A Phase 1 interventional study of M3814 100 mg and M3814 200 mg in Advanced Solid Tumors, sponsored by EMD Serono Research & Development Institute, Inc.. Completed at 26 sites in 8 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-10-15.
Sponsored by EMD Serono Research & Development Institute, Inc. · Phase 1, Interventional, and Treatment
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).
EMD Serono Research & Development Institute, Inc. is the lead sponsor of 85 studies on the registry; 8 are open to participants now.
Of its 46 completed or terminated interventional studies of FDA-regulated products, 38 (83%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Poor vital organ functions defined as:
Main exclusion criteria for Ancillary Clinical Proof-of-Principle Part:
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 \[F/W\]).
Drug: M3814 100 mg · Radiation: Fractionated 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).
Drug: M3814 200 mg · Radiation: Fractionated 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).
Drug: M3814 300 mg · Radiation: Fractionated 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).
Drug: M3814 400 mg · Radiation: Fractionated 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).
Drug: M3814 100 mg · Radiation: Fractionated 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).
Drug: M3814 200 mg · Radiation: Fractionated 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).
Drug: M3814 300 mg · Radiation: Fractionated RT
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).
Drug: M3814 50 mg · Radiation: Fractionated RT · Drug: Cisplatin
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).
Radiation: Fractionated RT · Drug: Cisplatin
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.
Drug: M3814 100 mg · Radiation: Fractionated 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.
Drug: M3814 200 mg · Radiation: Fractionated 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
Drug: M3814 400 mg · Radiation: Fractionated RT
Participants received 100 mg of M3814 as capsule or tablet orally once daily.
Also known as: Peposertib, MSC2490484A
Participants received 200 mg of M3814 as capsule or tablet orally once daily.
Also known as: Peposertib, MSC2490484
Participants received 300 mg of M3814 as capsule or tablet orally once daily.
Also known as: Peposertib, MSC2490484
Participants received 400 mg of M3814 as capsule or tablet orally once daily.
Also known as: Peposertib, MSC2490484
Participants received 100 mg of M3814 as capsule orally once daily.
Also known as: Peposertib, MSC2490484
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.
Participants received Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 mg/m\^2.
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
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
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)
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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)
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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)
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG)
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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.
Time frame: Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year)
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
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Single Dose
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 1 and Fraction Day 6
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
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
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, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
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
Phase 1a (Arm A and Arm B): Total Body Clearance Following Oral Administration (CL/f) of M3814 After Single Dose
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.
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 hours post-dose on Fraction Day 1 and Fraction Day 6
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
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
Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose
tmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
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
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
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
Phase 1a (Arm A and Arm B): Oral Clearance in Plasma at Steady State (CLss/f) of M3814 After Multiple Dose
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Pre-dose, 0.5, 1, 2 and 4 hours post-dose on Fraction Day 10
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
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
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
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
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
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
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
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
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
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
First Participant First Visit (FPFV): 15 September 2015; Last Participant last Visit (LPLV): 19 November 2021
| Milestone | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 7 | 3 | 3 | 6 | 6 | 3 | 6 | 8 | 3 | 3 | 3 | 1 |
| Completed | 7 | 3 | 3 | 6 | 6 | 3 | 6 | 8 | 3 | 3 | 3 | 1 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 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 | 0 | 2 | 3 | 1 | 0 | 3 |
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.
| Participants | Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT | Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT |
|---|---|---|
| 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 | 2 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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) | 2 | 3 | 3 | 3 | 3 | 0 | 5 | 8 | 3 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Hemoglobin low: Grade 0 to Grade 1 | 1 | 0 | 0 | 2 | 0 | 3 | 0 | 3 | 0 |
| Hemoglobin low: Grade 0 to Grade 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 |
| Hemoglobin low: Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Hemoglobin low: Grade 1 to Grade 2 | 0 | 1 | 0 | 0 | 2 | 0 | 2 | 1 | 0 |
| Hemoglobin low: Grade 1 to Grade 3 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Leukocytes low: Grade 0 to Grade 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 3 | 1 |
| Leukocytes low: Grade 0 to Grade 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 1 |
| Leukocytes low: Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Leukocytes low: Grade 1 to Grade 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Lymphocytes low: Grade 0 to Grade 1 | 2 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Lymphocytes low: Grade 0 to Grade 2 | 1 | 0 | 1 | 1 | 2 | 0 | 2 | 1 | 0 |
| Lymphocytes low: Grade 0 to Grade 3 | 0 | 0 | 0 | 1 | 1 | 1 | 3 | 4 | 1 |
| Lymphocytes low: Grade 0 to Grade 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 |
| Lymphocytes low: Grade 1 to Grade 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Lymphocytes low: Grade 1 to Grade 3 | 2 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Lymphocytes low: Grade 1 to Grade 4 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
| Lymphocytes low: Grade 2 to Grade 3 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Lymphocytes low: Grade 2 to Grade 4 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neutrophil count decreased: Grade 0 to Grade 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 |
| Neutrophil count decreased: Grade 0 to Grade 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Neutrophil count decreased: Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Neutrophil count decreased: Grade 1 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Platelets count decreased: Grade 0 to Grade 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Platelets count decreased: Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phosphate low: Grade 0 to Grade 1 | 0 | 0 | 0 | 0 | 2 | 1 | 1 | 0 | 0 |
| Phosphate low: Grade 0 to Grade 2 | 0 | 1 | 0 | 2 | 0 | 0 | 1 | 0 | 1 |
| Phosphate low: Grade 1 to Grade 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Phosphate low: Grade 2 to Grade 3 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Potassium low: Grade 0 to Grade 2 | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 1 |
| Potassium low: Grade 0 to Grade 3 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Sodium low: Grade 0 to Grade 1 | 2 | 2 | 1 | 0 | 2 | 0 | 3 | 4 | 1 |
| Alanine aminotransferase: Grade 0 to Grade 1 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 3 | 0 |
| Alkaline phosphatase: Grade 0 to Grade 1 | 2 | 0 | 0 | 2 | 0 | 0 | 1 | 3 | 0 |
| Aspartate aminotransferase: Grade 0 to Grade 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 0 |
| Blood bilirubin increased: Grade 0 to Grade 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Glucose high: Grade 0 to Grade 1 | 3 | 0 | 0 | 3 | 2 | 2 | 1 | 0 | 0 |
| Glucose high: Grade 0 to Grade 2 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Glucose high: Grade 1 to Grade 2 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 1 | 1 |
| Glucose high: Grade 1 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Glucose high: Grade 2 to Grade 3 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 1 | 0 |
| Glucose low: Grade 0 to Grade 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Albumin low: Grade 0 to Grade 1 | 0 | 0 | 0 | 3 | 1 | 1 | 1 | 2 | 0 |
| Albumin low: Grade 0 to Grade 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Albumin low: Grade 1 to Grade 2 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
| Creatinine increased: Grade 0 to Grade 1 | 5 | 3 | 1 | 5 | 5 | 3 | 5 | 6 | 1 |
| Creatinine increased: Grade 0 to Grade 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Creatinine increased: Grade 0 to Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Creatinine increased: Grade 1 to Grade 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Number of Participants With Markedly Abnormal Vital Sign Measurements | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Number of Participants With Shifts From Normal Baseline to Abnormal Post-baseline in Electrocardiogram (ECG) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Complete response (CR) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 4 | 0 |
| Partial response (PR) | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 3 |
| Stable disease (SD) | 5 | 1 | 1 | 3 | 1 | 1 | 1 | 1 | 0 |
| Progressive disease (PD) | 1 | 0 | 1 | 1 | 5 | 2 | 3 | 0 | 0 |
| Not Evaluable | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 2 | 0 |
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.
| Participants | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Complete response (CR) | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 4 | 0 |
| Partial response (PR) | 3 | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 3 |
| Stable disease (SD) | 3 | 1 | 1 | 3 | 1 | 1 | 1 | 0 | 0 |
| Progressive disease (PD) | 1 | 0 | 1 | 1 | 5 | 2 | 3 | 0 | 0 |
| Not Evaluable | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 2 | 0 |
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.
| percentage change | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 | -25.81 (-88.06 to 0.00) | -41.29 (-60.00 to -22.58) | -3.95 (-7.89 to 0.00) | -21.95 (-82.14 to 10.61) | -20.84 (-81.25 to -2.13) | -9.52 (-28.0 to 9.82) | -40.00 (-100 to 6.98) | -100 (-100 to -61.11) | -52.78 (-71.43 to -43.55) |
Cmax was taken directly from the observed concentration-time curve.
| nanogram per milliliter (ng/mL) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 378 ± 91.2 | 1260 ± 12.5 | 515 ± 94.5 | 1630 ± 62.9 | 724 ± 77.8 | 799 ± 37.9 | 2260 ± 112.6 | 173 ± 87.2 | 599 ± 34.2 |
| Fraction Day 6 | 314 ± 150.4 | NA ± NA | 840 ± 20.8 | — | — | NA ± NA | — | — | — |
tmax was obtained directly from the concentration versus time curve.
| hours | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 2.03 (1.00 to 4.03) | 2.05 (1.00 to 2.18) | 3.98 (1.00 to 4.00) | 2.03 (0.95 to 3.75) | 1.18 (0.42 to 4.00) | 1.17 (1.00 to 2.15) | 1.00 (0.83 to 4.48) | 2.34 (0.98 to 4.08) | 1.00 (0.98 to 2.05) |
| Fraction Day 6 | 0.93 (0.50 to 4.02) | NA (NA to NA) | 2.01 (2.00 to 2.15) | — | — | NA (NA to NA) | — | — | — |
AUC0-24 of M3814 was defined as the area under the concentration time curve from time 0 to 24 hours post-dose.
| hour*nanogram per milliliter (h*ng/mL) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 2310 ± 52.2 | 7580 ± 49.5 | 4950 ± 71.1 | 14700 ± 56.1 | 2490 ± 191.6 | 3800 ± 71.7 | 14100 ± 97.7 | 969 ± 52.1 | 2890 ± 119.8 |
| Fraction Day 6 | 915 ± 133.0 | NA ± NA | 5780 ± 27.5 | — | — | NA ± NA | — | — | — |
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.
| h*ng/mL | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 2480 ± 55.4 | 8780 ± 63.4 | NA ± NA | 16500 ± 61.8 | 1640 ± 82.9 | 4060 ± 77.3 | 17300 ± 108.6 | 1360 ± 48.8 | 3580 ± 59.6 |
| Fraction Day 6 | 1200 ± 179.0 | — | 6890 ± 51.0 | — | — | NA ± NA | — | — | — |
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.
| hours | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 5.79 ± 47.6 | 7.81 ± 45.2 | NA ± NA | 7.10 ± 27.9 | 3.20 ± 135.8 | 5.84 ± 34.6 | 5.83 ± 16.1 | 5.42 ± 79.8 | 5.85 ± 17.3 |
| Fraction Day 6 | 6.57 ± 191.5 | — | 7.37 ± 79.1 | — | — | NA ± NA | — | — | — |
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.
| liter per hour | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 40.4 ± 55.4 | 22.8 ± 63.4 | NA ± NA | 24.2 ± 61.8 | 60.9 ± 82.9 | 49.2 ± 77.3 | 17.3 ± 108.6 | 36.6 ± 48.9 | 27.9 ± 59.6 |
| Fraction Day 6 | 83.2 ± 179.0 | — | 43.5 ± 51.0 | — | — | NA ± NA | — | — | — |
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.
| liters | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Fraction Day 1 | 337 ± 64.5 | 257 ± 16.5 | NA ± NA | 248 ± 45.6 | 280 ± 52.6 | 415 ± 61.2 | 146 ± 85.3 | 287 ± 48.0 | 235 ± 40.3 |
| Fraction Day 6 | 790 ± 91.1 | — | 463 ± 41.4 | — | — | NA ± NA | — | — | — |
Cmax was taken directly from the observed concentration-time curve.
| ng/mL | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Maximum Plasma Concentration (Cmax) of M3814 After Multiple Dose | 295 ± 97.1 | NA ± NA | — | 1560 ± 84.8 | 575 ± 29.9 | NA ± NA | 2020 ± 77.8 | 140 ± 60.3 | 392 ± 108.4 |
tmax was obtained directly from the concentration versus time curve.
| hours | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Time to Reach Maximum Plasma Concentration (Tmax) of M3814 After Multiple Dose | 2.00 (1.00 to 4.07) | NA (NA to NA) | — | 2.18 (0.97 to 4.00) | 1.88 (0.50 to 2.08) | NA (NA to NA) | 0.88 (0.75 to 1.00) | 2.00 (0.50 to 4.00) | 2.00 (0.63 to 2.00) |
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.
No measurements were reported for this outcome.
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.
| h*ng/mL | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 ± NA | NA ± NA | NA ± NA | NA ± NA | NA ± NA | NA ± NA | NA ± NA | NA ± NA | NA ± NA |
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.
| hours | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Apparent Terminal Half Life (t1/2) of M3814 After Multiple Dose | 8.37 ± 81.9 | NA ± NA | — | NA ± NA | NA ± NA | — | 5.39 ± 27.3 | 3.30 ± 159.7 | NA ± NA |
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
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.
| ratio | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 ± 52.6 | NA ± NA | — | NA ± NA | 1.44 ± 20.2 | NA ± NA | 0.777 ± 55.0 | 0.922 ± 56.0 | 0.855 ± 60.7 |
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.
| ratio | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|
| Phase 1a (Arm A and Arm B): Accumulation Ratio of Cmax (Racc (Cmax) of M3814 After Multiple Dose | 0.779 ± 108.1 | NA ± NA | — | 0.871 ± 55.9 | 1.13 ± 50.9 | NA ± NA | 0.868 ± 58.9 | 0.816 ± 53.3 | 0.654 ± 61.7 |
Cmax was taken directly from the observed concentration-time curve.
| ng/mL | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 mg) + RT |
|---|---|---|---|
| Ancillary cPoP: Maximum Observed Plasma Concentration (Cmax) of M3814 | 311 ± 148.2 | 504 ± 38.4 | NA ± NA |
tmax was obtained directly from the concentration versus time curve.
| hours | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 mg) + RT |
|---|---|---|---|
| Ancillary cPoP: Time to Reach Maximum Plasma Concentration (Tmax) of M3814 | 2.02 (2.02 to 2.42) | 1.03 (1.00 to 3.85) | NA (NA to NA) |
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.
| h*ng/mL | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 mg) + RT |
|---|---|---|---|
| Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4) of M3814 | NA (NA to NA) | NA (NA to NA) | NA (NA to NA) |
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.
| h*ng/mL | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 mg) + RT |
|---|---|---|---|
| Ancillary cPoP: Area Under the Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) (AUC0-t) of M3814 | 841 ± 172.4 | 1130 ± 47.2 | NA ± NA |
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose.
| h*ng/mL/mg | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 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 ± 172.4 | 5.65 ± 47.2 | NA ± NA |
AUC0-4/Dose was defined as AUC from time of dosing to the time zero to 4 hours divided by dose.
| h*ng/mL/mg | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 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 ± NA | NA ± NA | NA ± NA |
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).
| ng/mL/mg | Ancillary cPoP: M3814 Capsule (100 mg) + RT | Ancillary cPOP: M3814 Capsule (200 mg) + RT | Ancillary cPOP: M3814 Capsule (400 mg) + RT |
|---|---|---|---|
| Ancillary cPoP: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3814 | 3.11 ± 148.2 | 2.52 ± 38.4 | NA ± NA |
Collected over Time from first dose of study treatment up to long term safety follow-up period (Up to approximately 1 year). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 4/7 (57.1%) | 1/7 (14.3%) | 7/7 (100%) |
| Phase 1a (Arm A): M3814 Capsule (200 mg) + RT | 2/3 (66.7%) | 0/3 (0%) | 3/3 (100%) |
| Phase 1a (Arm A): M3814 Capsule (300 mg) + RT | 2/3 (66.7%) | 2/3 (66.7%) | 2/3 (66.7%) |
| Phase 1a (Arm A): M3814 Capsule (400 mg) + RT | 6/6 (100%) | 2/6 (33.3%) | 6/6 (100%) |
| Phase 1a (Arm A): M3814 Tablet (100 mg) + RT | 3/6 (50%) | 1/6 (16.7%) | 6/6 (100%) |
| Phase 1a (Arm A): M3814 Tablet (200 mg) + RT | 2/3 (66.7%) | 0/3 (0%) | 3/3 (100%) |
| Phase 1a (Arm A): M3814 Tablet (300 mg) + RT | 3/6 (50%) | 3/6 (50%) | 6/6 (100%) |
| Phase 1a (Arm B): M3814 Capsule (50 mg) + CRT | 1/8 (12.5%) | 2/8 (25%) | 8/8 (100%) |
| Phase 1a (Arm B): M3814 Tablet (100 mg) + CRT | 1/3 (33.3%) | 1/3 (33.3%) | 3/3 (100%) |
| Ancillary cPoP: M3814 Capsule (100 mg) + RT | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) |
| Ancillary cPOP: M3814 Capsule (200 mg) + RT | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Ancillary cPOP: M3814 Capsule (400 mg) + RT | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Event | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| StomatitisGastrointestinal disorders | 1/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 2/6 | 0/8 | 0/3 | 0/3 | 0/3 | 0/1 |
| OdynophagiaGastrointestinal disorders | 0/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 1/8 | 1/3 | 0/3 | 0/3 | 0/1 |
| Disease progressionGeneral disorders | 1/7 | 0/3 | 1/3 | 1/6 | 1/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 0/3 | 0/1 |
| PyrexiaGeneral disorders | 0/7 | 0/3 | 1/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 0/3 | 0/1 |
| Muscle abscessInfections and infestations | 0/7 | 0/3 | 1/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 0/3 | 0/1 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 0/7 | 0/3 | 1/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 0/3 | 0/1 |
| Back painMusculoskeletal and connective tissue disorders | 0/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 1/3 | 0/1 |
| HydronephrosisRenal and urinary disorders | 0/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 1/3 | 0/3 | 0/1 |
| Ureteric stenosisRenal and urinary disorders | 0/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 1/3 | 0/3 | 0/1 |
| Deep vein thrombosisVascular disorders | 0/7 | 0/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 0/8 | 0/3 | 0/3 | 1/3 | 0/1 |
| Event | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ConstipationGastrointestinal disorders | 3/7 | 1/3 | 0/3 | 2/6 | 0/6 | 0/3 | 0/6 | 4/8 | 3/3 | 0/3 | 0/3 | 0/1 |
| StomatitisGastrointestinal disorders | 3/7 | 0/3 | 1/3 | 1/6 | 2/6 | 0/3 | 4/6 | 7/8 | 3/3 | 0/3 | 0/3 | 0/1 |
| DysgeusiaNervous system disorders | 1/7 | 1/3 | 0/3 | 0/6 | 0/6 | 0/3 | 0/6 | 5/8 | 3/3 | 0/3 | 0/3 | 0/1 |
| NauseaGastrointestinal disorders | 1/7 | 2/3 | 0/3 | 5/6 | 2/6 | 1/3 | 2/6 | 6/8 | 2/3 | 0/3 | 0/3 | 0/1 |
| FatigueGeneral disorders | 5/7 | 2/3 | 0/3 | 5/6 | 2/6 | 0/3 | 0/6 | 3/8 | 2/3 | 0/3 | 0/3 | 0/1 |
| Radiation skin injuryInjury, poisoning and procedural complications | 2/7 | 1/3 | 1/3 | 4/6 | 5/6 | 1/3 | 4/6 | 6/8 | 2/3 | 0/3 | 1/3 | 0/1 |
| Dry mouthGastrointestinal disorders | 2/7 | 0/3 | 0/3 | 0/6 | 0/6 | 1/3 | 0/6 | 5/8 | 2/3 | 0/3 | 0/3 | 0/1 |
| DysphagiaGastrointestinal disorders | 2/7 | 2/3 | 0/3 | 2/6 | 0/6 | 0/3 | 0/6 | 4/8 | 0/3 | 1/3 | 0/3 | 0/1 |
| VomitingGastrointestinal disorders | 1/7 | 2/3 | 0/3 | 2/6 | 0/6 | 1/3 | 3/6 | 3/8 | 2/3 | 0/3 | 0/3 | 0/1 |
| Weight decreasedInvestigations | 1/7 | 1/3 | 0/3 | 2/6 | 0/6 | 0/3 | 2/6 | 5/8 | 2/3 | 0/3 | 0/3 | 0/1 |
| Age, Categorical(Participants) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 4 | 2 | 2 | 2 | 3 | 2 | 4 | 7 | 2 | 2 | 1 | 0 | 31 |
| >=65 years | 3 | 1 | 1 | 4 | 3 | 1 | 2 | 1 | 1 | 1 | 2 | 1 | 21 |
| Sex: Female, Male(Participants) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 1 | 1 | 0 | 2 | 2 | 1 | 2 | 0 | 1 | 2 | 1 | 0 | 13 |
| Male | 6 | 2 | 3 | 4 | 4 | 2 | 4 | 8 | 2 | 1 | 2 | 1 | 39 |
| Ethnicity (NIH/OMB)(Participants) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 8 |
| Not Hispanic or Latino | 7 | 2 | 2 | 5 | 5 | 3 | 4 | 4 | 3 | 3 | 3 | 1 | 42 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 2 |
| Race (NIH/OMB)(Participants) | Phase 1a (Arm A): M3814 Capsule (100 mg) + RT | 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 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 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 2 |
| White | 7 | 3 | 3 | 5 | 6 | 3 | 5 | 5 | 3 | 2 | 3 | 1 | 46 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 |
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