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

Merck KGaA (EMD Serono)

Status and phase: Completed; Phase 1

Conditions: Solid Tumor; Advanced Solid Tumor

Treatments: Drug: M4344 10 mg BIW; Drug: M4344 20 mg BIW; Drug: M4344 80 mg BIW; Drug: M4344 400 mg; Drug: M4344 450 mg BIW; Drug: M4344 150 mg QD; Drug: M4344 700 mg BIW; Drug: M4344 160 mg BIW; Drug: M4344 40 mg BIW; Drug: M4344 250 mg QD; Drug: M4344 1050 mg BIW; Drug: M4344 1200 mg BIW; Drug: M4344 300 mg BIW; Drug: M4344 100 mg BID; Drug: Carboplatin; Drug: M4344 350 mg QD; Drug: M4344 500 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT02278250

VX14-803-001 (Other Identifier)

MS201922-0001

2014-003838-86 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 97 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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97 participants in 18 patient groups

Part A: M4344 10 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 10 mg BIW

Part A: M4344 20 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 20 mg BIW

Part A: M4344 40 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 40 mg BIW

Part A: M4344 80 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 80 mg BIW

Part A: M4344 160 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 160 mg BIW

Part A: M4344 300 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 300 mg BIW

Part A: M4344 450 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 450 mg BIW

Part A: M4344 700 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 700 mg BIW

Part A: M4344 1050 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 1050 mg BIW

Part A: M4344 1200 mg BIW

Experimental group

Description:

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.

Treatment:

Drug: M4344 1200 mg BIW

Part A2: M4344 100 mg BID

Experimental group

Description:

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.

Treatment:

Drug: M4344 100 mg BID

Part A2: M4344 150 mg QD

Experimental group

Description:

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.

Treatment:

Drug: M4344 150 mg QD

Part A2: M4344 250 mg QD

Experimental group

Description:

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.

Treatment:

Drug: M4344 250 mg QD

Part A2: M4344 350 mg QD

Experimental group

Description:

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.

Treatment:

Drug: M4344 350 mg QD

Part B1: M4344 350 mg + Carboplatin

Experimental group

Description:

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.

Treatment:

Drug: M4344 350 mg QD

Drug: Carboplatin

Part B1: M4344 400 mg + Carboplatin

Experimental group

Description:

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.

Treatment:

Drug: Carboplatin

Drug: M4344 400 mg

Part B1: M4344 500 mg + Carboplatin

Experimental group

Description:

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.

Treatment:

Drug: M4344 500 mg

Drug: Carboplatin

Part C: M4344 250 mg QD

Experimental group

Description:

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.

Treatment:

Drug: M4344 250 mg QD