Clinical Trials /

Study of M4344 in Combination With Niraparib

NCT04655183

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: MS201922_0010
  • NCT ID: NCT04655183

Conditions

  • Advanced Solid Tumor
  • Breast Cancer

Interventions

DrugSynonymsArms
NiraparibPart 1A (Dose escalation): Niraparib plus M4344 once daily
M4344MSC2580591A, VRT 1228692, VX-803Part 1A (Dose escalation): Niraparib plus M4344 once daily
NiraparibPart 2 (Dose expansion): PARPi resistant, Niraparib plus M4344
M4344MSC2580591A, VRT 1228692, VX-803Part 1B (Dose escalation): Niraparib plus M4344 once daily
NiraparibPart 1B (Dose escalation): Niraparib plus M4344 once daily
NiraparibPart 3 (Dose expansion): PARPi-naive, Niraparib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1A (Dose escalation): Niraparib plus M4344 once dailyExperimentalParticipants 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.
  • Niraparib
  • M4344
Part 1B (Dose escalation): Niraparib plus M4344 once dailyExperimentalParticipants 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.
  • M4344
  • Niraparib
Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344ExperimentalParticipants 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.
  • Niraparib
  • M4344
Part 3 (Dose expansion): PARPi-naive, NiraparibExperimentalParticipants 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.
  • Niraparib
Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344ExperimentalParticipants 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.
  • Niraparib
  • M4344

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs)
Time Frame:Day 1 up to Day 28
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Time Frame:From Baseline until 6.5 months
Safety Issue:
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.
Measure: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)
Safety Issue:
Description:
Measure: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: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
Safety Issue:
Description:
Measure:Part 1A and B: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Area Under Concentration From Time tlast Extrapolated to Infinity (AUCextra%) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Apparent Total Body Clearance From Plasma (CL/f) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Maximum Observed Concentration (Cmax) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Dose Normalized Maximum Observed Concentration (Cmax/Dose) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Plasma Concentration Observed Immediately Before Next Dosing (Ctrough) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure: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
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Metabolic Ratio of Maximum Observed Concentration MR(Cmax) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Accumulation Ratio for AUCtau (Racc[AUCtau]) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Accumulation Ratio for Maximum Observed Concentration (Racc[Cmax]) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Apparent Terminal Half-life (t1/2) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Time to Reach Maximum Plasma Concentration (tmax) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 1A and B: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:
Measure:Part 2 and Part 3: Number of Participants with Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Treatment-related TEAEs
Time Frame:From Baseline and up to 1 year
Safety Issue:
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.
Measure: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
Time Frame:From Baseline up to 1 year
Safety Issue:
Description:
Measure:Part 2: 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)
Safety Issue:
Description:
Measure:Part 2 and Part 3: Overall Survival (OS)
Time Frame:From Baseline until study closure or death, whichever comes first (assessed up to approximately 1 years)
Safety Issue:
Description:
Measure:Part 2 and Part 3: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame:From Baseline until disease progression or death (assessed up to approximately 1 years)
Safety Issue:
Description:
Measure:Part 3:Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator
Time Frame:From Baseline until disease progression (assessed up to approximately 1 years)
Safety Issue:
Description:
Measure:Part 2 and Part 3: Concentrations of M4344, Metabolites of M4344 and Niraparib
Time Frame: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

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

Last Updated

December 7, 2020