First in Human Study of M4344 in Participants With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT02278250
• Recruitment Status: Completed
• First Posted: October 29, 2014
• Last Update Posted: November 2, 2021
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumor; Advanced Solid Tumor	Drug: M4344; Drug: Carboplatin	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 98 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 26, 2015
• Actual Primary Completion Date: June 16, 2021
• Actual Study Completion Date: September 24, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: M4344 BIW; Dose escalation of M4344 administered BIW as a single agent.	Drug: M4344; Dose escalation of M4344 administered as a single agent.; Other Name: VX-803
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.; Other Name: VX-803
Experimental: Part A3: M4344 Drug holiday schedule; 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).	Drug: M4344; 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) applies to A3.; Other Name: VX-803
Experimental: Part B1: M4344 + Carboplatin; Dose escalation of M4344 in combination with carboplatin.	Drug: M4344; Dose escalation of M4344 administered as a single agent.; Other Name: VX-803; Drug: Carboplatin; Carboplatin will be administered in combination with escalated dose of M4344.
Experimental: Part C1: M4344 BID or once daily; 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.	Drug: M4344; Dose escalation of M4344 administered as a single agent.; Other Name: VX-803
Experimental: Part C2: M4344 BID or once daily; 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.	Drug: M4344; Dose escalation of M4344 administered as a single agent.; Other Name: VX-803
Experimental: Part C3: M4344 BID or once daily; 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).	Drug: M4344; Dose escalation of M4344 administered as a single agent.; Other Name: VX-803
Experimental: Part C4: M4344 Drug holiday schedule; 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.	Drug: M4344; M4344 at the Recommended Phase 2 dose (RP2D) from Part A3 in expansion cohorts.; Other Name: VX-803
Experimental: Part C5: M4344 Drug holiday schedule; 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.	Drug: M4344; M4344 at the Recommended Phase 2 dose (RP2D) from Part A3 in expansion cohorts.; Other Name: VX-803
Experimental: Part C6: M4344 Drug holiday schedule; 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).	Drug: M4344; M4344 at the Recommended Phase 2 dose (RP2D) from Part A3 in expansion cohorts.; Other Name: VX-803

Outcome Measures

Primary Outcome Measures :

1. 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) ]
2. Parts A, A2, A3, B1, C1, C2, C3, C4, C5 and C6: Number of Participants with Clinically Significant Changes in Clinical Laboratory Values (Serum Chemistry and Hematology), Vital Signs, and Electrocardiogram (ECG) Assessments [ 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) ]
   Number of participants with clinically significant changes in clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments were assessed.
3. Part A, A2 and A3: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 (RP2D) of Single-Agent M4344 Administered BIW or BID or Once Daily or Drug Holiday Schedule [ Time Frame: Evaluation for dose-limiting toxicity will be during Cycle 1 (each cycle is of 21 days) for each participant ]
4. 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 ]
5. Part C1, C2, C3, C4, C5 and C6: 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) ]

Secondary Outcome Measures :

1. 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) ]
2. 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) ]
3. 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) ]
4. 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) ]
5. 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) ]
6. 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) ]
7. 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) ]
8. 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) ]
9. 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) ]
10. 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) ]
11. 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) ]
12. 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) ]
13. 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) ]
14. 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) ]
15. 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) ]
16. 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) ]
17. 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) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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, 48109-5901

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, 8903

United States, New York

Memorial Sloan-Kettering Cancer Center (MSKCC)

New York, New York, United States, 10065

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

Wauwatosa, Wisconsin, United States, 53226

Netherlands

Erasmus Medisch Centrum

Rotterdam, Netherlands, 3075 EA

Spain

Hospital Clinic de Barcelona

Barcelona, Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain

"Fundacion Jimenez Diaz START Madrid. Oncology Phase I"

Madrid, Spain

START Madrid. Fundacion Jimenez Diaz- Oncologia-Fase I

Madrid, Spain

"Hospital Clinico Universitario de Valencia Servicio de Hematologia y Oncologia Medica"

Valencia, Spain

United Kingdom

Sarah Cannon Research Institute UK

London, Greater London, United Kingdom, W1G 6AD

Royal Marsden Hospital

Sutton, Surrey, United Kingdom

Sponsors and Collaborators

EMD Serono Research & Development Institute, Inc.

Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

More Information

Additional Information:

Trial Awareness and Transparency website 

US Medical Information website, Medical Resources 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jo U, Senatorov IS, Zimmermann A, Saha LK, Murai Y, Kim SH, Rajapakse VN, Elloumi F, Takahashi N, Schultz CW, Thomas A, Zenke FT, Pommier Y. Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents. Mol Cancer Ther. 2021 Aug;20(8):1431-1441. doi: 10.1158/1535-7163.MCT-20-1026. Epub 2021 May 27.

• Responsible Party: EMD Serono Research & Development Institute, Inc.
• ClinicalTrials.gov Identifier: NCT02278250
• Other Study ID Numbers: MS201922-0001; VX14-803-001 ( Other Identifier: Other ); 2014-003838-86 ( EudraCT Number )
• First Posted: October 29, 2014
• Last Update Posted: November 2, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 bit.ly/IPD21

Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):

VX14-803-001; VX-803; M4344; Advanced Solid Tumor; Cytotoxic Chemotherapy; Carboplatin

Additional relevant MeSH terms:

Neoplasms; Carboplatin; Antineoplastic Agents