Study of M4344 in Combination With Niraparib

NCT04655183 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: MS201922_0010
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Advanced Solid Tumor; Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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)

Secondary Outcomes (28)

• 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

  From Baseline until 6.5 months

• 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

Study Arms (5)

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.

Drug: Niraparib; Drug: M4344

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.

Drug: M4344; Drug: Niraparib

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.

Drug: Niraparib; Drug: M4344

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.

Drug: Niraparib

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.

Drug: Niraparib; Drug: M4344

Interventions

Niraparib DRUG

Niraparib will be administered orally, once daily.

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

M4344 DRUG

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

Also known as: MSC2580591A, VRT 1228692, VX-803

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

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms

Interventions

niraparib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Medical Responsible

  Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: November 27, 2020
• First Posted: December 7, 2020
• Study Start: December 1, 2020
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2023
• Last Updated: June 30, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share