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An Open Label, Multicenter, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the PARP1 Inhibitor M9466 in Combination with Topoisomerase 1 Inhibitor-based Regimens in Advanced Solid Tumors and Colorectal Cancer

M9466 in Combination with Topoisomerase 1 Inhibitors in Advanced Solid Tumors and Colorectal Cancer

Suzuki Tomoya

Merck Biopharma Co., Ltd.

1-8-1 Shimomeguro, Meguro-ku, Tokyo

MBJ_clinicaltrial_information@merckgroup.com

Contact for Clinical Trial Information

Merck Biopharma Co., Ltd.

1-8-1 Shimomeguro, Meguro-ku, Tokyo

+81-3-6756-0800

MBJ_clinicaltrial_information@merckgroup.com

Recruiting

Nov. 01, 2024

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

-M9466 + Irinotecan Run-in Cohort: Participants with locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator (that is [i.e.] participants who have exhausted all standard of care (SoC) options according to International Guidelines), and who may derive clinical benefit from the combination treatment with M9466 and irinotecan
-M9466 + FOLFIRI + Bevacizumab Dose Finding Cohorts: Participants with documented histopathological diagnosis of locally advanced or metastatic colorectal cancer (CRC), who were intolerant/refractory to or progressed after standard systemic therapies for the advanced/metastatic stage that included: Oxaliplatin and a fluoropyrimidine (administration in the adjuvant setting fulfills this criterion if progression occurred within 12 months of the last dose). Prior use of irinotecan is permitted; Either an anti- epidermal growth factor receptor (anti-EGFR) or an anti- Vascular endothelial growth factor (anti-VEGF) agent (not applicable if oxaliplatin was administered in the adjuvant setting); An immune checkpoint inhibitor for participants with known MSI-H status; Cetuximab and encorafenib +- binimetinib, if locally available, for participants with BRAF V600E mutations. Participants may have received maximally 1 previous regimen for the treatment of metastatic disease (with the exception of participants with MSI-H disease or BRAF positive disease who are allowed to have had up to 2 previous lines of treatment)
-Eastern Cooperative Oncology Group performance status (ECOG PS) less than or equal to (<=) 1
-Other protocol defined inclusion criteria could apply

-Persistence of AEs related to any prior treatments that have not recovered to Grade <= 1 by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) unless AEs are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator (for example [e.g.] neuropathy or alopecia)
-Participant has a history of malignancy within 3 years before the date of enrollment (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, benign prostate neoplasm/hypertrophy, or malignancy that in the opinion of the Investigator, is considered cured with minimal risk of recurrence within 3 years). Participants with history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) are excluded, irrespective of timeframe
-Participant with known polymorphisms in UGT1A1, DPYD or other enzymes known to predict for increased toxicity from irinotecan or 5 fluorouracil (5-FU) should be excluded; if status is unknown testing is not mandated, unless required by local guidance. Participants that discontinued prior 5-FU treatment due to toxicity are also excluded
-Participants with known brain metastases, except if clinically controlled, which is defined as individuals with central nervous system (CNS) tumors that have been treated and are asymptomatic, and who have discontinued steroids (for the treatment of CNS tumors) for > 28 days prior to first dose of study intervention
-Other protocol defined exclusion criteria could apply

Both

Advanced Solid Tumor

Experimental: M9466 + Irinotecan (Run-in Cohort)
Drug: M9466
-M9466 will be administered orally until progressive disease, unacceptable toxicity, death, or end of study.
-Other Names: HRS-1167
Drug: Irinotecan
-Irinotecan will be administered intravenously once every 2 weeks (q2w) until progressive disease, unacceptable toxicity, death, or end of study.

Experimental: M9466 + FOLFIRI (folinic acid, fluorouracil, irinotecan) + Bevacizumab (Dose Finding Cohorts)
Drug: M9466
-M9466 will be administered orally until progressive disease, unacceptable toxicity, death, or end of study.
-Other Names: HRS-1167
Drug: Irinotecan
-Irinotecan will be administered intravenously once every 2 weeks (q2w) until progressive disease, unacceptable toxicity, death, or end of study.

Drug: Folinic acid
-Folinic acid will be administered intravenously q2w as per standard of care.
-Other Names: Calcium folinate Leucovorin
Drug: Fluorouracil (5-FU)
-Fluorouracil will be administered intravenously as per standard of care.
-Other Names: 5-FU
Drug: Bevacizumab
-Bevacizumab will be administered intravenously, q2w until progressive disease, unacceptable toxicity, death, or end of study.

-Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Treatment Related TEAEs
-Number of Participants with Dose Limiting Toxicity (DLT)

+81-3-3542-2511

Oct. 02, 2024

No

USA/Spain/Korea/Australia