Study of M4344 in Combination With Niraparib

Merck KGaA (EMD Serono)

Status and phase: Withdrawn; Phase 2; Phase 1

Conditions: Breast Cancer; Advanced Solid Tumor

Treatments: Drug: Niraparib; Drug: M4344

Study type: Interventional

Funder types: Industry

Identifiers

NCT04655183

MS201922_0010

Details and patient eligibility

About

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.

Sex: All

Ages: 18+ years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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0 participants in 5 patient groups

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

Experimental group

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.

Treatment:

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: M4344

Drug: M4344

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

Experimental group

Description:

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.

Treatment:

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: M4344

Drug: M4344

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

Experimental group

Description:

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.

Treatment:

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: M4344

Drug: M4344

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

Experimental group

Description:

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.

Treatment:

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

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

Experimental group

Description:

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.

Treatment:

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: Niraparib

Drug: M4344

Drug: M4344