Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy

An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination With Radiotherapy in Patients With Advanced Solid Tumors

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02516813

Enrollment

Registered

2015-08-06

Start date

2015-09-15

Completion date

2021-11-19

Last updated

2024-10-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced Solid Tumors

Keywords

M3814, Advanced solid tumors, DNA-PK Inhibitor, Radiotherapy, Chemotherapy

Brief summary

M3814 was an investigational drug that is being evaluated for the treatment of participants with locally advanced tumors. The main purposes of this study was to determine the safety, the tolerability and the efficacy of M3814 in combination with radiotherapy and in combination with chemoradiotherapy (Radiotherapy + cisplatin).

Interventions

DRUGM3814 100 mg

Participants received 100 mg of M3814 as capsule or tablet orally once daily.

DRUGM3814 200 mg

Participants received 200 mg of M3814 as capsule or tablet orally once daily.

DRUGM3814 300 mg

Participants received 300 mg of M3814 as capsule or tablet orally once daily.

DRUGM3814 400 mg

Participants received 400 mg of M3814 as capsule or tablet orally once daily.

DRUGM3814 50 mg

Participants received 100 mg of M3814 as capsule orally once daily.

RADIATIONFractionated RT

Participants received fractionated palliative RT (3 Gray \[Gy\] \* 10 in Arm A and 2 Gy \* 33 to 35, 5 fractions per week \[F/W\]) in Arm B and received a single high dose of RT (10-25 Gy) capsule on Day 1 given on Lesion 1 and a single high dose of RT (10-25 Gy) on Day 2 given on Lesion 2 in ancillary CPoP part.

DRUGCisplatin

Participants received Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 mg/m\^2.

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

Inclusion criteria

* Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the head and neck region or thorax with an indication for fractionated palliative RT (Arm A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B) * Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B expansion cohort) * Ancillary cPoP Part: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm apart which are RT naïve with an indication for high dose palliative RT * Availability of archival tumor material, either as a block or slides (Phase Ia and Ib). If no archival material is available then a fresh biopsy should be taken * Willing to have tumor biopsies collected in Ancillary cPoP * Measurable or evaluable disease by RECIST v1.1 (not required for ancillary cPoP part of the study) * Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 * Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and Phase Ib) * Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.

Exclusion criteria

* Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or investigational medicinal product (IMP) within 28 days of first trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects. For subjects with rapidly growing tumors localized in the head and neck region or thorax where the treating physician cannot wait for 28 days, inclusion may take place if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1) * Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN) * Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or prior bone marrow/stem cell transplantation within 5 years before trial start. * Poor vital organ functions defined as: * Bone marrow impairment as evidenced by hemoglobin \<10.0 g/dL, neutrophil count \<1.0 × 109/L, platelets \<100 × 109/L * Renal impairment as evidenced by serum creatinine \>1.5 × upper limit of normal (ULN) * Liver function abnormality as defined by total bilirubin \>1.5 × ULN or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>2.5 × ULN (except for subjects with liver involvement, who can have AST/ALT \>5 × ULN) * History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, use of percutaneous endoscopic gastrostomy (PEG) tubes * Significant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score \>2. * Subjects currently receiving (or unable to stop using prior to receiving the first dose of trial drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior). * Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment). * If the planned radiation field includes any part of the esophagus and the subject has symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal endoscopy rules out the presence of esophagitis * Subjects where more than 10% of the total esophagus volume receives more than 50% of the prescribed RT dose Main

Design outcomes

Primary

Measure	Time frame	Description
Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to 5 weeks	DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic adverse event (AE)/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 5 weeks (Phase Ia, Arm A) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Evidence of study treatment-related hepatocellular injury for \> 3 days.
Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to 12 weeks	DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic AE/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 12 weeks (Phase Ia, Arm B) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B; Evidence of study treatment-related hepatocellular injury for \> 3 days.

Secondary

Measure	Time frame	Description
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Hematology Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTC v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in hematology parameter (hemoglobin low, leukocytes low, lymphocytes low, neutrophil count decreased, and platelet count decreased) were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Baseline to Worst Post-Baseline Grade in Biochemistry Parameters According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Number of participants with shifts from Baseline values (Grade 0/1/2) to worst post-baseline values (Grade 1/2/3/4) were reported as per NCI-CTCAE, v4.03 graded from Grade 1 to 5. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Shifts in biochemistry parameter (phosphate low, potassium low, sodium low, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood bilirubin increased, glucose high, glucose low, albumin low and creatinine increased) were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Vital sign assessments included assessments of heart rate, blood pressure, body weight and body temperature. Abnormal vital sign measurement was decided by Investigator. Number of participants with markedly abnormal vital sign measurements were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Electrocardiograms (ECG) was obtained after the participant has been in a supine position for at least 5 minutes. ECG parameters included heart rate, atrial ventricular conduction, QR and QT intervals (including QTcF), and possible arrhythmias. Any ECG finding that was judged by the investigator as a abnormal (worsening) compared with a baseline value was considered an adverse event. Number of participants with shifts from normal baseline values to abnormal post-baseline values in ECG were reported.
Phase 1a (Arm A and Arm B): Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Confirmed BOR was defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. 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. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: defined as 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. CR or PR must be confirmed by a subsequent tumor assessment, at least 4 weeks after initial documentation of CR or PR.
Phase 1a (Arm A and Arm B): Number of Participants With Unconfirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Unconfirmed BOR was defined as unconfirmed best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of randomization until disease progression. 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. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: defined as 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.
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	Cmax was taken directly from the observed concentration-time curve.
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	tmax was obtained directly from the concentration versus time curve.
Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Fraction Day 1 and Fraction Day 6	AUC0-24 of M3814 was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Phase 1a (Arm A and Arm B): Total Body Clearance Following Oral Administration (CL/f) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	The apparent total body clearance of study intervention following extravascular administration on FD1, taking into account the fraction of dose absorbed. CL/f = Dose oral (p.o.)/AUC0-inf. The predicted AUC0-inf should be used.
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6	Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	Cmax was taken directly from the observed concentration-time curve.
Phase 1a (Arm A and Arm B): Median Percent Change From Baseline in Tumor Size Measurement According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	The tumor size was defined as the sum of the longest diameters for the target lesions. The sum of lesion diameters was calculated using RECIST v1.1 and was assessed by Investigator.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUCtau) of M3814 After Multiple Dosing	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.
Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.
Phase 1a (Arm A and Arm B): Oral Clearance in Plasma at Steady State (CLss/f) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Phase 1a (Arm A and Arm B): Apparent Volume of Distribution at Steady-State (Vss/f) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.
Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2, 4 and 24 hours post-dose on Fraction Day 1 and Fraction Day 10	Accumulation ratio for AUC was calculated as AUC, after dosing on fraction Day 10 divided by AUC, after dosing on fraction Day 1 of cycle 1.
Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 1 and Fraction Day 10	Accumulation ratio for Cmax was calculated as Cmax, after dosing on fraction Day 10 divided by Cmax, after dosing on fraction Day 1 of cycle 1.
Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Cmax was taken directly from the observed concentration-time curve.
Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	tmax was obtained directly from the concentration versus time curve.
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2	AUC0-4hr is the area under the plasma concentration-time curve from time 0 to 4 hours post-dose. This is a measure of the average amount of study drug M3814 in the blood plasma over a period of 4 hours after the dose.
Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2	AUC0-4/Dose was defined as AUC from time of dosing to the time zero to 4 hours divided by dose.
Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814	Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2	Cmax/Dose was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose	Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10	tmax was obtained directly from the concentration versus time curve.
Phase 1a (Arm A and Arm B): Number of Participants With Grade Greater Than or Equal to (>=) 3 Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily have a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. As per NCI-CTCAE v4.03, Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death. Number of participants with Grade \>=3 TEAEs were reported.

Countries

Belgium, Denmark, Germany, Netherlands, Norway, Sweden, Switzerland, United States

Participant flow

Recruitment details

First Participant First Visit (FPFV): 15 September 2015; Last Participant last Visit (LPLV): 19 November 2021

Pre-assignment details

The study was planned to be conducted in 3 parts: Phase Ia (dose escalation), Phase Ib (dose expansion) and Ancillary clinical proof-of-principle (cPoP). Phase Ib part of the study was never initiated due to early discontinuation as per sponsor's decision.

Participants by arm

Arm	Count
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative radiotherapy (RT) received 100 milligrams (mg) of M3814 as capsule orally once daily on fraction day (FD) 6 in combination with RT (3 Gray \[Gy\] x 10, 5 fractions per week \[F/W\]).	7
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).	3
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).	3
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 400 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W).	6
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 100 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).	6
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).	3
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W).	6
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2).	8
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT Participants with squamous cell carcinoma of the head and neck (SCCHN) received 100 mg of M3814 as tablet orally once daily for 7 consecutive weeks in combination with fractionated RT (2 Gy X 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 (mg/m\^2).	3
Ancillary cPoP: M3814 Capsule (100 mg) + RT Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 centimeters \[cm\] apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 100 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.	3
Ancillary cPOP: M3814 Capsule (200 mg) + RT Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 200 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.	3
Ancillary cPOP: M3814 Capsule (400 mg) + RT Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 400 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2.	1
Total	52

Baseline characteristics

Characteristic	Total	Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Ancillary cPoP: M3814 Capsule (100 mg) + RT	Ancillary cPOP: M3814 Capsule (200 mg) + RT	Ancillary cPOP: M3814 Capsule (400 mg) + RT
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	21 Participants	1 Participants	1 Participants	4 Participants	3 Participants	3 Participants	1 Participants	2 Participants	1 Participants	1 Participants	1 Participants	2 Participants	1 Participants
Age, Categorical Between 18 and 65 years	31 Participants	2 Participants	2 Participants	2 Participants	4 Participants	3 Participants	2 Participants	4 Participants	7 Participants	2 Participants	2 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	1 Participants	1 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	4 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants	2 Participants	2 Participants	5 Participants	7 Participants	5 Participants	3 Participants	4 Participants	4 Participants	3 Participants	3 Participants	3 Participants	1 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 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	0 Participants
Race (NIH/OMB) Asian	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 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	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	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	46 Participants	3 Participants	3 Participants	5 Participants	7 Participants	6 Participants	3 Participants	5 Participants	5 Participants	3 Participants	2 Participants	3 Participants	1 Participants
Sex: Female, Male Female	13 Participants	1 Participants	0 Participants	2 Participants	1 Participants	2 Participants	1 Participants	2 Participants	0 Participants	1 Participants	2 Participants	1 Participants	0 Participants
Sex: Female, Male Male	39 Participants	2 Participants	3 Participants	4 Participants	6 Participants	4 Participants	2 Participants	4 Participants	8 Participants	2 Participants	1 Participants	2 Participants	1 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	EG011 affected / at risk
deaths Total, all-cause mortality	4 / 7	2 / 3	2 / 3	6 / 6	3 / 6	2 / 3	3 / 6	1 / 8	1 / 3	0 / 3	0 / 3	0 / 1
other Total, other adverse events	7 / 7	3 / 3	2 / 3	6 / 6	6 / 6	3 / 3	6 / 6	8 / 8	3 / 3	2 / 3	3 / 3	0 / 1
serious Total, serious adverse events	1 / 7	0 / 3	2 / 3	2 / 6	1 / 6	0 / 3	3 / 6	2 / 8	1 / 3	1 / 3	1 / 3	0 / 1

Outcome results

Primary

Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic adverse event (AE)/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 5 weeks (Phase Ia, Arm A) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Evidence of study treatment-related hepatocellular injury for \> 3 days.

Time frame: Time from first dose of study treatment up to 5 weeks

Population: Dose-Escalation Analysis Set included all participants treated in dose-escalation cohorts who received at least 80% of the M3813 and RT planned dose and completed the DLT period (5 weeks after the start of RT) or who experienced a DLT during DLT period regardless of the amount of treatment received.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	1 Participants
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	0 Participants
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	2 Participants
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	3 Participants
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	1 Participants
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	0 Participants
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	3 Participants

Primary

Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

DLT: any Grade (Gr) greater than or equal to (\>=) 3 nonhematologic AE/any Gr\>=4 hematologic AE that is related to any of study treatments and occurs during the DLT period of 12 weeks (Phase Ia, Arm B) after the first dose of M3814. Following are considered as DLTs: Gr3 thrombocytopenia with medically concerning bleeding; Febrile neutropenia; Any toxicity/study treatment-related adverse event (TEAE) that, in opinion of Safety Monitoring Committee (SMC), is of potential clinical significance such that further dose escalation would expose participants to unacceptable risk; Any toxicity related to study treatments that causes participant to receive less than 80 percent (%) of the planned RT dose; Any toxicity related to study treatments leading to an interruption of RT longer than 1 week in Arm B; Evidence of study treatment-related hepatocellular injury for \> 3 days.

Time frame: Time from first dose of study treatment up to 12 weeks

Population: Dose-Escalation Analysis Set included all participants treated in dose-escalation cohorts who received at least 80% of the M3814 and RT planned dose and completed the DLT period (12 weeks after the start of RT) or who experienced a DLT during DLT period regardless of the amount of treatment received.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	2 Participants
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm B): Number of Participants Who Experienced at Least One Dose-limiting Toxicity (DLT) According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)	2 Participants

Secondary

Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814

AUC0-4hr is the area under the plasma concentration-time curve from time 0 to 4 hours post-dose. This is a measure of the average amount of study drug M3814 in the blood plasma over a period of 4 hours after the dose.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2

Population: Pharmacokinetic analysis set: all participants who received at least the first dose of the treatment (either M3814 or RT) and provided \>= 3 valid post-dose concentration points within 6 hours (0-6 hours inclusive). Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

Arm	Measure	Value (MEDIAN)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814	NA h*ng/mL
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814	NA h*ng/mL
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814	NA h*ng/mL

Secondary

Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814

Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814	841 h*ng/mL	Geometric Coefficient of Variation 172.4
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814	1130 h*ng/mL	Geometric Coefficient of Variation 47.2
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814	NA h*ng/mL	—

Secondary

Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814

AUC0-4/Dose was defined as AUC from time of dosing to the time zero to 4 hours divided by dose.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 2

Arm	Measure	Value (GEOMETRIC_MEAN)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814	NA h*ng/mL/mg
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814	NA h*ng/mL/mg
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to 4 Hours (AUC0-4)/Dose of M3814	NA h*ng/mL/mg

Secondary

Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814

AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814	8.41 h*ng/mL/mg	Geometric Coefficient of Variation 172.4
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814	5.65 h*ng/mL/mg	Geometric Coefficient of Variation 47.2
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M3814	NA h*ng/mL/mg	—

Secondary

Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814

Cmax/Dose was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. Cmax/dose was measured in nanogram per milliliter per milligram (ng/mL/mg).

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814	3.11 ng/mL/mg	Geometric Coefficient of Variation 148.2
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814	2.52 ng/mL/mg	Geometric Coefficient of Variation 38.4
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814	NA ng/mL/mg	—

Secondary

Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814

Cmax was taken directly from the observed concentration-time curve.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814	311 ng/mL	Geometric Coefficient of Variation 148.2
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814	504 ng/mL	Geometric Coefficient of Variation 38.4
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814	NA ng/mL	—

Secondary

Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814

tmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 2

Arm	Measure	Value (MEDIAN)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814	2.02 hours
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814	1.03 hours
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814	NA hours

Secondary

Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose

Accumulation ratio for AUC was calculated as AUC, after dosing on fraction Day 10 divided by AUC, after dosing on fraction Day 1 of cycle 1.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 24 hours post-dose on Fraction Day 1 and Fraction Day 10

Population: Pharmacokinetic analysis set included all participants who received at least the first dose of the treatment (either M3814 or RT) and provided \>= 3 valid post-dose concentration points within 6 hours (0-6 hours inclusive). Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	1.38 ratio	Geometric Coefficient of Variation 52.6
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	NA ratio	—
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	NA ratio	—
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	1.44 ratio	Geometric Coefficient of Variation 20.2
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	NA ratio	—
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	0.777 ratio	Geometric Coefficient of Variation 55
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	0.922 ratio	Geometric Coefficient of Variation 56
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Area Under the Concentration-Time Curve (AUC) [Racc(AUC0-24)] of M3814 After Multiple Dose	0.855 ratio	Geometric Coefficient of Variation 60.7

Secondary

Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose

Accumulation ratio for Cmax was calculated as Cmax, after dosing on fraction Day 10 divided by Cmax, after dosing on fraction Day 1 of cycle 1.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 1 and Fraction Day 10

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	0.779 ratio	Geometric Coefficient of Variation 108.1
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	NA ratio	—
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	0.871 ratio	Geometric Coefficient of Variation 55.9
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	1.13 ratio	Geometric Coefficient of Variation 50.9
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	NA ratio	—
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	0.868 ratio	Geometric Coefficient of Variation 58.9
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	0.816 ratio	Geometric Coefficient of Variation 53.3
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose	0.654 ratio	Geometric Coefficient of Variation 61.7

Secondary

Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose

t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	8.37 hours	Geometric Coefficient of Variation 81.9
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	NA hours	—
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	NA hours	—
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	NA hours	—
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	5.39 hours	Geometric Coefficient of Variation 27.3
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	3.30 hours	Geometric Coefficient of Variation 159.7
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose	NA hours	—

Secondary

Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose

t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 6	6.57 hours	Geometric Coefficient of Variation 191.5
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	5.79 hours	Geometric Coefficient of Variation 47.6
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	7.81 hours	Geometric Coefficient of Variation 45.2
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	NA hours	—
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 6	7.37 hours	Geometric Coefficient of Variation 79.1
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	7.10 hours	Geometric Coefficient of Variation 27.9
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	3.20 hours	Geometric Coefficient of Variation 135.8
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 6	NA hours	—
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	5.84 hours	Geometric Coefficient of Variation 34.6
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	5.83 hours	Geometric Coefficient of Variation 16.1
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	5.42 hours	Geometric Coefficient of Variation 79.8
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Single Dose	Fraction Day 1	5.85 hours	Geometric Coefficient of Variation 17.3

Secondary

Phase 1a (Arm A and Arm B): Apparent Volume of Distribution at Steady-State (Vss/f) of M3814 After Multiple Dose

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10

Population: As per changes in planned analysis, the pharmacokinetic parameters (Vss/f) was not assessed.

Secondary

Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose

Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 6	790 liters	Geometric Coefficient of Variation 91.1
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	337 liters	Geometric Coefficient of Variation 64.5
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	257 liters	Geometric Coefficient of Variation 16.5
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	NA liters	—
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 6	463 liters	Geometric Coefficient of Variation 41.4
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	248 liters	Geometric Coefficient of Variation 45.6
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	280 liters	Geometric Coefficient of Variation 52.6
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 6	NA liters	—
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	415 liters	Geometric Coefficient of Variation 61.2
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	146 liters	Geometric Coefficient of Variation 85.3
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	287 liters	Geometric Coefficient of Variation 48
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Apparent Volume of Distribution (Vz/f) of M3814 After Single Dose	Fraction Day 1	235 liters	Geometric Coefficient of Variation 40.3

Secondary

Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose

AUC0-24 of M3814 was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Fraction Day 1 and Fraction Day 6

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	2310 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 52.2
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 6	915 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 133
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	7580 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 49.5
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 6	NA hournanogram per milliliter (hng/mL)	—
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 6	5780 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 27.5
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	4950 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 71.1
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	14700 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 56.1
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	2490 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 191.6
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 6	NA hournanogram per milliliter (hng/mL)	—
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	3800 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 71.7
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	14100 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 97.7
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	969 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 52.1
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M3814 After Single Dose	Fraction Day 1	2890 hournanogram per milliliter (hng/mL)	Geometric Coefficient of Variation 119.8

Secondary

Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUCtau) of M3814 After Multiple Dosing

AUCtau was defined as area under the plasma concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10

Population: As per changes in planned analysis, the pharmacokinetic parameters (AUCtau) was not assessed.

Secondary

Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose

The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10

Population: PK Analysis Set has been used here. The AUC-inf for peposertib cannot be calculated accurately when the sampling scheme is limited to 0-4 hours and the tmax ranges from 1 to 4 hours especially considering a half-life of 6 hours. Since the sampling scheme only covers 0-4 hours, the terminal elimination phase is not captured. As a result, it was not possible to calculate data for AUC0-inf because dosing interval was too small to have reliable results.

Arm	Measure	Value (GEOMETRIC_MEAN)
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Multiple Dose	NA h*ng/mL

Secondary

Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 6	1200 h*ng/mL	Geometric Coefficient of Variation 179
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	2480 h*ng/mL	Geometric Coefficient of Variation 55.4
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	8780 h*ng/mL	Geometric Coefficient of Variation 63.4
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	NA h*ng/mL	—
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 6	6890 h*ng/mL	Geometric Coefficient of Variation 51
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	16500 h*ng/mL	Geometric Coefficient of Variation 61.8
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	1640 h*ng/mL	Geometric Coefficient of Variation 82.9
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 6	NA h*ng/mL	—
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	4060 h*ng/mL	Geometric Coefficient of Variation 77.3
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	17300 h*ng/mL	Geometric Coefficient of Variation 108.6
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	1360 h*ng/mL	Geometric Coefficient of Variation 48.8
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Area Under the Plasma Concentration-Time From Time Zero Extrapolated to Infinity (AUC0-inf) of M3814 After Single Dose	Fraction Day 1	3580 h*ng/mL	Geometric Coefficient of Variation 59.6

Secondary

Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose

Cmax was taken directly from the observed concentration-time curve.

Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	295 ng/mL	Geometric Coefficient of Variation 97.1
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	NA ng/mL	—
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	1560 ng/mL	Geometric Coefficient of Variation 84.8
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	575 ng/mL	Geometric Coefficient of Variation 29.9
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	NA ng/mL	—
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	2020 ng/mL	Geometric Coefficient of Variation 77.8
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	140 ng/mL	Geometric Coefficient of Variation 60.3
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose	392 ng/mL	Geometric Coefficient of Variation 108.4

Secondary

Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose

Cmax was taken directly from the observed concentration-time curve.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	378 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 91.2
Phase 1a (Arm A): M3814 Capsule (100 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 6	314 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 150.4
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	1260 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 12.5
Phase 1a (Arm A): M3814 Capsule (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 6	NA nanogram per milliliter (ng/mL)	—
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 6	840 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 20.8
Phase 1a (Arm A): M3814 Capsule (300 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	515 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 94.5
Phase 1a (Arm A): M3814 Capsule (400 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	1630 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 62.9
Phase 1a (Arm A): M3814 Tablet (100 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	724 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 77.8
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 6	NA nanogram per milliliter (ng/mL)	—
Phase 1a (Arm A): M3814 Tablet (200 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	799 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 37.9
Phase 1a (Arm A): M3814 Tablet (300 mg) + RT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	2260 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 112.6
Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	173 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 87.2
Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT	Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Single Dose	Fraction Day 1	599 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 34.2

Secondary

Phase 1a (Arm A and Arm B): Median Percent Change From Baseline in Tumor Size Measurement According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator

The tumor size was defined as the sum of the longest diameters for the target lesions. The sum of lesion diameters was calculated using RECIST v1.1 and was assessed by Investigator.