The purpose of this study was to evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily dose schedule in participants with advanced solid tumors. This investigation is a three part study examining M4344 alone and in combination with carboplatin to determine the safety and maximum tolerated dose.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
97
Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Massachusetts General Hospital
Boston, Massachusetts, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: 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 are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to safety follow-up visit (Week 124.9)
Part A: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to safety follow-up visit (Week 124.9)
Part A: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
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Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.
Washington University in St. Louis
St Louis, Missouri, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Memorial Sloan-Kettering Cancer Center (MSKCC)
New York, New York, United States
Tennessee Oncology
Nashville, Tennessee, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Froedtert & The Medical College of Wisconsin
Wauwatosa, Wisconsin, United States
Erasmus Medisch Centrum
Rotterdam, Netherlands
Hospital Clinic de Barcelona
Barcelona, Spain
...and 6 more locations
Time frame: up to safety follow-up visit (Week 124.9)
Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was decided by investigator. Number of participants with clinically significant abnormalities in 12-Lead ECGs were reported.
Time frame: up to safety follow-up visit (Week 124.9)
Part A: Maximum Tolerated Dose (MTD) of M4344 Administered Twice Weekly (BIW)
MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: 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 are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to safety follow-up visit (Week 39)
Part A2: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to safety follow-up visit (Week 39)
Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings were reported. Clinical relevance was decided by Investigator.
Time frame: up to safety follow-up visit (Week 39)
Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical Significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to safety follow-up visit (Week 39)
Part A2: Maximum Tolerated Dose (MTD) of M4344 Administered With a Dose Dense Schedule
MTD as per NCI-CTCAE v5.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. Serious AE: 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 are defined as AEs that were reported or worsened on or after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to Safety follow-up (Week 92.3)
Part B1: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v4.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to Safety follow-up (Week 92.3)
Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
Time frame: up to Safety follow-up (Week 92.3)
Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by Investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to Safety follow-up (Week 92.3)
Part B1: Maximum Tolerated Dose (MTD) of M4344 (Monotherapy) Administered in Combination With Carboplatin
MTD as per NCI-CTCAE v4.0 is defined as highest dose for a given schedule at which there is no more than 1 dose- limiting toxicity (DLT) in 6 participants. DLT: as related/possibly drug-related: Neutropenia Grade (Gr)4 for \> 7 days duration/requiring hemopoietic growth factors; Febrile neutropenia; Infection with Gr3/4 neutropenia; Thrombocytopenia Gr3; Thrombocytopenia Gr4 for \> 7 days duration/requiring hemopoietic growth factors; Gr3/4 toxicity to organs other than bone marrow; Gr3/4 increase in bilirubin unless increase is due to inhibition of bilirubin glucuronidation; Death due to drug-related complications; Cardiac: QTc prolongation, Gr2/greater ventricular arrhythmia, severe sustained/symptomatic sinus bradycardia, persistent supraventricular arrhythmia, Symptoms suggestive of congestive heart failure, Troponin-T level consistent with myocardial infarction; drug-related toxicity causes interruption of treatment for \> 2 weeks.
Time frame: up to Cycle 1 (each cycle is of 21 days)
Part C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related AEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
AE: any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, regardless if it is considered related to medicinal product. Serious AE: AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: AEs that were reported/worsened on/after start of study drug dosing through the Safety Follow-up Visit. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment related AEs: reasonably related to the study drug/study treatment. AE could medically (pharmacologically/clinically) be attributed to the study drug/study treatment under study in this clinical study protocol.
Time frame: up to Safety follow-up (Week 31.1)
Part C: Number of Participants With Grade 3 or 4 (Greater Than [>] 20 Percent [%] of Total) in Laboratory Parameters Based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0)
Laboratory parameters: hematology and chemistry. Blood samples were collected for analysis of following hematology parameters: Hemoglobin, Erythrocytes, mean corpuscular hemoglobin (MCH), MCH concentration, Mean corpuscular volume, Reticulocytes, Platelets, Leukocytes, Eosinophils, Basophils, Neutrophils, Lymphocytes, Monocytes. Blood samples were collected for analysis of following chemistry parameters: Glucose, Blood urea nitrogen/Urea, Creatinine, Sodium, Potassium, Calcium, Chloride, Magnesium, Bicarbonate, Inorganic phosphate, Total bilirubin, Direct bilirubin, Total protein, Albumin, Creatine kinase, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Uric acid, Thyroid stimulating hormone. Number of participants with Grade 3 or 4 (\>20% of total) in laboratory parameters were reported as per NCI-CTCAE v5.0 graded from Grade 1 to 5. Grade 1: Mild, Grade 2: Moderate; Grade 3: Severe. Grade 4: Life-threatening and Grade 5: Death.
Time frame: up to Safety follow-up (Week 31.1)
Part C: Number of Participants With Clinically Relevant Findings in Vital Signs
Vital signs included body temperature, heart rate, systolic and diastolic blood pressure and respiration rate. Number of participants with clinically relevant findings in vital signs were reported. Clinical relevance was decided by Investigator.
Time frame: up to Safety follow-up (Week 31.1)
Part C: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs)
ECG parameters included PR interval, RR interval, QT interval, QRS duration, QTc intervals (derived using Fridericia's correction method) and heart rate. A 12-lead ECG was recorded with the participant in a supine position after a rest of at least 5 minutes using an ECG machine. Clinical significance was determined by investigator. Number of participants with clinically significant abnormalities in 12-lead ECGs were reported.
Time frame: up to Safety follow-up (Week 31.1)
Part C: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by the Investigator
OR is defined as the confirmed assessment of best overall response of complete response (CR) or partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 6.4 years
Part A: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus 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 calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344
Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax 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, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
AUC0-t/Dose was defined as AUC from time of dosing to the time of the last measurable concentration divided by dose. AUC0-t/dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 4.3 years
Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first dose of study treatment up to 4.3 years
Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus 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 calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344
Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 8 divided by Cmax, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (Racc [AUC0-t]) of M4344
Accumulation ratio of AUC0-t was calculated as AUC0-t, after dosing on Day 8 divided by AUC0-t, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344
Accumulation ratio of AUC was calculated as AUC, after dosing on Day 8 divided by AUC, after dosing on Day 1 of Cycle 1.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax 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, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose. AUC0-inf/Dose was measured in nanogram\*hour per milliliter per milligram (ng\*h/mL/mg).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose on Cycle 1 Day 1 (each cycle is of 21 days)
Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
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, 3, 4, 6, 8, 12 (in BID arms), 24 hours post-dose (in QD arms) on Day 1 and Day 8 of Cycle 1 (each cycle is of 21 days)
Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
SD is defined as neither sufficient increase to qualify for progression disease (PD) nor sufficient shrinkage to qualify for partial response (PR). PR: at least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first dose of study treatment up to 6.2 years
Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 6.2 years
Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus 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 calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Terminal Elimination Half-Life (T1/2) of M4344
Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Apparent Clearance (CL/f) of M4344
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344
Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344
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 and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Dose Normalized Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero Extrapolated to Infinity (AUC0-inf/Dose) of M4344
AUC0-inf/Dose was defined as AUC extrapolated to infinity divided by dose.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hours post-dose on Cycle 1 Day 2 (each cycle is of 21 days)
Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
The OR was defined as the confirmed assessment of best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions.
Time frame: Time from first dose of study treatment up to 5.2 years
Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
Confirmed BOR is defined as best response of any of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the treatment start date until documented disease progression. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30%reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions.
Time frame: Time from first dose of study treatment up to 6.4 years
Part C: Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Investigator
PFS is defined as the time from start of study treatment to progression disease (PD) or death. PD: at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates.
Time frame: Time from first dose of study treatment up to 6.4 years
Part C: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator
DOR was defined for participants with confirmed response, as the time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from first documentation of objective response, assessed up to 6.4 years
Part C: Overall Survival (OS)
OS was defined as the time from treatment start to the date of death due to any cause. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date. OS was measured using Kaplan-Meier (KM) estimates.
Time frame: Time from first dose of study treatment up to 6.4 years
Part C: Maximum Observed Plasma Concentration (Cmax) of M4344
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)
Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344
Area under the plasma concentration versus 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 calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)
Part C: Time to Reach Maximum Plasma Concentration (Tmax) of M4344
Tmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose up to 2 hours post-dose on Cycle 1 Day 1; Pre-dose up to 1 hours post-dose on Cycle 1 Day 8 and Cycle 1 Day 15 (each cycle is of 21 days)