Advanced Solid TumorPhase 1/2NCT04655183
Study of M4344 in Combination With Niraparib
A Phase 1/2 study testing Niraparib and M4344 in people with Advanced Solid Tumor and Breast Cancer, run by EMD Serono Research & Development Institute, Inc..
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumor, Breast Cancer
- What is being tested?
- Niraparib and M4344
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Dec 2020to 1 Sep 2023
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 14Show fewer
- 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
Who cannot join
- 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
About this study
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 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
- Being tested
- Niraparib, M4344
- Keywords
- M4344, MSC2580591A, VX-803, VRT 1228692, ATR inhibitor, Advanced Solid Tumor, Breast Cancer, Niraparib
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NiraparibDrug
Niraparib will be administered orally, once daily.
M4344Drug
Also called MSC2580591A, VRT 1228692, VX-803
M4344 will be administered once daily or on an intermittent schedule in combination with niraparib.
NiraparibDrug
Niraparib will be administered orally once daily at the RDE as determined in Part 1 of this study.
M4344Drug
Also called MSC2580591A, VRT 1228692, VX-803
M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib.
NiraparibDrug
Niraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A.
NiraparibDrug
Niraparib will be administered as single agent at the approved dose.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Niraparib; Drug: M4344 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs)
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Number of participants with clinically significant changes from baseline in vital signs, 12-Lead Electrocardiogram (ECG) assessments findings and laboratory parameters will be reported.
Measured: From Baseline until 6.5 months
Part 1A and B: Objective response (OR) According to RECIST Version 1.1 Assessed by Investigator
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: From Baseline up to 1 year
Part 2: Progression Free Survival (PFS) According to RECIST Version 1.1 Assessed by Investigator
Measured: From Baseline until disease progression or death (assessed up to approximately 1 years)
Part 2 and Part 3: Overall Survival (OS)
Measured: 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
Measured: 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
Measured: From Baseline until disease progression (assessed up to approximately 1 years)
Part 2 and Part 3: Concentrations of M4344, Metabolites of M4344 and Niraparib
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Dec 2020
- Study start1 Dec 2020 (estimated)
- Primary completion1 Sep 2023 (estimated)
- Study completion1 Sep 2023 (estimated)
Why it stopped: Trial withdrawn based on portfolio prioritization; oral ATRi M1774 in combination with niraparib is under investigation in DDRiver Solid Tumor 301
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Solid TumorStudies of the same condition, open and under way.
- More trials run by EMD Serono Research & Development Institute, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04655183
- Sponsor's protocol ID
- MS201922_0010
- Status last verified
- Jun 2021
- First submitted
- 27 Nov 2020
- Last updated
- 30 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04655183
- Acronym / sponsor ID
- MS201922_0010
- Conditions
- Advanced Solid Tumor, Breast Cancer
- Keywords
- M4344, MSC2580591A, VX-803, VRT 1228692, ATR inhibitor, Advanced Solid Tumor, Breast Cancer, Niraparib
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Trial withdrawn based on portfolio prioritization; oral ATRi M1774 in combination with niraparib is under investigation in DDRiver Solid Tumor 301
- Enrolment
- 0 participants (actual)
- Lead sponsor
- EMD Serono Research & Development Institute, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 1 Dec 2020 (estimated)
- Primary completion
- 1 Sep 2023 (estimated)
- Study completion
- 1 Sep 2023 (estimated)
- First posted
- 7 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Part 1A (Dose escalation): Niraparib plus M4344 once daily | Experimental | Drug: Niraparib, Drug: M4344Participants 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. |
| Part 1B (Dose escalation): Niraparib plus M4344 once daily | Experimental | Drug: M4344, Drug: NiraparibParticipants 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. |
| Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344 | Experimental | Drug: Niraparib, Drug: M4344Participants 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. |
| Part 3 (Dose expansion): PARPi-naive, Niraparib | Experimental | Drug: NiraparibParticipants 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. |
| Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344 | Experimental | Drug: Niraparib, Drug: M4344Participants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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:
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NiraparibNiraparib will be administered orally, once daily. | Drug | Part 1A (Dose escalation): Niraparib plus M4344 once daily |
| M4344Also: MSC2580591A, VRT 1228692, VX-803M4344 will be administered once daily or on an intermittent schedule in combination with niraparib. | Drug | Part 1A (Dose escalation): Niraparib plus M4344 once daily |
| NiraparibNiraparib will be administered orally once daily at the RDE as determined in Part 1 of this study. | Drug | Part 2 (Dose expansion): PARPi resistant, Niraparib plus M4344, Part 3 (Dose expansion): PARPi-naive, Niraparib plus M4344 |
| M4344Also: MSC2580591A, VRT 1228692, VX-803M4344 will be administered at a dose and schedule that was determined as RDE in Part 1A in combination with niraparib. | Drug | 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 plus M4344 |
| NiraparibNiraparib will be administered orally, once daily. Dose of niraparib will be escalated beyond the dose in Part 1A. | Drug | Part 1B (Dose escalation): Niraparib plus M4344 once daily |
| NiraparibNiraparib will be administered as single agent at the approved dose. | Drug | Part 3 (Dose expansion): PARPi-naive, Niraparib |
Primary outcome
Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: From Baseline until disease progression or death (assessed up to approximately 1 years)
28 secondary outcomes
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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)
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)
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)
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
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2021.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- US Medical Information website, Medical ResourcesLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Niraparib and M4344 in people with Advanced Solid Tumor and Breast Cancer, run by EMD Serono Research & Development Institute, Inc..
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 30 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part 1 A and B: Number of Participants with Dose Limiting Toxicities (DLTs) (time frame: Day 1 up to Day 28). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jun 2021.