants who had confirmed esophagitis and in whom radiation planning target volume will include any portion of the esophagus, the participant is not eligible unless an esophageal endoscopy rules out the presence of esophagitis * Participants in whom more than 10 percent (%) of the total esophagus volume might receive more than 15 gray (Gy) (50% of the prescribed radiotherapy \[RT\] dose) * Participants who have had previous radiotherapy to the same region as intended to be irradiated in this study within the past 12 months * Participants who had had extensive previous radiotherapy on \>= 30% of bone marrow reserve or prior bone marrow/stem cell transplantation within 5 years before study start * If participant hepatic metastatic lesion is selected to be irradiated: - the non-tumor liver volume \< 700 milli liters (mL); - Child-Pugh score \>= 8 * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | Day 1 up to Day 21 | A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported. |
| Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | Day 1 up to Day 28 | A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported. |
| Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22 | Area under the plasma concentration versus time curve from time zero to 6 hours post dosing for M3814 was reported. |
| Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22 | Cmax was obtained directly from the concentration versus time curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported. |
| Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported. |
| Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Time from first study intervention up to long term safety follow-up period (Up to 516 days) | Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. |
| Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. |
| Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. |
| Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Time from first study intervention up to long term safety follow-up period (Up to 516 days) | Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. |
| Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. |
| Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. |
| Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Time from first study intervention up to long term safety follow-up period (Up to 516 days) | ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value. |
| Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value. |
| Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value. |
| Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Cmax was obtained directly from the concentration versus time curve. |
| Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15 | Cmax was obtained directly from the concentration versus time curve. |
| Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Cmax was obtained directly from the concentration versus time curve. |
| Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 10 | Cmax was obtained directly from the concentration versus time curve. |
| Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15 | Tmax was obtained directly from the concentration versus time curve. |
| Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15 | Tmax was obtained directly from the concentration versus time curve. |
| Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | Tmax was obtained directly from the concentration versus time curve postdose. |
| Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | Tmax was obtained directly from the concentration versus time curve postdose. |
| Part A: Minimum Observed Drug Concentration (Cmin) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Part B: Minimum Observed Drug Concentration (Cmin) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve. |
| Part A: Average Plasma Concentration of M3814 Observed Post-dose (Cavg) | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. |
| Part B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg) | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve. |
| Part A: Fluctuation Index of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg). |
| Part B: Fluctuation Index of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg). |
| Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ). |
| Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ). |
| Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf. |
| Part B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-infcalculated as AUC0-t + AUCextra. |
| Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15 | Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1. |
| Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 10 divided by Cmax, after dosing on Day 1. |
| Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15 | Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 15 divided by AUC0-t, after dosing on Day 1. |
| Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1; Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 10 divided by AUC0-t, after dosing on Day 1. |
| Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z). |
| Part B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z). |
| Part A: Apparent Clearance (CL/f) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Part B: Apparent Clearance (CL/f) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Part A: Terminal Elimination Rate Constant (Lambda z) of M3814 | Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1 | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Part B: Terminal Elimination Rate Constant (Lambda z) of M3814 | Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1 | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Part A: Number of Participants With Positive Antidrug Antibody (ADA) | Time from first study intervention up to long term safety follow-up period (Up to 516 Days) | Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. |
| Part B: Number of Participants With Positive Antidrug Antibody (ADA) | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. |
| Part FE: Number of Participants With Positive Antidrug Antibody (ADA) | Part FE: From the first study intervention to 508 days | Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. |
| Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first study intervention up to long term safety follow-up period (Up to 516 Days) | Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported. |
| Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported. |
| Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported. |
| Part A: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 516 Days | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part B: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 513 Days | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 44 Weeks | DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | Time from first study intervention up to long term safety follow-up period (Up to 516 Days) | Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method. |
| Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method. |
| Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method. |
| Part A: Overall Survival | Time from first study intervention up to long term safety follow-up period (Up to 1359 Days) | Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part A: M3814 250 mg BID + Avelumab 800 mg Q2W arm. Participants that are still alive at the time of analysis will be censored and counted into the analysis. |
| Part B: Overall Survival | Time from first study intervention up to long term safety follow-up period (Up to 1359 Days) | Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part B of the study. Participants that are still alive at the time of analysis will be censored and counted into the analysis. |
| Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Time from first study intervention up to long term safety follow-up period (Up to 516 days) | An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported. |
| Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | Time from first study intervention up to long term safety follow-up period (Up to 516 Days) | Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point. |
| Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point. |
| Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point. |
| Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0 | Time from first study intervention up to long term safety follow-up period (Up to 512.4 Days) | Number of participants with radiotherapy-induced toxicities (mucositis and radiation dermatitis) were reported. |
| Part FE: Overall Survival | Time from first study intervention up to long term safety follow-up period (Up to 1359 Days) | Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Participants that are still alive at the time of analysis will be censored and counted into the analysis. |
| Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Time from first study intervention up to long term safety follow-up period (Up to 513 Days) | An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported. |
| Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Time from first study intervention up to long term safety follow-up period (Up to 404 Days) | An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported. |
| Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | Time from first study intervention up to long term safety follow-up period (Up to 516 days) | The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported. |
Countries
United States
Participant flow
Recruitment details
First participant signed informed consent: 27-Nov-2018; Clinical data cutoff date: 05 Aug 2022
Pre-assignment details
This study was conducted in 3 parts; Part A, Part B and Part Food Effect (FE). Participants who enrolled in Part A of study were not eligible to participate in Part B and Part FE.
Participants by arm
| Arm | Count |
|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W Participants received 100 milligrams (mg) of M3814 orally twice daily (BID) along with 800 mg of Avelumab once every 2 weeks (Q2W) from Day 1 until progressive disease (PD) or unacceptable toxicity. M3814 will be administered without food. | 4 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W Participants received 200 mg of M3814 orally BID along with 800 mg of Avelumab Q2W from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 11 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W Participants received 250 mg of M3814 orally BID along with 800 mg of Avelumab Q2W from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 4 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W Participants received 300 mg of M3814 orally BID along with 800 mg of Avelumab Q2W from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 6 |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W Participants received 400 mg of M3814 orally BID along with 800 mg of Avelumab Q2W from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 4 |
| Part B: M3814 100 mg BID + Avelumab 800 mg Q2W + RT Participants received 100 mg of M3814 along with radiotherapy (RT) at 3 grays (Gy) once daily (QD) starting on Day 1 for 5 days per week for 2 weeks in combination with intravenous infusion of Avelumab at a dose of 800 mg Q2W starting from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 3 |
| Part B: M3814 150 mg BID +Avelumab 800 mg Q2W + RT Participants received 150 mg of M3814 along with RT at 3 Gy QD starting on Day 1 for 5 days per week for 2 weeks in combination with intravenous infusion of Avelumab at a dose of 800 mg Q2W starting from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 3 |
| Part B: M3814 200 mg BID + Avelumab 800 mg Q2W + RT Participants received 200 mg of M3814 along with RT at 3 Gy QD starting on Day 1 for 5 days per week for 2 weeks in combination with intravenous infusion of Avelumab at a dose of 800 mg Q2W starting from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 4 |
| Part B: M3814 250 mg BID + Avelumab 800 mg Q2W + RT Participants received 250 mg of M3814 along with RT at 3 Gy QD starting on Day 1 for 5 days per week for 2 weeks in combination with intravenous infusion of Avelumab at a dose of 800 mg Q2W starting from Day 1 until PD or unacceptable toxicity. M3814 will be administered without food. | 9 |
| Part Food Effect: M3814 100 mg BID + Avelumab 800 mg Q2W Participants were administered 100 mg M3814 tablet orally BID in combination with i.v of avelumab at a dose of 800 mg Q2W throughout the whole study under fasted condition with the exception of fed condition on Day 1 and Day 22. The summary statistics for demographics, safety and efficacy is based on dose level but not fast/fed condition which is not fit for purpose. | 4 |
| Part Food Effect: M3814 200 mg BID + Avelumab 800 mg Q2W Participants were administered 200 mg M3814 tablet orally BID in combination with i.v of avelumab at a dose of 800 mg Q2W throughout the whole study under fasted condition with the exception of fed condition on Day 1 and Day 22. The summary statistics for demographics, safety and efficacy is based on dose level but not fast/fed condition which is not fit for purpose. | 5 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 2 | 6 | 3 | 5 | 2 | 0 | 2 | 3 | 4 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 | 1 | 2 | 2 | 1 | 0 | 2 | 0 | 0 |
| Overall Study | Other | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 | 0 | 0 | 1 | 0 | 0 | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part B: M3814 100 mg BID + Avelumab 800 mg Q2W + RT | Part B: M3814 150 mg BID +Avelumab 800 mg Q2W + RT | Part B: M3814 200 mg BID + Avelumab 800 mg Q2W + RT | Part B: M3814 250 mg BID + Avelumab 800 mg Q2W + RT | Part Food Effect: M3814 100 mg BID + Avelumab 800 mg Q2W | Part Food Effect: M3814 200 mg BID + Avelumab 800 mg Q2W | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59 Years STANDARD_DEVIATION 17.5 | 55 Years STANDARD_DEVIATION 19.6 | 53 Years STANDARD_DEVIATION 18.6 | 64 Years STANDARD_DEVIATION 4.1 | 53 Years STANDARD_DEVIATION 7.7 | 59 Years STANDARD_DEVIATION 17.3 | 69 Years STANDARD_DEVIATION 13.8 | 62 Years STANDARD_DEVIATION 7.2 | 61 Years STANDARD_DEVIATION 8.6 | 64 Years STANDARD_DEVIATION 9.3 | 68 Years STANDARD_DEVIATION 17.3 | 60 Years STANDARD_DEVIATION 13.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 10 Participants | 4 Participants | 6 Participants | 4 Participants | 2 Participants | 3 Participants | 4 Participants | 8 Participants | 4 Participants | 5 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 6 Participants | 3 Participants | 6 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 8 Participants | 4 Participants | 4 Participants | 44 Participants |
| Sex: Female, Male Female | 0 Participants | 6 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 4 Participants | 32 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants | 2 Participants | 1 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 6 / 11 | 3 / 4 | 5 / 6 | 2 / 4 | 0 / 3 | 2 / 3 | 3 / 4 | 4 / 9 | 2 / 4 | 2 / 5 |
| other Total, other adverse events | 3 / 4 | 11 / 11 | 4 / 4 | 6 / 6 | 4 / 4 | 3 / 3 | 3 / 3 | 4 / 4 | 9 / 9 | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 0 / 4 | 6 / 11 | 4 / 4 | 4 / 6 | 4 / 4 | 2 / 3 | 1 / 3 | 1 / 4 | 6 / 9 | 2 / 4 | 3 / 5 |
Outcome results
Primary
Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.
Time frame: Day 1 up to Day 21
Population: DLT analysis set included all participants who received at least 34 of 42 daily doses of M3814 and 2 administrations of avelumab during the DLT evaluation period and remained on study for the entirety of the DLT evaluation period, or participants who experienced a DLT during the DLT evaluation period and received any amount of any study intervention. The DLT evaluation period was defined as the first 21 days of the study, following the start of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 1 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 3 Participants |
Primary
Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0
A DLT was defined as any Grade more than or equal to \>= 3 nonhematologic Adverse Event(AE) or any Grade\>= 4 hematologic,, occurring during the DLT period that is related to any of the study interventions. In addition, a DLT is considered: Grade 3 thrombocytopenia with medically concerning bleeding, Any febrile neutropenia. A study intervention-related Treatment emergent Adverse Event(TEAE) is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. Any toxicity related to study intervention that causes the participant to receive less than 80% of M3814 during DLT period, evidence of study treatment-related hepatocellular injury for more than 3 days, such as\> 5-fold elevations above the Upper Limits of Normal (ULN) of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase(AST) with or without elevation of serum total bilirubin to \> 2 × ULN. Number of Participants with DLT Grade \>= 3 were reported.
Time frame: Day 1 up to Day 28
Population: DLT analysis set included all participants who received 8 of 10 daily doses of peposertib, 8 fractions of radiotherapy, and 3 administrations of avelumab during the DLT evaluation period and remained on study for the entirety of the DLT evaluation period or participants who experienced a DLT during the DLT evaluation period and received any amount of any study intervention. The DLT evaluation period was defined as the first 28days of the study, following the start of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0 | 0 Participants |
Primary
Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22
Population: The Pharmacokinetic (PK) Analysis Set included all subjects who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 1 | 563 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 100.5 |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 15 | 1370 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 63.2 |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 22 | 1070 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 99.4 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 1 | 950 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 119.6 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 15 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Maximum Observed Plasma Concentration (Cmax) of M3814 | Day 22 | NA nanogram per milliliter (ng/mL) | — |
Primary
Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814
Area under the plasma concentration versus time curve from time zero to 6 hours post dosing for M3814 was reported.
Time frame: Pre-dose, 1, 2, 4 and 6 hours post-dose on Day 1; Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15; Pre-dose, 2, 4 and 6 hours post-dose on Day 22
Population: The Pharmacokinetic (PK) Analysis Set included all subjects who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 1 | 1520 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 159.7 |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 15 | 6250 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 86.4 |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 22 | NA hour*nanogram per milliliter (h*ng/mL) | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 1 | NA hour*nanogram per milliliter (h*ng/mL) | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 15 | NA hour*nanogram per milliliter (h*ng/mL) | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part Food Effect (FE): Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to 6 Hour (AUC0-6hour) of M3814 | Day 22 | NA hour*nanogram per milliliter (h*ng/mL) | — |
Secondary
Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814
Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 15 divided by AUC0-t, after dosing on Day 1.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814 | 2.36 ratio | Geometric Coefficient of Variation 34.4 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814 | 1.57 ratio | Geometric Coefficient of Variation 74 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814 | NA ratio | — |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of AUC [Racc (AUC 0-12)] of M3814 | 4.32 ratio | Geometric Coefficient of Variation 36.7 |
Secondary
Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Days 1 and 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814 | 1.77 ratio | Geometric Coefficient of Variation 95.1 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814 | 1.47 ratio | Geometric Coefficient of Variation 28.7 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814 | NA ratio | — |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Accumulation Ratio of Maximum Observed Drug Concentration [Racc(Cmax)] of M3814 | 2.61 ratio | Geometric Coefficient of Variation 45 |
Secondary
Part A: Apparent Clearance (CL/f) of M3814
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for CL/f was not collected.
Secondary
Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814
The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z).
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Vz/f was not collected.
Secondary
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814
Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for AUC0-inf was not collected.
Secondary
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814
Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for AUC0-t was not collected.
Secondary
Part A: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)
Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Cavg was not collected.
Secondary
Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 15.8 percent change | Standard Deviation 17.27 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 15.3 percent change | Standard Deviation 15.38 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | -4.5 percent change | Standard Deviation 2.34 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 4.9 percent change | Standard Deviation 8.07 |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 13.6 percent change | Standard Deviation 26.97 |
Secondary
Part A: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 516 Days
Population: Full Analysis Set: All participants who receive at least one dose of study intervention. Data could not be calculated as none of the participants showed objective response.
Secondary
Part A: Fluctuation Index of M3814
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg).
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Fluctuation Index was not collected.
Secondary
Part A: Minimum Observed Drug Concentration (Cmin) of M3814
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Cmin was not collected.
Secondary
Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
Population: The PK Analysis Set included all participants who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 693 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 131.1 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 2370 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 38.8 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | NA nanogram per milliliter (ng/mL) | — |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 2360 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 33.6 |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | NA nanogram per milliliter (ng/mL) | — |
Secondary
Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814 | 5.60 hour | Geometric Coefficient of Variation 21.8 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814 | 6.26 hour | Geometric Coefficient of Variation 158.4 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814 | NA hour | — |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Doses: Apparent Terminal Half-life (t1/2) of M3814 | 11.4 hour | Geometric Coefficient of Variation 60.3 |
Secondary
Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
Tmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.08 hour |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.16 hour |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | NA hour |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.87 hour |
Secondary
Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 7 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 4 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 5 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 4 Participants |
Secondary
Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
Secondary
Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
Secondary
Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
Population: Full Analysis Set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 7 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 3 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 3 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 4 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 2 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 1 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 2 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
Secondary
Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
Population: Safety Analysis Set included all participants who receive at least one dose of any study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 4 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 1 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 1 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 2 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 1 Participants |
Secondary
Part A: Number of Participants With Positive Antidrug Antibody (ADA)
Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
Population: Safety Analysis Set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Positive Antidrug Antibody (ADA) | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Positive Antidrug Antibody (ADA) | 5 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Positive Antidrug Antibody (ADA) | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Positive Antidrug Antibody (ADA) | 2 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Positive Antidrug Antibody (ADA) | 0 Participants |
Secondary
Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 3 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAE | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Related TEAE | 3 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Related TEAE | 10 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 11 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAE | 6 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Related TEAE | 3 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 4 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAE | 4 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 6 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAE | 4 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Related TEAE | 4 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Related TEAE | 4 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 4 Participants |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAE | 4 Participants |
Secondary
Part A: Overall Survival
Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part A: M3814 250 mg BID + Avelumab 800 mg Q2W arm. Participants that are still alive at the time of analysis will be censored and counted into the analysis.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Overall Survival | 25.5 months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Overall Survival | 23.7 months |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Overall Survival | NA months |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Overall Survival | 3.4 months |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Overall Survival | 7.2 months |
Secondary
Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator
Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 516 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 5.1 months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 1.9 months |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 3.3 months |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 1.8 months |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | 2.6 months |
Secondary
Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 2.37 hour | Geometric Coefficient of Variation 17.9 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 3.94 hour | Geometric Coefficient of Variation 40.9 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 2.25 hour | Geometric Coefficient of Variation 27.4 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 5.24 hour | Geometric Coefficient of Variation 53.7 |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 3.51 hour | Geometric Coefficient of Variation 35.5 |
Secondary
Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: The PK Analysis Set included all participants who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 392 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 43.8 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 1030 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 78.2 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 2340 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 98.9 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 1710 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 99.8 |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Maximum Observed Plasma Concentration (Cmax) of M3814 | 3190 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 40.6 |
Secondary
Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
Tmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 15
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.06 hour |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 2.02 hour |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.03 hour |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.51 hour |
| Part A: M3814 400 mg BID + Avelumab 800 mg Q2W | Part A: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.08 hour |
Secondary
Part A: Terminal Elimination Rate Constant (Lambda z) of M3814
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for lambda z was not collected.
Secondary
Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814
Accumulation ratio of AUC0-12 was calculated as AUC0-t, after dosing on Day 10 divided by AUC0-t, after dosing on Day 1.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1; Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814 | NA ratio | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814 | NA ratio | — |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814 | 1.44 ratio | Geometric Coefficient of Variation 22.9 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of AUC [Racc (AUC 0-24)] of M3814 | 1.96 ratio | Geometric Coefficient of Variation 25.6 |
Secondary
Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 10 divided by Cmax, after dosing on Day 1.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814 | NA ratio | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814 | 0.838 ratio | Geometric Coefficient of Variation 24.8 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814 | 2.15 ratio | Geometric Coefficient of Variation 30.3 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Accumulation Ratio of Cmax [Racc(Cmax)] of M3814 | 1.34 ratio | Geometric Coefficient of Variation 39.3 |
Secondary
Part B: Apparent Clearance (CL/f) of M3814
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for CL/f was not collected.
Secondary
Part B: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M3814
The apparent volume of distribution during the terminal phase following extravascular administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-inf multiplied by Lambda z).
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Vz/f was not collected.
Secondary
Part B: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814
Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-infcalculated as AUC0-t + AUCextra.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for AUC0-inf was not collected.
Secondary
Part B: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of M3814
Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for AUC0-t was not collected.
Secondary
Part B: Average Plasma Concentration of M3814 Observed Post-dose (Cavg)
Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Cavg was not collected.
Secondary
Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 8.4 percent change | Standard Deviation 19.59 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 0.3 percent change | Standard Deviation 21.05 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | -18.5 percent change | Standard Deviation 8.19 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | -0.7 percent change | Standard Deviation 19.59 |
Secondary
Part B: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 513 Days
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Data could not be calculated as none of the participants showed objective response.
Secondary
Part B: Fluctuation Index of M3814
Fluctuation index is defined as percentage fluctuation (variation between maximum and minimum concentration at steady state), calculated as: 100\*(\[Cmax Cmin\]/Cavg).
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Fluctuation Index was not collected.
Secondary
Part B: Minimum Observed Drug Concentration (Cmin) of M3814
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for Cmin was not collected.
Secondary
Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814 | NA hour | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814 | NA hour | — |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814 | 7.50 hour | Geometric Coefficient of Variation 12.8 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Apparent Terminal Half-life (t1/2) of M3814 | 11.5 hour | Geometric Coefficient of Variation 38.2 |
Secondary
Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 10
Population: The PK Analysis Set included all participants who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | NA ng/mL | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 1220 ng/mL | Geometric Coefficient of Variation 5.8 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 1420 ng/mL | Geometric Coefficient of Variation 71.4 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 3150 ng/mL | Geometric Coefficient of Variation 63.6 |
Secondary
Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
Tmax was obtained directly from the concentration versus time curve postdose.
Time frame: Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | NA hour |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 2.18 hour |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 2.28 hour |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Multiple Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 2.01 hour |
Secondary
Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 2 Participants |
Secondary
Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
Secondary
Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
Secondary
Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Full Analysis Set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 2 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 1 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 3 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 2 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 4 Participants |
Secondary
Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 3 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 5 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 2 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
Secondary
Part B: Number of Participants With Positive Antidrug Antibody (ADA)
Blood samples were analyzed by a validated homogenous bridging electrochemiluminescence assay to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Positive Antidrug Antibody (ADA) | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Positive Antidrug Antibody (ADA) | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Positive Antidrug Antibody (ADA) | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Positive Antidrug Antibody (ADA) | 3 Participants |
Secondary
Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0
Number of participants with radiotherapy-induced toxicities (mucositis and radiation dermatitis) were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 512.4 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0 | 0 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0 | 0 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Radiotherapy (RT)-Induced Toxicity According to NCI-CTCAE v 5.0 | 0 Participants |
Secondary
Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 3 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 3 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 3 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 3 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 4 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 4 Participants |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 1 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 9 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 6 Participants |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Number of Participants With Treatment-Emergent Adverse Events, Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 8 Participants |
Secondary
Part B: Overall Survival
Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Median, is estimated by Kaplan-Meier method which stands for the time that half of the participants are expected to be alive. Depending on the observed number of deaths, time of censoring for each participant, median survival time may not be reached or estimated (few deaths will lead the KM curve never crosses 50% survival line), hence median was not calculable for Part B of the study. Participants that are still alive at the time of analysis will be censored and counted into the analysis.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Overall Survival | NA months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Overall Survival | NA months |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Overall Survival | NA months |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Overall Survival | NA months |
Secondary
Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator
Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 513 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 1.9 months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 1.7 months |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 3.4 months |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 1.9 months |
Secondary
Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1;Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | NA hour | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 6.56 hour | Geometric Coefficient of Variation 30.4 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 6.95 hour | Geometric Coefficient of Variation 33.8 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Apparent Terminal Half-life (t1/2) of M3814 | 7.79 hour | Geometric Coefficient of Variation 39.3 |
Secondary
Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: The PK Analysis Set included all participants who received at least one administration of M3814 and avelumab and had at least one measurable post-dose PK sample. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | NA ng/mL | — |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 1460 ng/mL | Geometric Coefficient of Variation 19 |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 854 ng/mL | Geometric Coefficient of Variation 66.2 |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Maximum Observed Drug Concentration (Cmax) of M3814 | 2380 ng/mL | Geometric Coefficient of Variation 44.8 |
Secondary
Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814
Tmax was obtained directly from the concentration versus time curve postdose.
Time frame: Pre-dose, 2, 4 and 6 hours post-dose on Day 10
Population: PK Analysis Set included all participants who received at least 1 administration of peposertib and avelumab and had at least 1 measurable post-dose PK sample. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | NA hour |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 0.93 hour |
| Part A: M3814 250 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.42 hour |
| Part A: M3814 300 mg BID + Avelumab 800 mg Q2W | Part B: Single Dose: Time to Reach the Maximum Plasma Concentration (Tmax) of M3814 | 1.47 hour |
Secondary
Part B: Terminal Elimination Rate Constant (Lambda z) of M3814
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 1, 2, 4 and 6 hour post-dose on Day 1
Population: As described in the Statistical Analysis Plan Section 7 Changes to planned analyses, data for lambda z was not collected.
Secondary
Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1
Tumor size is derived as the best percent change from baseline in target lesions (sum of longest diameter for non-nodal lesions and short axis for nodal lesions) at each time point.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | 6.1 percent change | Standard Deviation 14.98 |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Best Percent Change From Baseline in Tumor Size According to RECIST v 1.1 | -13.3 percent change | Standard Deviation 27.04 |
Secondary
Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first documentation of objective response until date of first documentation of PD or death due to any cause, whichever occurred first, assessed up to 44 Weeks
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator | NA months |
Secondary
Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values
The laboratory measurements included hematology and biochemistry values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with abnormalities Grade \>= 3 in laboratory test values were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Abnormalities Grade Greater Than or Equals to (>=) 3 in Laboratory Test Values | 0 Participants |
Secondary
Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
Number of participants with clinically meaningful change from baseline in ECG parameters were reported. Clinically Meaningful Change was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
Secondary
Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
Number of participants with clinically meaningful change from baseline in vital signs. Clinically Meaningful Change was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
Secondary
Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 2 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Not Evaluable | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Complete Response | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Partial Response | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Stable Disease or Non-CR/Non-PD | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Confirmed Best Overall Response (BOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Progressive Disease | 1 Participants |
Secondary
Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score
ECOG PS score is widely used by doctors and researchers to assess how a participants disease is progressing and is used to assess how the disease affects the daily living abilities of the participant and determine appropriate treatment and prognosis. The score ranges from Grade0 to Grade5, where Grade0=Fully active, able to carry on all pre-disease performance without restriction, Grade1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade5=Death.ECOG performance status was reported in terms of number of participants with baseline value vs worst post-baseline value.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 1 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 0 | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 0 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 1 | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 3 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 4 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score 2 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score 5 | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 1, worst post-baseline score Missing | 0 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance: Baseline Score Versus (Vs) Worst Post-baseline Score | Baseline score 0, worst post-baseline score Missing | 0 Participants |
Secondary
Part FE: Number of Participants With Positive Antidrug Antibody (ADA)
Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.
Time frame: Part FE: From the first study intervention to 508 days
Population: Safety Analysis Set included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Positive Antidrug Antibody (ADA) | 1 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Positive Antidrug Antibody (ADA) | 1 Participants |
Secondary
Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
An Adverse Event(AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign, symptom, or disease associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: AE that resulted in death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. Number of participants with TEAEs, treatment related TEAEs and serious TEAEs were reported.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Safety Analysis Set included all participants who received at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 4 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 3 Participants |
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 2 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | TEAEs | 5 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Treatment-related TEAEs | 5 Participants |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-related TEAEs and Serious TEAEs According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Serious TEAEs | 3 Participants |
Secondary
Part FE: Overall Survival
Overall survival was defined as the time from treatment start to the date of death, regardless of the actual cause of the participant's death. The overall survival was analyzed by using the Kaplan-Meier method. Participants that are still alive at the time of analysis will be censored and counted into the analysis.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 1359 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention. Here Overall Number of Participants Analyzed are equivalent to the number of participants who were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Overall Survival | 6.4 months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Overall Survival | 8.5 months |
Secondary
Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator
Progression-Free Survival was calculated as the time from the start of any study intervention to the date of first documentation of objective progression of disease or death due to any cause, whichever occurs first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. The PFS was analyzed by using the Kaplan-Meier method.
Time frame: Time from first study intervention up to long term safety follow-up period (Up to 404 Days)
Population: Full Analysis Set included all participants who receive at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: M3814 100 mg BID + Avelumab 800 mg Q2W | Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 2.7 months |
| Part A: M3814 200 mg BID + Avelumab 800 mg Q2W | Part FE: Progression-free Survival (PFS) Time According to RECIST v 1.1 Assessed by Investigator | 8.5 months |