Phase 1
Completed N=97
First in Human Study of M4344 in Participants With Advanced Solid Tumors
Solid Tumors · Advanced Solid Tumor
Source: ClinicalTrials.gov NCT02278250 ↗
Enrolled (actual)
97
Serious AEs
50.5%
Results posted
Mar 2023
Primary outcomePrimary: Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) — 2; 1; 2; 1 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |
2; 1; 2; 1; 1; 2 | — |
| PRIMARY 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) |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part A: Number of Participants With Clinically Relevant Findings in Vital Signs |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part A: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part A: Maximum Tolerated Dose (MTD) of M4344 Administered Twice Weekly (BIW) |
NA | — |
| PRIMARY Part A2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |
7; 5; 7; 7 | — |
| PRIMARY 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) |
1; 1; 2; 3; 3; 2 | — |
| PRIMARY Part A2: Number of Participants With Clinically Relevant Findings in Vital Signs |
0; 0; 0; 0 | — |
| PRIMARY Part A2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) |
0; 0; 0; 0 | — |
| PRIMARY Part A2: Maximum Tolerated Dose (MTD) of M4344 Administered With a Dose Dense Schedule |
250 | — |
| PRIMARY Part B1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |
3; 7; 6 | — |
| PRIMARY 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) |
1; 1; 5; 1; 3; 3 | — |
| PRIMARY Part B1: Number of Participants With Clinically Relevant Findings in Vital Signs |
0; 0; 0 | — |
| PRIMARY Part B1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) |
0; 0; 0 | — |
| PRIMARY Part B1: Maximum Tolerated Dose (MTD) of M4344 (Monotherapy) Administered in Combination With Carboplatin |
NA | — |
| PRIMARY 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 |
13; 13 | — |
| PRIMARY 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) |
8; 6; 7; 4; 3 | — |
| PRIMARY Part C: Number of Participants With Clinically Relevant Findings in Vital Signs |
— | — |
| PRIMARY Part C: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECGs) |
6 | — |
| PRIMARY 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 |
0.0 | — |
| SECONDARY Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Terminal Elimination Half-Life (T1/2) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Apparent Clearance (CL/f) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY 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 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY 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 |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Part A: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
0.0; 0.0; 0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Part A: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
0; 1; 0; 0; 0; 0 | — |
| SECONDARY Part A2: Maximum Observed Plasma Concentration (Cmax) of M4344 |
111; 124; 517; 265; 114; 244 | — |
| SECONDARY Part A2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 |
217; 436; 1210; 680 | — |
| SECONDARY Part A2: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 |
216; 414; 1230; 703; 236; 627 | — |
| SECONDARY Part A2: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 |
1.45; 1.62; 1.50; 1.10; 1.03; 1.28 | — |
| SECONDARY Part A2: Terminal Elimination Half-Life (T1/2) of M4344 |
1.32; 2.47; 1.74; 2.37; 1.36; 1.31 | — |
| SECONDARY Part A2: Apparent Clearance (CL/f) of M4344 |
461; 344; 207; 515; 424; 239 | — |
| SECONDARY Part A2: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 |
876; 1220; 519; 1760 | — |
| SECONDARY Part A2: Accumulation Ratio for Maximum Observed Plasma Concentration (Racc [Cmax]) of M4344 |
1.08; 2.26; 0.733; NA | — |
| SECONDARY 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 |
1.00; 1.42; 0.672; NA | — |
| SECONDARY Part A2: Accumulation Ratio for Area Under the Plasma Concentration Time Curve (Racc [AUC]) of M4344 |
0.997; 1.32; 0.676; NA | — |
| SECONDARY Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 |
1.11; 0.829; 2.07; 0.758; 1.14; 1.63 | — |
| SECONDARY 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 |
2.17; 2.91; 4.84; 1.94 | — |
| SECONDARY Part A2: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 |
2.16; 2.76; 4.93; 2.01; 2.36; 4.18 | — |
| SECONDARY Part A2: Number of Participants With Stable Disease (SD) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
1; 1; 4; 2 | — |
| SECONDARY Part A2: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 |
309; 114; 367 | — |
| SECONDARY Part B1: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 |
392; 268; 1450 | — |
| SECONDARY Part B1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M4344 |
NA; 368; 2570 | — |
| SECONDARY Part B1:Time to Reach Maximum Plasma Concentration (Tmax) of M4344 |
1.52; 1.50; 1.96 | — |
| SECONDARY Part B1: Terminal Elimination Half-Life (T1/2) of M4344 |
NA; 1.03; 3.77 | — |
| SECONDARY Part B1: Apparent Clearance (CL/f) of M4344 |
NA; 1090; 194 | — |
| SECONDARY Part B1: Apparent Volume of Distribution During Terminal Phase (Vz/f) of M4344 |
NA; 1620; 1060 | — |
| SECONDARY Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M4344 |
0.884; 0.286; 0.735 | — |
| SECONDARY Part B1: Dose Normalized Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t/Dose) of M4344 |
1.12; 0.669; 2.90 | — |
| SECONDARY 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 |
NA; 0.920; 5.15 | — |
| SECONDARY Part B1: Percentage of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |
0.0; 14.3; 0.0 | — |
| SECONDARY Part C: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 |
0; 0; 3; 8; 0; 2 | — |
| SECONDARY Part C: Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 as Assessed by Investigator |
1.6 | — |
| SECONDARY Part C: Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator |
— | — |
| SECONDARY Part C: Overall Survival (OS) |
1.91; 0.79; 1.61; 3.98; 2.53; 2.63 | — |
| SECONDARY Part C: Maximum Observed Plasma Concentration (Cmax) of M4344 |
— | — |
| SECONDARY Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M4344 |
— | — |
| SECONDARY Part C: Time to Reach Maximum Plasma Concentration (Tmax) of M4344 |
— | — |
Eligibility Criteria
Inclusion Criteria
- 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
- Other protocol defined inclusion criteria could apply
Exclusion Criteria
- 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
- Other protocol defined exclusion criteria could apply
Data sourced from ClinicalTrials.gov (NCT02278250). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.