Back to results

Study of M4344 in Combination With Niraparib

Primary Purpose

Advanced Solid Tumor, Breast Cancer

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Niraparib

M4344

Niraparib

M4344

Niraparib

About this trial

This is an interventional treatment trial for Advanced Solid Tumor focused on measuring M4344, MSC2580591A, VX-803, VRT 1228692, ATR inhibitor, Advanced Solid Tumor, Breast Cancer, Niraparib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participants in All Parts:
Have Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (ECOG 0-2 for Phase II)
Participants with human immunodeficiency virus (HIV) infection are eligible if they are on effective anti-retroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction
Participants with a history of hepatitis C virus (HCV) infection are eligible if they have been treated and cured
Participants in Part 1:
Are participants with advanced solid tumors, except for advanced prostate cancer, for whom no standard of care therapy exists, or in whom conventional therapy is not reliably effective, or in whom treatment with study intervention can be reasonably expected to provide clinical benefit
Participants in Part 2:
Are participants with advanced Germline Breast Cancer Gene (BRCA)1/2-Mutant Wild Type (gBRCA1/2)-mutant, Poly(ADP-Ribose) Polymerase Inhibitor(s) (PARPi)-resistant Human Epidermal Growth Factor Receptor 2 Negative (HER2)- breast cancer. There is no limit for prior lines of chemotherapy for metastatic disease
Participants with at least one measurable lesion that is suitable for repeated assessment as per RECIST 1.1
Participants in Part 3:
Are participants with advanced BRCA1/2 wild-type, Homologous Recombination Repair Gene Mutated (HRRm) Human Epidermal Growth Factor Receptor 2 Negative (HER2)- breast cancer
Participants must not have had prior treatment with a PARPi in any disease setting
All participants with at least one measurable or non-measurable but evaluable lesion that is suitable for repeated assessment as per RECIST 1.1
Other protocol defined inclusion criteria could apply

Exclusion Criteria:

Participants with clinically relevant (that is [i.e], active), uncontrolled intercurrent illness including, but not limited to, severe active infection (i.e. requiring hospitalization and/or intravenous antibiotics), uncontrolled arterial hypertension, i.e. systolic blood pressure (BP) > 140 millimeter of mercury (mmHg), diastolic BP > 90 mmHg, symptomatic congestive heart failure (>= New York Heart Association Classification Class II), unstable angina pectoris or myocardial infarction, cardiac arrhythmia requiring medication, cerebral vascular accident/stroke, or any psychiatric illness/social situations that would limit compliance with study requirements
Participants with a known additional malignancy that is progressing and/or requires active treatment. In addition, participants must not have a known history or current diagnosis of Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) at any time or have been diagnosed with another malignancy within 3 years of starting treatment. Exceptions include fully resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully resected ductal carcinoma in situ, and Stage IA, Grade I endometrioid endometrial cancer with no myometrial invasion, that has undergone curative therapy
Participants diagnosed with hereditary diseases characterized by genetic defects of Deoxyribonucleic acid (DNA) repair mechanisms, including ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy
Treatment with live or live attenuated vaccine within 30 days of dosing
Participants with clinically relevant, uncontrolled intercurrent illness, unstable brain metastases, has a known additional malignancy that is progressing and/or requires active treatment
Received hematopoietic growth factor (example, granulocyte colony-stimulating factor, erythropoietin) within 14 days prior to the first dose of study intervention
Participants receiving treatment with proton-pump inhibitors that cannot be discontinued at least 1 week before first dose of study intervention and for the duration of the study
Other protocol defined inclusion criteria could apply

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Part 1A (Dose escalation): Niraparib plus M4344 once daily

Part 1B (Dose escalation): Niraparib plus M4344 once daily

Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344

Part 3 (Dose expansion): PARPi-naive, Niraparib

Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs)

Part 1 A and B: Number of Participants with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs

Part 2: Objective response (OR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Assessed by Investigator

Part 3: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator

Secondary Outcome Measures

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.

Part 1A and B: Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator

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

Part 1A and B: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M4344, Metabolites of M4344 and Niraparib

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

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

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

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

Part 1A and B: Area Under Concentration From Time tlast Extrapolated to Infinity (AUCextra%) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Apparent Total Body Clearance From Plasma (CL/f) of M4344, Metabolites of M4344 and Niraparib

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

Part 1A and B: Maximum Observed Concentration (Cmax) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Dose Normalized Maximum Observed Concentration (Cmax/Dose) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Plasma Concentration Observed Immediately Before Next Dosing (Ctrough) of M4344, Metabolites of M4344 and Niraparib

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

Part 1A and B: Metabolic Ratio of Maximum Observed Concentration MR(Cmax) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Accumulation Ratio for AUCtau (Racc[AUCtau]) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Accumulation Ratio for Maximum Observed Concentration (Racc[Cmax]) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Apparent Terminal Half-life (t1/2) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Time to Reach Maximum Plasma Concentration (tmax) of M4344, Metabolites of M4344 and Niraparib

Part 1A and B: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M4344, Metabolites of M4344 and Niraparib

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.

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

Part 2: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator

Part 2 and Part 3: Overall Survival (OS)

Part 2 and Part 3: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Part 3:Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator

Part 2 and Part 3: Concentrations of M4344, Metabolites of M4344 and Niraparib

Full Information

NCT ID

NCT04655183

First Posted

November 27, 2020

Last Updated

June 24, 2021

Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

1. Study Identification

Unique Protocol Identification Number

NCT04655183

Brief Title

Study of M4344 in Combination With Niraparib

Official Title

A Phase I Dose Escalation Study of ATR Inhibitor M4344 in Combination With Niraparib in Participants With Advanced Solid Tumors Followed by Phase II Cohort Expansion in Participants With Breast Cancer With DNA Damage Response (DDR) Mutations

Study Type

Interventional

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Withdrawn

Why Stopped

Trial withdrawn based on portfolio prioritization; oral ATRi M1774 in combination with niraparib is under investigation in DDRiver Solid Tumor 301

Study Start Date

December 1, 2020 (Anticipated)

Primary Completion Date

September 1, 2023 (Anticipated)

Study Completion Date

September 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

EMD Serono Research & Development Institute, Inc.

Collaborators

Merck KGaA, Darmstadt, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Tumor, Breast Cancer

Keywords

M4344, MSC2580591A, VX-803, VRT 1228692, ATR inhibitor, Advanced Solid Tumor, Breast Cancer, Niraparib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1A (Dose escalation): Niraparib plus M4344 once daily

Arm Type

Experimental

Arm Description

Arm Title

Part 1B (Dose escalation): Niraparib plus M4344 once daily

Arm Type

Experimental

Arm Description

Arm Title

Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344

Arm Type

Experimental

Arm Description

Arm Title

Part 3 (Dose expansion): PARPi-naive, Niraparib

Arm Type

Experimental

Arm Description

Arm Title

Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Niraparib

Intervention Description

Niraparib will be administered orally, once daily.

Intervention Type

Drug

Intervention Name(s)

M4344

Other Intervention Name(s)

MSC2580591A, VRT 1228692, VX-803

Intervention Description

M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.

Intervention Type

Drug

Intervention Name(s)

Niraparib

Intervention Description

Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.

Intervention Type

Drug

Intervention Name(s)

M4344

Other Intervention Name(s)

MSC2580591A, VRT 1228692, VX-803

Intervention Description

M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.

Intervention Type

Drug

Intervention Name(s)

Niraparib

Intervention Description

Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.

Intervention Type

Drug

Intervention Name(s)

Niraparib

Intervention Description

Niraparib will be administered as single agent at the approved dose.

Primary Outcome Measure Information:

Title

Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs)

Time Frame

Day 1 up to Day 28

Title

Part 1 A and B: Number of Participants with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs

Time Frame

From Baseline until 6.5 months

Title

Part 2: Objective response (OR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Assessed by Investigator

Time Frame

From Baseline until disease progression (assessed up to approximately 1 years)

Title

Part 3: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator

Time Frame

From Baseline until disease progression or death (assessed up to approximately 1 years)

Secondary Outcome Measure Information:

Title

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

Description

Number of participants with clinically significant changes from baseline in vital signs, 12-Lead Electrocardiogram (ECG) assessments findings and laboratory parameters will be reported.

Time Frame

From Baseline until 6.5 months

Title

Part 1A and B: Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator

Time Frame

From Baseline until disease progression (assessed up to approximately 6.5 months)

Title

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

Time Frame