A Phase I/II Adaptive Study of DES-1357 in Participants With Deficient Mismatch Repair (dMMR) and/or Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer (mCRC)

Study Identifier:
DES-1357-101
CT.gov Identifier:
NCT07807800
EudraCT Identifier:
202652776930
EU Trial (CTIS) Number:
2026-527769-30-00
Study Contact Information:
(210) 593-5651 or [email protected]
Will Be Recruiting

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Study Summary

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.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Bowel (Colorectal)
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: EXPERIMENTAL: Part 1: Dose Escalation
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Drug: Participants will receive DES-1357 orally once daily (QD) in 21-day treatment cycles with a starting dose of 150 milligrams (mg). The planned escalation dose levels are 300 and 600 mg to identify the maximum tolerated dose (MTD) for DES-1357.
Drug: Drug: DES-1357
Drug: DES-1357 oral capsules.
Drug: EXPERIMENTAL: Part 2: Dose Optimization - Dosing Schedule A
Drug: Participants will receive DES-1357 orally QD in Dosing Schedule A. The dosing schedules will be selected based on the escalation ranges of Part 1, to determine the RP2D for expansion in Part 3.
Drug: EXPERIMENTAL: Part 2: Dose Optimization - Dosing Schedule B
Drug: Participants will receive DES-1357 orally QD in Dosing Schedule B. The dosing schedules will be selected based on the escalation ranges of Part 1, to determine the RP2D for expansion in Part 3.
Drug: EXPERIMENTAL: Part 3: Dose Expansion
Drug: Participants will receive DES-1357 orally QD at the RP2D determined in Part 2 to further assess its efficacy and safety.
Study Status
Indicates the current recruitment status or the expanded access status
Will Be Recruiting

Requirements information
Inclusion criteria
  • Individuals must meet all of the following criteria to be included in the study:
  • 1. Have read, understood, and signed the Informed Consent Form (ICF).
  • 2. Male or female aged greater than or equal to (>=) 18 years at the time of signing the ICF.
  • 3. 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.
  • 4. 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)
  • 5. Measurable disease according to RECIST version 1.1.
  • 6. Adequate organ function:
  • 1. Absolute neutrophil count >=1,500 cells per/μL
  • 2. Platelets >=100,000 cells/μL
  • 3. Hemoglobin >=9 grams per deciliter (g/dL)
  • 4. Total bilirubin less than or equal to (<=) 1.5*the Upper Limit of Normal (ULN) (<=3*ULN if attributable to known Gilbert's syndrome)
  • 5. Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) <=5*ULN if liver metastasis present; if liver metastasis is not present, then AST/ALT <=3*ULN.
  • 7. Measured creatinine clearance >=60 milliliter per minute (mL/min) per Cockcroft-Gault formula.
  • 8. 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.
  • 9. Have agreed to tissue sampling (biopsy [if available], baseline archival tissue, and/or fresh frozen tissue [if available]).
  • 10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
  • 11. An estimated life expectancy of at least 3 months based on investigator judgment.
  • 12. 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.
  • 13. Negative serum pregnancy test result at screening and on Cycle 1 Day 1 for WOCBP.
  • 14. 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).
Exclusion criteria
  • Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in this study:
  • 1. Cytologically and/or genetically confirmed proficient mismatch repair (pMMR) and/or MSS.
  • 2. Evidence of severe gastrointestinal malabsorption as determined by the investigator.
  • 3. History or presence of dysphagia.
  • 4. Symptomatic or clinically significant bowel obstruction, perforation, or high risk for obstruction as determined by the investigator.
  • 5. Hypersensitivity to any component of DES-1357.
  • 6. 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.
  • 7. Has an active infection.
  • 8. 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.
  • 9. Has active or uncontrolled hepatitis B or C infection. Participants are eligible if they:
  • 1. Have been curatively treated for hepatitis C virus infection as demonstrated clinically and by viral serologies
  • 2. 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
  • 10. Uncontrolled diabetes as determined by the investigator.
  • 11. Cardiovascular and/or cerebrovascular event in the prior 6 months before screening.
  • 12. Has received prior treatment with a Werner Syndrome Helicase (WRN) inhibitor.
  • 13. Has been diagnosed with Werner Syndrome.
  • 14. Primary Central Nervous System (CNS) tumor/CNS metastasis.
  • 15. 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.
  • 16. Is pregnant or breastfeeding, is planning to become pregnant during the study.
  • 17. Is planning to donate/bank or retrieve eggs (ova, oocytes) or donate sperm during the study.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START New Jersey
East Brunswick, NJ, United States, 08816
Investigator
Neel Belani
Status
Will Be Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)