Description:
The purpose of this study is to evaluate the safety and tolerability of multiple ascending
doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily
dose schedule in participants with advanced solid tumors. This investigation is a three part
study examining M4344 alone and in combination with carboplatin to determine the safety and
maximum tolerated dose.
Title
- Brief Title: First in Human Study of M4344 in Participants With Advanced Solid Tumors
- Official Title: An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M4344 (Formerly VX-803) as a Single Agent and in Combination With Cytotoxic Chemotherapy in Participants With Advanced Solid Tumors
Clinical Trial IDs
- ORG STUDY ID:
MS201922-0001
- SECONDARY ID:
VX14-803-001
- SECONDARY ID:
2014-003838-86
- NCT ID:
NCT02278250
Conditions
- Solid Tumor
- Advanced Solid Tumor
Interventions
Drug | Synonyms | Arms |
---|
M4344 | VX-803 | Part A2: M4344 BID or once daily |
Carboplatin | | Part B1: M4344 + Carboplatin |
M4344 | VX-803 | Part A3: M4344 Drug holiday schedule |
M4344 | VX-803 | Part C4: M4344 Drug holiday schedule |
Purpose
The purpose of this study is to evaluate the safety and tolerability of multiple ascending
doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily
dose schedule in participants with advanced solid tumors. This investigation is a three part
study examining M4344 alone and in combination with carboplatin to determine the safety and
maximum tolerated dose.
Trial Arms
Name | Type | Description | Interventions |
---|
Part A: M4344 BIW | Experimental | Dose escalation of M4344 administered BIW as a single agent. | |
Part A2: M4344 BID or once daily | Experimental | Dose escalation of M4344 administered BID or once daily as a single agent. | |
Part A3: M4344 Drug holiday schedule | Experimental | Dose escalation of M4344 administered in a drug holiday schedule (different schedule with either 3 days once daily (QD) or BID followed by 4 days of pausing, 5 days of QD or BID followed by 2 days of pausing, 7 days of QD or BID dosing followed by 7 days of pausing or 14 days of QD or BID dosing followed by 7 days of pausing may be explored. Other dosing holiday schedules may be explored if agreed by the sponsor and Investigators). | |
Part B1: M4344 + Carboplatin | Experimental | Dose escalation of M4344 in combination with carboplatin. | |
Part C1: M4344 BID or once daily | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ARID1A. | |
Part C2: M4344 BID or once daily | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the genes ATRX and/or DAXX. | |
Part C3: M4344 BID or once daily | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM). | |
Part C4: M4344 Drug holiday schedule | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ARID1A. | |
Part C5: M4344 Drug holiday schedule | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the genes ATRX and/or DAXX. | |
Part C6: M4344 Drug holiday schedule | Experimental | An expanded cohort study to confirm the potential effect of M4344 in participants whose tumor carry a loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM). | |
Eligibility Criteria
Inclusion Criteria:
- Part A, A2 and A3: Participants with one histologically or cytologically confirmed
malignant advanced solid tumor, for which no standard therapy is available which may
convey clinical benefit
- Part B1: Participants with one histologically or cytologically confirmed malignant
advanced solid tumor, for which no standard therapy is available which may convey
clinical benefit and/or participants must have progressed after at least 1 prior
chemotherapy regimen in the metastatic setting, and for which carboplatin would be
considered standard of care.
- Part C: Participants with 1 histologically or cytologically confirmed malignant
advanced solid tumors for which no recommended standard therapy is available (that is,
participants who have exhausted all standard of care options according to National
Comprehensive Cancer Network [NCCN] Guidance) which may convey clinical benefit, and
whose tumor has at least 1 of the following biomarkers as determined by a central
trial assay or by an assay with appropriate regulatory status: - C1 or C4:
loss-of-function mutations in the gene ARID1A - C2 or C5: loss-of-function mutations
in the genes ATRX and/or DAXX - C3 or C6: loss-of-function mutation in the gene ataxia
telangiectasia mutated (ATM) - This mandatory biomarker assessment must be conducted
during screening on a fresh tumor biopsy (or a biopsy obtained after the end of the
previous treatment regimen). If this is not possible for medical reason(s), available
archival tumor material can be used (historical data should not be used to confirm
biomarker status)
- Measurable disease either according to RECIST criteria (Version 1.1)
- WHO performance status of 0 or 1
- Life expectancy of greater than or equal to (>=)12 weeks
- Hematological and biochemical indices within acceptable ranges at Screening
- Other protocol defined inclusion criteria could apply
Exclusion Criteria:
- Radiotherapy, unless brief course for palliative therapy, endocrine therapy,
target-specific therapy, immunotherapy, or chemotherapy during the 4 weeks (6 weeks
for nitrosoureas and Mitomycin-C, and 4 weeks for investigational medicinal products)
or 4 drug half-lives before first dose of study drug, whichever is greater
- Part B1: More than 6 cycles of prior therapy with carboplatin
- Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia
or certain Grade 1 toxicities, which in the opinion of the investigator should not
exclude the participant
- Part B1: Any known history of Grade 4 thrombocytopenia with any prior chemotherapy
regimen
- Brain metastases unless asymptomatic, treated, stable, and not requiring steroids for
at least 4 weeks before first dose of study drug
- Female participants who are already pregnant or lactating, or plan to become pregnant
within 6 months of the last dose of study drug are excluded. Female participants of
childbearing potential must adhere to contraception guidelines. Female participants
will be considered to be of nonchildbearing potential if they have undergone surgical
hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years with
a screening serum follicle-stimulating hormone (FSH) level within the laboratory's
reference range for postmenopausal females.
- Male participants with partners of childbearing potential must agree to adhere to
contraception guidelines. Men with pregnant or lactating partners or partners who plan
to become pregnant during the study or within 6 months of the last dose of study drug
are excluded.
- Major surgery less than or equal to (<=) 4 weeks before first dose of study drug or
incomplete recovery from a prior major surgical procedure
- Serious co-morbid medical conditions, including clinically-significant cardiac disease
- Other protocol defined exclusion criteria could apply
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Parts A, A2, A3, B1, C1, C2, C3, C4, C5 and C6: Number of Participants with Treatment Emergent Adverse Events and Serious Adverse Events |
Time Frame: | Part A, A2, A3, B1: From baseline until 14 days after discontinuation of study treatment (assessed up to approximately 6 years); Part C1, C2, C3, C4, C5, C6: up to 30 days after discontinuation of study treatment (assessed up to approximately 6 years) |
Safety Issue: | |
Description: | Number of participants with clinically significant changes in clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments were assessed. |
Secondary Outcome Measures
Measure: | Part A: Area Under the Concentration Curve (AUC) of M4344 |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part A: Maximum Observed Plasma Concentration (Cmax) of M4344 |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part A: Time to Reach Maximum Plasma Concentration (tmax) of M4344 |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part A2 and A3: Area Under the Concentration Curve (AUC) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part A2 and A3: Maximum Observed Plasma Concentration (Cmax) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part A2 and A3: Time to Reach Maximum Plasma Concentration (tmax) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 1, Day 15 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Parts A, A2, A3 and B1: Objective Tumor Response (OR) and Disease Stabilization (SD) as Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 |
Time Frame: | Every 2 Cycles (each cycle is of 21 days) until tumor progression (approximately up to 6 years) |
Safety Issue: | |
Description: | |
Measure: | Part B1: Area Under the Concentration Curve (AUC) of M4344 |
Time Frame: | Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part B1: Maximum Observed Plasma Concentration (Cmax) of M4344 |
Time Frame: | Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part B1: Time to Reach Maximum Plasma Concentration (tmax) of M4344 |
Time Frame: | Cycle 1, Day 2 up to Cycle 1, Day 9 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) as Assessed by Investigator |
Time Frame: | Baseline, until disease progression or start of new anti-cancer treatment line (approximately up to 6 years) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Duration of Response Assessed From Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
Time Frame: | Baseline until PD, death, or last adequate tumor assessment (approximately up to 6 years) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Progression Free Survival (PFS) as Evaluated by RECIST Version 1.1 |
Time Frame: | Baseline until tumor progression (approximately up to 6 years) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Overall Survival (OS) |
Time Frame: | Assessed every 3 months for up to 1 year or more or until study closure, whichever comes first (approximately up to 6 years) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Area Under the Concentration Curve (AUC) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Maximum Observed Plasma Concentration (Cmax) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Measure: | Part C1, C2, C3, C4, C5 and C6: Time to Reach Maximum Plasma Concentration (tmax) of M4344 and Metabolites |
Time Frame: | Cycle 1, Day 1 up to Cycle 12, Day 1 (each cycle is of 21 days) |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | EMD Serono Research & Development Institute, Inc. |
Trial Keywords
- VX14-803-001
- VX-803
- M4344
- Advanced Solid Tumor
- Cytotoxic Chemotherapy
- Carboplatin
Last Updated
July 29, 2021