Metastatic Solid Tumors
Conditions
Keywords
M6223, Bintrafusp alfa, Metastatic Solid Tumors
Brief summary
The main purpose of this study was to determine the safety, tolerability, pharmacokinetics (PK), immunogenicity and (if observed) the maximum tolerated dose (MTD) of M6223 as a single agent (Part 1A) for both the every 2 weeks (Q2W) regimen and the every 3 weeks (Q3W) regimen and of M6223 combined with bintrafusp alfa (Part 1B) for Q2W regimen in participants with metastatic or locally advanced solid unresectable tumors.
Interventions
DRUGM6223
Participants received an intravenous (IV) infusion of M6223 at escalated doses every 2 weeks (Q2W) or every 3 weeks (Q3W) on Day 1 of each Cycle (Each cycle is of 14 days) according to the recommendation of the SMC(Safety Monitoring Committee) until the maximum tolerated dose(MTD) has been reached or confirmed disease progression.
DRUGBintrafusp alfa
Participants received an IV infusion of bintrafusp alfa Q2W on Day 1 of each Cycle (Cycle is 14 days) until confirmed disease progression.
Sponsors
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants have histologically or cytologically proven locally advanced or advanced solid malignancies who are refractory to or have progressed under standard treatment and have no other treatment options known to confer clinical benefit * Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening * Participant has a formalin-fixed paraffin-embedded block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides suitable for immunohistochemistry-based staining of protein expression * Participants with life expectancy of at least 12 weeks * Participants with measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) * Adequate hematological, hepatic and renal function as defined in the protocol * Other protocol defined inclusion criteria may apply
Exclusion criteria
* Participants with persisting toxicity related to prior therapy Grade greater than (\>) 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, however, alopecia, sensory neuropathy Grade less than or equal to (\<=) 2, or other non-immune-related Grade \<= 2 not constituting a safety risk * Participants with prior organ transplantation including allogeneic stem cell transplantation * Participants with prior toxicity related to an immune checkpoint inhibitor Grade greater than equal to (\>=) 3 NCI-CTCAE Version 5.0 unless resolved to Grade \<= 1 prior to study inclusion * Participants with current significant cardiac conduction abnormalities, including corrected QT interval (QTcF, corrected with Fridericia formula) prolongation of \> 450 milli seconds (ms) on triplicate 12-lead ECG or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome * A history of vascular, cardiovascular or cerebrovascular disease like, cerebral vascular accident/stroke (less than \[\<\] 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class \>= II), deep vein thrombosis (\< 3 months prior to enrollment) or pulmonary thrombosis/embolism (\< 3 months prior to enrollment) * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A and 1B: 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 to Day 28 | A DLT is defined as any Grade ≥ 3 non-hematologic AE or any Grade ≥ 4 hematologic AE according to the NCI-CTCAE, occurring during the DLT observation period (28 days from first administration of study intervention) that is not clearly related to the underlying disease or any previous or concomitant medication, concomitant disease or unrelated illness. A DLT must be confirmed by the Safety Monitoring Committee. DLT is considered if the following related AEs occur: • Grade ≥ 3 neutropenia with clinical signs/symptoms (e.g., febrile neutropenia). • Grade ≥ 3 thrombocytopenia with medically concerning bleeding. • A study intervention-related treatment-emergent AE that in the opinion of the SMC is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk. • Grade ≥ 3 hematological AE with symptoms that require growth factor support or transfusion to prevent further damage to the participant. |
| Part 1A and 1B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Approximately 2 years 11 months | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention. |
| Part 1A and 1B: Number of Participants With TEAES With Severity of Grade Greater or Equal to 3 and TEAEs Leading to Deaths | Approximately 2 years 11 months | An adverse event (AE) is any untoward medical occurrence in a participant temporally associated with the use of the study intervention, regardless of causality. A serious AE results in death, is life-threatening, requires/prolongs hospitalization, causes disability/incapacity, leads to a congenital anomaly/birth defect, or is otherwise medically significant. Treatment-emergent adverse events (TEAEs) are those that begin or worsen after the first dose through 30 days post-treatment, and include both serious and non-serious events. Treatment-related TEAEs are those reasonably related to the study intervention. Severity is graded per CTCAE v24.1: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe/medically significant), Grade 4 (life-threatening/disabling), Grade 5 (death related to AE). |
| Part 1A and 1B: Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Approximately 2 years 11 months | Number of participants with clinically meaningful change from baseline in laboratory parameters were reported. Clinically meaningful abnormalities (identified as laboratory values having CTCAE grades \>= 3). Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation. |
| Part 1A and 1B: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Approximately 2 years 11 months | Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance 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 1A and 1B: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | Approximately 2 years 11 months | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Relevance was decided by the investigator. Number of participants with clinically relevant change from baseline in vital signs were reported. Clinical relevance was defined as increase more than equal to (\>=) 3° temperature, \>40 beats heart rate increase, \>40 mmHG increase in systolic or diastolic blood pressure, \>10 breaths in respiratory rate increase. |
| Part 1A and 1B: Number of Participants With Worsened Post Baseline Shift in Eastern Cooperative Oncology Group Performance Status | Approximately 2 years 11 months | The number of participants who experienced worse post baseline shift were assessed as per ECOG performance status score recorded during the treatment. The ECOG score is categorized as Grade 0, 1, 2, 3 and 4 where Grade 0=fully active, Grade 1=restricted in physically strenuous activity, Grade 2=unable to carry out any work activities, Grade 3=capable of only limited self-care and Grade 4=completely disabled. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) | Area under the serum concentration-time curve from time zero to the last sampling time at which the concentration is at or above lower limit of quantification (LLQ). AUC0-t was calculated according to the mixed log linear trapezoidal rule. The full form of unit of measure h\*mcg/mL is hours · micrograms per milliliter. |
| Part 1A and Part 1B: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) | Area under the serum concentration time curve from time zero to infinity, calculated as AUC0 t + AUCextra. AUCextra represents an extrapolated value obtained by Clast/λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above LLQ and λz is elimination rate constant. |
| Part 1A and Part 1B: Area Under Serum Concentration-Time Curve Over a Dosing Interval From Time Zero to Tau (AUC-tau) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycle 1 (Cycle is of 21 days in Q3W regimen) | Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval. |
| Part 1A and Part 1B: Maximum Observed Serum Concentration (Cmax) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) | Maximum measured serum concentration, calculated from the serum concentration vs. time profile of the individual participants. |
| Part 1A and Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) | Ctrough is the concentration prior to study drug administration. |
| Part 1A and Part 1B: Time to Reach Maximum Serum Concentration (Tmax) of M6223 | Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only) | Time taken to reach maximum concentration of M66223 after admistration is reported. |
| Part 1A and Part 1B: Apparent Terminal Half-Life (t1/2) of M6223 | Cycle 1 and 2: Day 1 (-2h, EOI, 4-6h), Day 2 (25-31h), Day 5 (±1h), Day 8 (±1h); Cycle 3 to end of treatment: Day 1 (-2h pre-dose only) | Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/ λz, where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Part 1A and Part 1B: Elimination Rate Constant (Lambda z) of M6223 | Pre-dose up to 14 days (in Q2W regimen) or 21 days (in Q3W regimen) post-dose of Cycles 1, 2, and 4 (Each cycle is of 14 days in Q2W regimen and each Cycle is of 21 days in Q3W regimen) | Elimination rate constant was obtained from linear regression of the terminal phase of the log transformed concentration-time data. |
| Part 1B: Maximum Observed Serum Concentration (Cmax) of Bintrafusp Alfa | Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose | Maximum measured serum concentration, calculated from the serum concentration vs. time profile of the individual participants. |
| Part 1B: Serum Concentration Observed Immediately Before Next Dosing (Ctrough) of Bintrafusp Alfa | Day 1 of Treatment of Cycles 1 and 4 from time zero to 14 days postdose | Ctrough is the concentration prior to study drug administration. |
| Part IA and 1B: Number of Participants With Positive Antidrug Antibody (ADA) Assays | Pre-dose of Day 1 Cycle 1 (Each Cycle is of 14 days in Q2W regimen and 21 days in Q3W regimen) up to end of safety follow-up visit ( approximately 2 years 11 months) | 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 1A and IB: Best Overall Response According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator | From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months) | The ORR is defined as the number of participants with a documented BOR (complete response (CR) or partial response (PR)) by the investigator during treatment with avelumab plus axitinib as firstline therapy. The BOR is defined as the best tumor response recorded during the observation period. The definitions of tumor responses are as follows: Complete or PR as the best adjudication result (CR \> PR \> stable disease \[SD\] \> progressive disease \[PD\], not Evaluable \[NE\]) complies with the RECIST tumor assessment guidelines as closely as possible in clinical practice. |
| Part 1A and 1B: Duration of Response (DOR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator | From first study drug administration until documented disease progression or death due to any cause whichever occurs first( approximately 2 years 11 months) | DOR was defined for participants with a confirmed objective response as the time from first documentation of a confirmed objective response (CR or PR) according to RECIST 1.1 to the date of first documentation of objective PD or death due to any cause, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. |
| Part 1A and 1B: Time to Tumor Response (TTR) According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator | From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)) | TTR was defined for participants who achieved objective response as time from first study drug administration to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. CR was defined as a score of 1 (no uptake above background), 2 (uptake \<= mediastinum), or 3 (uptake \<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow. PR was defined as \>=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>=50% decrease in SPD of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. |
| Part 1A and 1B: Disease Control According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator | From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months)) | Disease control rate was defined as percentage of participants with disease control. Disease Control (DC) was defined as the best overall response of CR, PR, or stable disease (SD). CR: score of 1 (no uptake above background), 2 (uptake \<= mediastinum), or 3 (uptake less than \<mediastinum but \<=liver) with or without a residual mass on Positron Emission Tomography 5-Point Scale, for lymph nodes and extra lymphatic sites; no new lesions; no evidence of fluorodeoxyglucose -avid disease in bone marrow. PR: \>=50% decrease in SPD of up to six of the largest dominant lymph nodes, no increase in size of other nodes, liver, or spleen volume, a \>=50% decrease in Sum of the Products of Diameters of hepatic and splenic nodules, absence of other organ involvement, and no new sites of disease. SD: \<50% decrease in SDP of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease met. |
| Part 1A and 1B: Progression-free Survival Time According to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed as Per Investigator | From first study drug administration until documented disease progression or death due to any cause whichever occurs first (approximately 2 years 11 months) | Progression Free Survival (PFS) time is defined as the time from start date of treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever occurs first. The tumor response will be determined according to RECIST 1.1 and assessed by the investigator. |
| Part 1A and 1B: Overall Survival | From first study drug administration to the date of death due to any cause (approximately 2 years 11 months) | Overall survival was defined as the time (in months) from first study drug administration to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. |
Countries
Canada, United States
Contacts
STUDY_DIRECTORMedical Responsible
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58 Years STANDARD_DEVIATION 13.2 |
| Race/Ethnicity, Customized Ethnicity-Hispanic or Latino | 6 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Ethnicity-Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Race-Asian | 5 Participants |
| Race/Ethnicity, Customized Race-Black or African American | 2 Participants |
| Race/Ethnicity, Customized Race-Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race-Other | 2 Participants |
| Race/Ethnicity, Customized Race-White | 44 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 0 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 | 0 / 1 | 1 / 1 | 3 / 3 | 1 / 3 | 4 / 9 | 5 / 11 | 3 / 4 | 5 / 8 | 3 / 7 | 5 / 7 | 2 / 4 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 9 / 9 | 11 / 11 | 3 / 4 | 7 / 8 | 7 / 7 | 7 / 7 | 3 / 4 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 3 | 0 / 3 | 2 / 9 | 4 / 11 | 2 / 4 | 2 / 8 | 2 / 7 | 6 / 7 | 4 / 4 |
Outcome results
None listed