Clinical Trial - NCT02278250

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

Recruiting

Sponsor: EMD Serono Research & Development Institute, Inc.

Collaborators: Merck KGaA, Darmstadt, Germany

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT02278250

Protocol Info

Short Description: Phase 1 VX-803 +/- Cytotoxic Chemotherapy in Solid Tumors
Long Description: An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-803 as a Single Agent and in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors
MGH Status: Open
Sponsor: Vertex
Disease Program: Phase I

Next Steps


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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, and cisplatin to determine the safety and maximum tolerated dose.
Condition Title Intervention Phase
Solid Tumor Advanced Solid Tumor M4344 Carboplatin Phase 1
Study Type Interventional
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

Primary Outcome Measures

Parts A, A2, B1, C1, C2, C3: Number of Participants with Treatment Emergent Adverse Events and Serious Adverse Events [Time Frame: From baseline until 14 Days after discontinuation of study treatment (assessed up to 6 years)] [Designated as safety issue: ]

Parts A, A2, B1, C1, C2, C3: Number of Participants with Clinically Significant Changes in Clinical Laboratory Values (Serum Chemistry and Hematology), Vital Signs, and Electrocardiogram (ECG) Assessments [Time Frame: From baseline until 14 Days after discontinuation of study treatment (assessed up to 6 years)] [Designated as safety issue: ]

Part A, A2: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 (RP2D) of Single-Agent M4344 Administered BIW or BID or Once Daily [Time Frame: Evaluation for dose-limiting toxicity will be during Cycle 1 (each cycle is of 21 days) for each participant] [Designated as safety issue: ]

Part B1: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 (RP2D) of M4344 Administered in Combination with Carboplatin [Time Frame: Evaluation for dose-limiting toxicity will be during Cycle 1 (each cycle is of 21 days) for each participant] [Designated as safety issue: ]

Part C1, C2, C3: Proportion of Participants With Objective Response according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Assessed by the Investigator [Time Frame: Baseline until disease progression or start of new anti-cancer treatment line (approximately up to 6 years)] [Designated as safety issue: ]


Secondary Outcome Measures

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

Part A2: 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)] [Designated as safety issue: ]

Part A2: 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)] [Designated as safety issue: ]

Part A2: 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)] [Designated as safety issue: ]

Parts A, A2, 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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

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)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Part C1, C2, C3: Progression Free Survival (PFS) as Evaluated by RECIST Version 1.1 [Time Frame: Baseline until tumor progression (approximately up to 6 years)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Part C1, C2, C3: 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)] [Designated as safety issue: ]

Time-Matched Change from Baseline in Plasma PK Concentrations [Time Frame: Pre-dose on Day 1 till safety follow-up (approximately up to 6 years)] [Designated as safety issue: ]

Time-Matched Change from Baseline in Digital Electrocardiogram (ECG) Measures [Time Frame: Pre-dose on Day 1 till safety follow-up (approximately up to 6 years)] [Designated as safety issue: ]

Estimated Enrollment: 85
Study Start Date: January 2015
Estimated Study Completion Date: June 2020
Estimated Primary Completion Date: June 2020
Arms Assigned Interventions

Experimental:Part A: M4344 BIW

Dose escalation of M4344 administered BIW as a single agent.

Experimental:Part A2: M4344 BID or once daily

Dose escalation of M4344 administered BID or once daily as a single agent.
Drug:M4344
Dose escalation of M4344 administered as a single agent.

Experimental:Part B1: M4344 + Carboplatin

Dose escalation of M4344 in combination with carboplatin.
Drug:Carboplatin
Carboplatin will be administered in combination with escalated dose of M4344.

Experimental:Part C1: M4344

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.

Experimental:Part C2: M4344

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.

Experimental:Part C3: M4344

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

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

  • Part A and A2: 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.
  • Parts C1, C2, and C3: 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: loss-of-function mutations in the gene ARID1A - C2: loss-of-function mutations in the genes ATRX and/or DAXX - C3: loss-of-function mutation in the gene ataxia telangiectasia mutated (ATM) - This mandatory biomarker assessment must be conducted during prescreening 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 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

a. Part B1: Any known history of Grade 4 thrombocytopenia with any prior chemotherapy regimen (not applicable for Parts C1, C2, and C3)

  • 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT02278250

Locations

  • United States, California
    • City Of Hope National Medical Center Duarte, California, United States, 91010
  • United States, Massachusetts
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02114
  • United States, Michigan
    • University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109
  • United States, Missouri
    • Washington University in St. Louis Saint Louis, Missouri, United States, 63110
  • United States, New Jersey
    • Rutgers Cancer Institute of New Jersey New Brunswick, New Jersey, United States, 08903
  • United States, Tennessee
    • Tennessee Oncology Nashville, Tennessee, United States, 37203
    • Vanderbilt University Medical Center Nashville, Tennessee, United States, 37232
  • United States, Wisconsin
    • Froedtert & The Medical College of Wisconsin Milwaukee, Wisconsin, United States, 53226
  • Netherlands,
    • Erasmus Medisch Centrum Rotterdam, , Netherlands, 3075 EA
  • Spain,
    • Hospital Universitari Vall d'Hebron Barcelona, , Spain, 08035
    • Hospital Clinic i Provincial de Barcelona Barcelona, , Spain, 08036
    • START Madrid. Fundacion Jimenez Diaz Madrid, , Spain, 28040
    • Hospital Clinico Universitario de Valencia Valencia, , Spain, 46010
  • United Kingdom, Greater London
    • Sarah Cannon Research Institute UK London, Greater London, United Kingdom, W1G 6AD
  • United Kingdom, Surrey
    • Royal Marsden Hospital Sutton, Surrey, United Kingdom,

Sponsors and Collaborators

EMD Serono Research & Development Institute, Inc.

Merck KGaA, Darmstadt, Germany

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT02278250
Other Study ID Numbers: VX14-803-001
Study First Received:
Last Updated:
Health Authority:

Keywords provided by EMD Serono:

VX14-803-001

VX-803

M4344

Advanced Solid Tumor

Cytotoxic Chemotherapy

Gemcitabine

Cisplatin

Carboplatin

Additional relevant MeSH terms:

Neoplasms

Carboplatin

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on April 09, 2020