Study of M4344 in Combination With Niraparib

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 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.

Study Overview

• Status: Withdrawn
• Conditions: Breast Cancer; Advanced Solid Tumor
• Intervention / Treatment: Drug: Niraparib; Drug: M4344; Drug: Niraparib; Drug: M4344; Drug: Niraparib; Drug: Niraparib

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1A (Dose escalation): Niraparib plus M4344 once daily; 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; Niraparib will be administered orally, once daily.; Drug: M4344; M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.; Drug: M4344; M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.; Drug: Niraparib; Niraparib will be administered as single agent at the approved dose.
Experimental: Part 1B (Dose escalation): Niraparib plus M4344 once daily; 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: Niraparib; Niraparib will be administered orally, once daily.; Drug: M4344; M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.; Drug: M4344; M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.; Drug: Niraparib; Niraparib will be administered as single agent at the approved dose.
Experimental: Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344; 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; Niraparib will be administered orally, once daily.; Drug: M4344; M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.; Drug: M4344; M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.; Drug: Niraparib; Niraparib will be administered as single agent at the approved dose.
Experimental: Part 3 (Dose expansion): PARPi-naive, Niraparib; 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; Niraparib will be administered orally, once daily.; Drug: Niraparib; Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.; Drug: Niraparib; Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.; Drug: Niraparib; Niraparib will be administered as single agent at the approved dose.
Experimental: Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344; 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; Niraparib will be administered orally, once daily.; Drug: M4344; M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.; Drug: M4344; M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.; Other Names: VX-803; MSC2580591A; VRT 1228692; Drug: Niraparib; Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.; Drug: Niraparib; Niraparib will be administered as single agent at the approved dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2020
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 1, 2023

Study Registration Dates

• First Submitted: November 27, 2020
• First Submitted That Met QC Criteria: November 27, 2020
• First Posted (Actual): December 7, 2020

Study Record Updates

• Last Update Posted (Actual): June 30, 2021
• Last Update Submitted That Met QC Criteria: June 24, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Breast Cancer; Niraparib; Advanced Solid Tumor; ATR inhibitor; M4344; VX-803; MSC2580591A; VRT 1228692
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib
• Other Study ID Numbers: MS201922_0010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No