This study is conducted sequentially in 3 parts. The primary objective for Part 1 is to determine the maximum tolerated dose of DES-1357 in participants with confirmed dMMR/MSI-H colorectal cancer (CRC). The primary objective for Part 2 is to assess the chronic tolerability and to identify the recommended Phase 2 dose (RP2D), to evaluate preliminary antitumor activity of the selected dose level of DES-1357, and to assess the pharmacokinetics (PK) and pharmacodynamics of DES-1357. The primary objective for Part 3 is to evaluate antitumor activity of the selected dose level of DES-1357.
Have read, understood, and signed the Informed Consent Form (ICF).
Male or female aged greater than or equal to (>=) 18 years at the time of signing the ICF.
Histologically or cytologically confirmed carcinoma of the colon and/or rectum deemed unresectable and/or with evidence of metastases, that has been cytologically or genetically confirmed as dMMR, and/or MSI-H.
Demonstrated disease progression and/or intolerability to prior treatment with any of the following: pembrolizumab, nivolumab (±ipilimumab), dostarlimab, chemotherapy (ie, FOLFOX, FOLFIRI, CAPEOX, or FOLFOXIRI [±bevacizumab]), encorafenib/cetuximab, trastuzumab-based combinations, KRAS inhibitor/EGFR inhibitor, regorafenib, or TAS-102 (±bevacizumab)
Cytologically and/or genetically confirmed proficient mismatch repair (pMMR) and/or MSS.
Evidence of severe gastrointestinal malabsorption as determined by the investigator.
History or presence of dysphagia.
Symptomatic or clinically significant bowel obstruction, perforation, or high risk for obstruction as determined by the investigator.
Sequential
DES-1357
DrugDES-1357 oral capsules.
Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
A DLT is a toxicity that occurs during cycle 1 that meets the protocol-defined DLT criteria and is graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 6.0
Part 2: Incidence and Severity of Treatment- related Treatment Emergent Adverse Events (TEAEs) Through at least 3 Cycles of DES-1357
A TEAE is defined as an AE with onset dates on or after the start of the study treatment or AEs that started prior to the start of the study treatment but worsened in severity after start of the study treatment.
Part 2: Best Overall Response (BOR)
Best overall response is defined as the single best patient level response category (Complete Response \[CR\], Partial Response \[PR\], Stable Disease \[SD\], Progressive disease \[PD\], or Not Evaluable \[NE\]) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Part 2: Maximum Observed Concentration (Cmax) of DES-1357
Part 1: Number of Participants With Treatment-related Adverse Events (AEs) Including TEAEs and Serious AEs
Participants with treatment related AEs, TEAEs and SAEs will be reported, plus treatment-related delays, dose reductions, and/or treatment discontinuations.
Part 2: ORR According to RECIST Version 1.1
ORR is defined as the percentage of participants with a confirmed objective response (CR or PR) as determined per RECIST Version 1.1.
Part 2 and Part 3: Disease Control Rate (DCR) According to RECIST Version 1.1
DCR is defined as the percentage of participants who achieve best response of CR, PR, or SD per RECIST version 1.1.
Part 3: Duration of Response (DOR) According to RECIST Version 1.1
DOR is defined as the time from the first objective response (CR or PR) to the first documented PD per RECIST version 1.1 or death.
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