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

NCT ID: NCT02278250

Last Updated: 2023-03-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 97 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-26
• Study Completion Date: 2021-09-24

Brief Summary

The purpose of this study was 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.

Conditions

Solid Tumor; Advanced Solid Tumor

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A: M4344 10 mg BIW

Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 10 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 20 mg BIW

Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 20 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 40 mg BIW

Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 40 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 80 mg BIW

Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 80 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 160 mg BIW

Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 160 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 300 mg BIW

Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 300 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 450 mg BIW

Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 450 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 700 mg BIW

Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 700 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 1050 mg BIW

Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 1050 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A: M4344 1200 mg BIW

Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 1200 mg BIW

Intervention Type: DRUG

Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A2: M4344 100 mg BID

Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 100 mg BID

Intervention Type: DRUG

Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A2: M4344 150 mg QD

Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 150 mg QD

Intervention Type: DRUG

Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A2: M4344 250 mg QD

Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 250 mg QD

Intervention Type: DRUG

Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part A2: M4344 350 mg QD

Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 350 mg QD

Intervention Type: DRUG

Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part B1: M4344 350 mg + Carboplatin

Participants received M4344 at a dose of 350 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of Area under the concentration versus time curve 5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 350 mg QD

Intervention Type: DRUG

Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Carboplatin

Intervention Type: DRUG

Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part B1: M4344 400 mg + Carboplatin

Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 400 mg

Intervention Type: DRUG

Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Carboplatin

Intervention Type: DRUG

Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part B1: M4344 500 mg + Carboplatin

Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 in combination with intravenous infusion of Carboplatin at a dose of AUC5 on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 500 mg

Intervention Type: DRUG

Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Carboplatin

Intervention Type: DRUG

Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Part C: M4344 250 mg QD

Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Group Type: EXPERIMENTAL

M4344 250 mg QD

Intervention Type: DRUG

Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Interventions

M4344 10 mg BIW

Participants received M4344 at a dose of 10 milligrams (mg) orally twice weekly (BIW) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 20 mg BIW

Participants received M4344 at a dose of 20 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 40 mg BIW

Participants received M4344 at a dose of 40 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 80 mg BIW

Participants received M4344 at a dose of 80 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 160 mg BIW

Participants received M4344 at a dose of 160 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 300 mg BIW

Participants received M4344 at a dose of 300 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 450 mg BIW

Participants received M4344 at a dose of 450 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 700 mg BIW

Participants received M4344 at a dose of 700 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 1050 mg BIW

Participants received M4344 at a dose of 1050 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 1200 mg BIW

Participants received M4344 at a dose of 1200 mg orally BIW until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 100 mg BID

Participants received M4344 at a dose of 100 mg orally twice daily (BID) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 150 mg QD

Participants received M4344 at a dose of 150 mg orally once daily (QD) until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 250 mg QD

Participants received M4344 at a dose of 250 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 350 mg QD

Participants received M4344 at a dose of 350 mg orally QD until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 400 mg

Participants received M4344 at a dose of 400 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

M4344 500 mg

Participants received M4344 at a dose of 500 mg orally on Day 2 and Day 9 until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

Carboplatin

Participants received intravenous infusion of Carboplatin at a dose of Area Under Curve5 (AUC5) on Day 1 of 21-day cycle until disease progression, death, unacceptable toxicity, new anticancer treatment was started, or study withdrawal.

Intervention Type: DRUG

Other Intervention Names

VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803; VX-803

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

EMD Serono Research & Development Institute, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Responsible

Role: STUDY_DIRECTOR

EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Washington University in St. Louis

St Louis, Missouri, United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Memorial Sloan-Kettering Cancer Center (MSKCC)

New York, New York, United States

Tennessee Oncology

Nashville, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Froedtert & The Medical College of Wisconsin

Wauwatosa, Wisconsin, United States

Erasmus Medisch Centrum

Rotterdam, , Netherlands

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

Sarah Cannon Research Institute UK

London, Greater London, United Kingdom

Royal Marsden Hospital

Sutton, Surrey, United Kingdom

Countries

United States; Netherlands; Spain; United Kingdom

References

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.

Reference Type: RESULT

PMID: 34045232 (View on PubMed)

Burris HA, Berlin J, Arkenau T, Cote GM, Lolkema MP, Ferrer-Playan J, Kalapur A, Bolleddula J, Locatelli G, Goddemeier T, Gounaris I, de Bono J. A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours. Br J Cancer. 2024 Apr;130(7):1131-1140. doi: 10.1038/s41416-023-02436-2. Epub 2024 Jan 29.

Reference Type: DERIVED

PMID: 38287179 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS201922-0001

Trial Awareness and Transparency website

https://medical.emdserono.com/en_US/home.html

US Medical Information website, Medical Resources

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217341&amp;parentIdentifier=MS201922-0001&amp;attachmentIdentifier=ea28386b-b325-41e6-9020-84aea7f8b7dc&amp;fileName=20220504_MS201922-0001_CT.gov_SAP_Redaction.pdf&amp;versionIdentifier=

Related Info

Other Identifiers

VX14-803-001

Identifier Type: OTHER

Identifier Source: secondary_id

2014-003838-86

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MS201922-0001

Identifier Type: -

Identifier Source: org_study_id