A Study of DES-1357 in People With Deficient Mismatch Repair (dMMR)/Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer (mCRC)

Prior treatment

• Cardiovascular and/or cerebrovascular event in the prior 6 months before screening.
• Has received prior treatment with a Werner Syndrome Helicase (WRN) inhibitor.
• Ongoing toxicities from prior anti-cancer therapy that have not resolved to baseline or grade \<=1 (according to NCI-CTCAE version 6.0), except for alopecia and endocrinopathies that are stable under medication.

Other illness

• Symptomatic or clinically significant bowel obstruction, perforation, or high risk for obstruction as determined by the investigator.
• Hypersensitivity to any component of DES-1357.
• Has an active infection.
• Uncontrolled diabetes as determined by the investigator.
• Has been diagnosed with Werner Syndrome.

Lab values

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than (\>) 470 milliseconds (msec) based on triplicate 12-lead ECGs obtained at screening.
• Has known Human Immunodeficiency Virus (HIV) infection that is not under control. All of these criteria are required: undetectable viral RNA, CD4+ counts/levels \>=350, no history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic infection within the past 12 months, and clinically stable for at least 3 months on the same anti-HIV medications.
• Has active or uncontrolled hepatitis B or C infection. Participants are eligible if they:
  • Have been curatively treated for hepatitis C virus infection as demonstrated clinically and by viral serologies
  • For hepatitis B, if the participant has a positive hepatitis B surface antigen result, viral load must be below 2000 international units per milliliter (IU/mL) in the absence of antiviral therapy for the last 12 weeks, and AST/ALT \<=3\*ULN

Other

• Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in this study:
• 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.
• Primary Central Nervous System (CNS) tumor/CNS metastasis.
• Is pregnant or breastfeeding, is planning to become pregnant during the study.
• Is planning to donate/bank or retrieve eggs (ova, oocytes) or donate sperm during the study.

• Individuals must meet all of the following criteria to be included in the study:
• 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)
• Measurable disease according to RECIST version 1.1.
• Adequate organ function:
  • Absolute neutrophil count \>=1,500 cells per/μL
  • Platelets \>=100,000 cells/μL
  • Hemoglobin \>=9 grams per deciliter (g/dL)
  • Total bilirubin less than or equal to (\<=) 1.5\*the Upper Limit of Normal (ULN) (\<=3\*ULN if attributable to known Gilbert's syndrome)
  • Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) \<=5\*ULN if liver metastasis present; if liver metastasis is not present, then AST/ALT \<=3\*ULN.
• Measured creatinine clearance \>=60 milliliter per minute (mL/min) per Cockcroft-Gault formula.
• Prothrombin time (PT) or international normalized ratio and Partial Thromboplastin Time (PTT) \<=1.5\*ULN, unless receiving anti-coagulant therapy; Note: activated PTT can be used instead of PTT if it is the site's standard practice.
• Have agreed to tissue sampling (biopsy \[if available\], baseline archival tissue, and/or fresh frozen tissue \[if available\]).
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• An estimated life expectancy of at least 3 months based on investigator judgment.
• Women of childbearing potential (WOCBP) and men must agree to use 2 highly effective methods of contraception or practice abstinence from 4 weeks before the first dose of DES-1357, throughout the study, and for 6 months after the last dose of DES-1357; men must refrain from donating or banking sperm during the same period.
• Negative serum pregnancy test result at screening and on Cycle 1 Day 1 for WOCBP.
• Female participants who are not WOCBP should meet at least 1 of the following criteria:
  • have undergone a documented hysterectomy, bilateral oophorectomy and/or bilateral salpingectomy; have medically confirmed ovarian failure, or achieved postmenopausal status (defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, or have a serum follicle-stimulating hormone level within the laboratory's reference range for postmenopausal women).