Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Trial withdrawn based on portfolio prioritization; oral ATRi M1774 in combination with niraparib is under investigation in DDRiver Solid Tumor 301
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Merck KGaA, Darmstadt, Germany | INDUSTRY |
Not provided
Not provided
Not provided
Not provided
Study will include 3 parts. Aim of Part 1 of this study is to establish the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) for M4344 (is an Ataxia Telangiectasia Mutated and Rad3-related [ATR] inhibitors) in combination with niraparib in participants with advanced solid tumors. Aim of Parts 2 and 3 of the study is to provide clinical proof-of-concept for the preclinically predicted synergistic efficacy of ATR and poly(ADP-Ribose) polymerase (PARP) inhibitors (PARPi) in defined populations of participants with advanced breast cancer (aBC) with DDR mutations with an unmet medical need.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1A (Dose escalation): Niraparib plus M4344 once daily | Experimental | Participants with baseline body weight < 77 kilograms (kg) or baseline platelet count < 150, 000 per cubic millimeter will be included in this Part. Dose escalation of M4344 administered along with niraparib. |
|
| Part 1B (Dose escalation): Niraparib plus M4344 once daily | Experimental | Participants with baseline body weight > =77 kilograms (kg) and baseline platelet count >=150, 000 per cubic millimeter will be included in this Part. M4344 will be administered at a dose and schedule that was determined as the recommended dose for expansion (RDE) in Part 1A. Dose of niraparib will be escalated to the next higher dose level. |
|
| Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344 | Experimental | Participants with Poly(ADP-ribose) polymerase inhibitor (PARPi) resistant, germline breast cancer 1/2 mutated (gBRCA1/2m) human epidermal growth factor receptor 2 (HER2) negative advanced Breast Cancer (aBC) will receive the combination of niraparib and M4344 at the RDE which was determined in Part 1. |
|
| Part 3 (Dose expansion): PARPi-naive, Niraparib | Experimental | Participants with PARPi-naive germline BRCA1/2 wild type (gBRCAwt) homologous recombination repair gene mutated (HRRm) advanced breast cancer (aBC) will be randomized to receive niraparib as a single agent. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Niraparib | Drug | Niraparib will be administered orally, once daily. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs) | Day 1 up to Day 28 | |
| Part 1 A and B: Number of Participants with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs | From Baseline until 6.5 months | |
| Part 2: Objective response (OR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Assessed by Investigator | From Baseline until disease progression (assessed up to approximately 1 years) | |
| Part 3: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator | From Baseline until disease progression or death (assessed up to approximately 1 years) |
| Measure | Description | Time Frame |
|---|---|---|
| Part 1 A and B: Number of Participants with Clinically Significant Changes From Baseline in Vital Signs, 12-Lead Electrocardiogram (ECG) Assessments Findings and Laboratory parameters | Number of participants with clinically significant changes from baseline in vital signs, 12-Lead Electrocardiogram (ECG) assessments findings and laboratory parameters will be reported. | From Baseline until 6.5 months |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Study Director |
Not provided
Not provided
| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
| US Medical Information website, Medical Resources | View source |
Not provided
Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C545685 | niraparib |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344 | Experimental | Participants with PARPi-naive germline BRCA1/2 wild type (gBRCAwt) homologous recombination repair gene mutated (HRRm) advanced breast cancer (aBC) will be randomized to receive the combination of niraparib and M4344 at the RDE as determined in Part 1 of this study. |
|
| M4344 | Drug | M4344 will be administered once daily or on an intermittent schedule in combination with niraparib. |
|
|
| Niraparib | Drug | Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study. |
|
| M4344 | Drug | M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib. |
|
|
| Niraparib | Drug | Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A. |
|
| Niraparib | Drug | Niraparib will be administered as single agent at the approved dose. |
|
| Part 1A and B: Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator | From Baseline until disease progression (assessed up to approximately 6.5 months) |
| Part 1 A and B: Area Under the Concentration-time Curve From Time Zero to the Last Sampling time (AUC 0-tlast) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Dose Normalized Area Under Concentration-Time Curve Within One Dosing Interval (AUC0-tau/Dose) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Dose Normalized Area Under Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-last/Dose) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Dose Normalized Area Under Concentration-Time Curve From Time Zero (dosing time) Extrapolated to Infinity (AUC0-inf/Dose) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Area Under Concentration From Time tlast Extrapolated to Infinity (AUCextra%) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Apparent Total Body Clearance From Plasma (CL/f) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Apparent Total Body Clearance From Plasma at Steady State Following Extravascular Administration (CLss/F) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Maximum Observed Concentration (Cmax) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Dose Normalized Maximum Observed Concentration (Cmax/Dose) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Plasma Concentration Observed Immediately Before Next Dosing (Ctrough) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Metabolic Ratio of Area Under Plasma Concentration-Time Curve Within One Dosing Interval MR(AUC0-tau) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Metabolic Ratio of Maximum Observed Concentration MR(Cmax) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Accumulation Ratio for AUCtau (Racc[AUCtau]) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Accumulation Ratio for Maximum Observed Concentration (Racc[Cmax]) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Apparent Terminal Half-life (t1/2) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Time to Reach Maximum Plasma Concentration (tmax) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 1A and B: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M4344, Metabolites of M4344 and Niraparib | Cycle 1 Day 1 to Cycle 4 Day 1 and every second cycle thereafter Day 1 (each cycle is of 28 days), assessed up to approximately 6.5 months |
| Part 2 and Part 3: Number of Participants with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Treatment-related TEAEs | Number of participants with clinically significant changes from baseline in vital signs, 12-Lead Electrocardiogram (ECG) assessments findings and laboratory parameters will be reported. | From Baseline and up to 1 year |
| Part 2 and Part 3: Number of Participants with Clinically Significant Change From Baseline in Vital Signs, 12-Lead Electrocardiogram (ECG) Assessments Findings and Laboratory parameters | From Baseline up to 1 year |
| Part 2: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator | From Baseline until disease progression or death (assessed up to approximately 1 years) |
| Part 2 and Part 3: Overall Survival (OS) | From Baseline until study closure or death, whichever comes first (assessed up to approximately 1 years) |
| Part 2 and Part 3: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From Baseline until disease progression or death (assessed up to approximately 1 years) |
| Part 3:Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator | From Baseline until disease progression (assessed up to approximately 1 years) |
| Part 2 and Part 3: Concentrations of M4344, Metabolites of M4344 and Niraparib | Cycle 1, Day 1 to Cycle 2 Day 1 and subsequently every other cycle Day 1 (each cycle is of 28 days), assessed up to approximately 1 year |
| D017437 |
| Skin and Connective Tissue Diseases |