First in Human Study of M4344 in Participants With Advanced Solid Tumors

NCT02278250 | Completed Phase 1 Results DMC

• 3 other identifiers: MS201922-0001VX14-803-0012014-003838-86
• Study Type: interventional
• Target: 97
• Locations: 4 countries
• Sites: 16

Brief Summary

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.

Conditions

Solid Tumor; Advanced Solid Tumor

Keywords

VX14-803-001; VX-803; M4344; Advanced Solid Tumor; Cytotoxic Chemotherapy; Carboplatin

Outcome Measures

Primary Outcomes (20)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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 from first dose of study treatment up to 6.4 years

Secondary Outcomes (47)

• Part A: Maximum Observed Plasma Concentration (Cmax) of M4344

  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

  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

  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

  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

  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)

Study Arms (18)

Part A: M4344 10 mg BIW

EXPERIMENTAL

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.

Drug: M4344 10 mg BIW

Part A: M4344 20 mg BIW

EXPERIMENTAL

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.

Drug: M4344 20 mg BIW

Part A: M4344 40 mg BIW

EXPERIMENTAL

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.

Drug: M4344 40 mg BIW

Part A: M4344 80 mg BIW

EXPERIMENTAL

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.

Drug: M4344 80 mg BIW

Part A: M4344 160 mg BIW

EXPERIMENTAL

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.

Drug: M4344 160 mg BIW

Part A: M4344 300 mg BIW

EXPERIMENTAL

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.

Drug: M4344 300 mg BIW

Part A: M4344 450 mg BIW

EXPERIMENTAL

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.

Drug: M4344 450 mg BIW

Part A: M4344 700 mg BIW

EXPERIMENTAL

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.

Drug: M4344 700 mg BIW

Part A: M4344 1050 mg BIW

EXPERIMENTAL

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.

Drug: M4344 1050 mg BIW

Part A: M4344 1200 mg BIW

EXPERIMENTAL

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.

Drug: M4344 1200 mg BIW

Part A2: M4344 100 mg BID

EXPERIMENTAL

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.

Drug: M4344 100 mg BID

Part A2: M4344 150 mg QD

EXPERIMENTAL

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.

Drug: M4344 150 mg QD

Part A2: M4344 250 mg QD

EXPERIMENTAL

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.

Drug: M4344 250 mg QD

Part A2: M4344 350 mg QD

EXPERIMENTAL

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.

Drug: M4344 350 mg QD

Part B1: M4344 350 mg + Carboplatin

EXPERIMENTAL

Participants received M4344 at a dose of 350 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of Area under the concentration versus time curve 5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Drug: M4344 350 mg QD; Drug: Carboplatin

Part B1: M4344 400 mg + Carboplatin

EXPERIMENTAL

Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Drug: M4344 400 mg; Drug: Carboplatin

Part B1: M4344 500 mg + Carboplatin

EXPERIMENTAL

Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Drug: M4344 500 mg; Drug: Carboplatin

Part C: M4344 250 mg QD

EXPERIMENTAL

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.

Drug: M4344 250 mg QD

Interventions

M4344 10 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 10 mg BIW

M4344 20 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 20 mg BIW

M4344 40 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 40 mg BIW

M4344 80 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 80 mg BIW

M4344 160 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 160 mg BIW

M4344 300 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 300 mg BIW

M4344 450 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 450 mg BIW

M4344 700 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 700 mg BIW

M4344 1050 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 1050 mg BIW

M4344 1200 mg BIW DRUG

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.

Also known as: VX-803

Part A: M4344 1200 mg BIW

M4344 100 mg BID DRUG

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.

Also known as: VX-803

Part A2: M4344 100 mg BID

M4344 150 mg QD DRUG

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.

Also known as: VX-803

Part A2: M4344 150 mg QD

M4344 250 mg QD DRUG

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.

Also known as: VX-803

Part A2: M4344 250 mg QD; Part C: M4344 250 mg QD

M4344 350 mg QD DRUG

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.

Also known as: VX-803

Part A2: M4344 350 mg QD; Part B1: M4344 350 mg + Carboplatin

M4344 400 mg DRUG

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.

Also known as: VX-803

Part B1: M4344 400 mg + Carboplatin

M4344 500 mg DRUG

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.

Also known as: VX-803

Part B1: M4344 500 mg + Carboplatin

Carboplatin DRUG

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.

Part B1: M4344 350 mg + Carboplatin; Part B1: M4344 400 mg + Carboplatin; Part B1: M4344 500 mg + Carboplatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A, A2 and A3: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit
• Part B1: Participants with one histologically or cytologically confirmed malignant advanced solid tumor, for which no standard therapy is available which may convey clinical benefit and/or participants must have progressed after at least 1 prior chemotherapy regimen in the metastatic setting, and for which carboplatin would be considered standard of care.
• Part C: Participants with 1 histologically or cytologically confirmed malignant advanced solid tumors for which no recommended standard therapy is available (that is, participants who have exhausted all standard of care options according to National Comprehensive Cancer Network \[NCCN\] Guidance) which may convey clinical benefit, and whose tumor has at least 1 of the following biomarkers as determined by a central trial assay or by an assay with appropriate regulatory status: - C1 or C4: loss-of-function mutations in the gene ARID1A - C2 or C5: loss-of-function mutations in the genes ATRX and/or DAXX - C3 or C6: loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM) - This mandatory biomarker assessment must be conducted during screening on a fresh tumor biopsy (or a biopsy obtained after the end of the previous treatment regimen). If this is not possible for medical reason(s), available archival tumor material can be used (historical data should not be used to confirm biomarker status)
• Measurable disease either according to RECIST criteria (Version 1.1)
• WHO performance status of 0 or 1
• Life expectancy of greater than or equal to (\>=)12 weeks
• Hematological and biochemical indices within acceptable ranges at Screening

You may not qualify if:

• Radiotherapy, unless brief course for palliative therapy, endocrine therapy, target-specific therapy, immunotherapy, or chemotherapy during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C, and 4 weeks for investigational medicinal products) or 4 drug half-lives before first dose of study drug, whichever is greater
• Part B1: More than 6 cycles of prior therapy with carboplatin
• Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the investigator should not exclude the participant
• Part B1: Any known history of Grade 4 thrombocytopenia with any prior chemotherapy regimen
• Brain metastases unless asymptomatic, treated, stable, and not requiring steroids for at least 4 weeks before first dose of study drug
• Female participants who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded. Female participants of childbearing potential must adhere to contraception guidelines. Female participants will be considered to be of nonchildbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years with a screening serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females.
• Male participants with partners of childbearing potential must agree to adhere to contraception guidelines. Men with pregnant or lactating partners or partners who plan to become pregnant during the study or within 6 months of the last dose of study drug are excluded.
• Major surgery less than or equal to (\<=) 4 weeks before first dose of study drug or incomplete recovery from a prior major surgical procedure
• Serious co-morbid medical conditions, including clinically-significant cardiac disease

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (16)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109-5901, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 8903, United States

Location

Memorial Sloan-Kettering Cancer Center (MSKCC)

New York, New York, 10065, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Froedtert & The Medical College of Wisconsin

Wauwatosa, Wisconsin, 53226, United States

Location

Erasmus Medisch Centrum

Rotterdam, 3075 EA, Netherlands

Location

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

"Fundacion Jimenez Diaz START Madrid. Oncology Phase I"

Madrid, Spain

Location

START Madrid. Fundacion Jimenez Diaz- Oncologia-Fase I

Madrid, Spain

Location

"Hospital Clinico Universitario de Valencia Servicio de Hematologia y Oncologia Medica"

Valencia, Spain

Location

Sarah Cannon Research Institute UK

London, Greater London, W1G 6AD, United Kingdom

Location

Royal Marsden Hospital

Sutton, Surrey, United Kingdom

Location

Related Publications (2)

• Jo U, Senatorov IS, Zimmermann A, Saha LK, Murai Y, Kim SH, Rajapakse VN, Elloumi F, Takahashi N, Schultz CW, Thomas A, Zenke FT, Pommier Y. Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents. Mol Cancer Ther. 2021 Aug;20(8):1431-1441. doi: 10.1158/1535-7163.MCT-20-1026. Epub 2021 May 27.

  PMID: 34045232 RESULT

• Burris HA, Berlin J, Arkenau T, Cote GM, Lolkema MP, Ferrer-Playan J, Kalapur A, Bolleddula J, Locatelli G, Goddemeier T, Gounaris I, de Bono J. A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours. Br J Cancer. 2024 Apr;130(7):1131-1140. doi: 10.1038/s41416-023-02436-2. Epub 2024 Jan 29.

  PMID: 38287179 DERIVED

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources
• Related Info

MeSH Terms

Interventions

BID protein, human; Carboplatin

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2014
• First Posted: October 29, 2014
• Study Start: January 26, 2015
• Primary Completion: June 16, 2021
• Study Completion: September 24, 2021
• Last Updated: March 16, 2023
• Results First Posted: March 16, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2); US (8); NL (1); ES (5)