ONC201 (dordaviprone) for safety and prevention of colorectal polyps in high-risk adults.

Phase I Trial of ONC201 for Chemoprevention of Colorectal Cancer

This trial tests whether different doses of ONC201 (dordaviprone) are safe and can help prevent new colorectal polyps in adults with familial adenomatous polyposis or a history of multiple adenomas.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Cancer Institute (NCI) (NIH)
• Drugs / interventions: chemotherapy
• Locations: 5 sites (Ann Arbor, Michigan and 4 other locations)
• Trial ID: NCT05630794 on ClinicalTrials.gov

What this trial studies

This Phase 1, dose-escalation trial gives oral ONC201 (dordaviprone) to adults at high risk for recurrent colorectal adenomas (FAP or multiple prior polyps) to determine safety and tolerability. Participants undergo standard-of-care colonoscopy with biopsies and blood sampling before and after treatment to measure tissue and serum biomarkers including TRAIL, cytokines, proliferation and apoptosis markers, and immune cell infiltration. Secondary objectives identify doses that increase TRAIL expression in adenomas and normal mucosa, and exploratory work includes organoid growth and correlations between biomarker changes and any toxicity. The study is being conducted at three U.S. academic centers.

Who should consider this trial

Good fit: Adults (>=18) who are at high risk for recurrent colorectal adenomas—defined by a diagnosis of familial adenomatous polyposis or recent colonoscopy showing >5 small adenomas or >=3 adenomas with at least one >=10 mm—who have good organ function, ECOG <=1, and are scheduled for a standard colonoscopy are ideal candidates.

Not a fit: Patients with other hereditary syndromes such as HNPCC, active advanced colorectal cancer, significant organ dysfunction, inability to undergo colonoscopy/biopsy, or who are not in the high-risk categories are unlikely to benefit from this prevention-focused study.

Why it matters

Potential benefit: If successful, ONC201 could become a new preventive option to reduce adenoma formation and lower colorectal cancer risk in high-risk patients.

How similar studies have performed: ONC201 has produced tumor-killing effects in preclinical models and shown activity in early oncology trials, but using it for prevention in otherwise healthy high-risk individuals is a novel approach.

Eligibility criteria

Inclusion Criteria:

* Be identified as high risk for recurrent colorectal adenomas, as defined by:

  * A diagnosis of FAP AND/OR
  * Findings of either \> 5 small (less than 1 cm) adenomas OR \>= 3 with at least one \>= 10 mm on most recent colonoscopy performed in the past 5 years
* Be \>= 18 years of age on day of signing informed consent
* Have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
* Leukocytes \>= 3,000/microliter
* Absolute neutrophil count \>= 1,000/microliter
* Platelets \>= 100,000/microliter
* Total bilirubin within normal institutional limits
* Aspartate aminotransferase (AST) (serum (glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (\[SGPT\]) =\< 1.5 x institutional upper limit of normal
* Creatinine =\< 1.5 x institutional upper limit of normal
* Participant is due to undergo a standard of care lower gastrointestinal (GI) colonoscopy for detection and removal of colorectal polyps. On this colonoscopy, participant is required to have:

  * Two (2) adenomatous polyps of at least five (5) mm in size
  * At least one (1) polyp within reach of a flexible sigmoidoscope (which will be retained in the colon or rectum and marked)
  * In addition to polypectomy, six (6) biopsies of normal colonic mucosa \>= 1 cm from a collected polyp will also be collected
* Willing to undergo a second, research intent endoscopic procedure (either sigmoidoscopy or colonoscopy), approximately 12 weeks after initiating ONC201 treatment
* Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
* Life expectancy of at least 5-years
* ONC201 is an imipridone agent with the potential for teratogenic or abortifacient effects. For this reason and because imipridones potential teratogenic effects are unknown, men and women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for four weeks after study treatment is completed. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should STOP the study medication and inform her study physician immediately
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Prior history of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome
* Participants may not be currently receiving any other investigational agents or have received any investigational agents within the past four weeks
* Prior history of invasive colorectal cancer
* Prior invasive active neoplasm that is progressing or requires active treatment within 3 years from registration. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Participants with a history of prior invasive neoplasm diagnosed and treated greater than 3 years form registration may be considered with consultation of the primary investigator
* Prior history of exposure to cytotoxic chemotherapy or ONC201
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant and women who are nursing are excluded from this study because ONC201 is an imipridone agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201
* Concomitant use of strong/moderate CYP3A4/5 inducers/inhibitors. These agents must be discontinued at least 72-hours prior to beginning ONC201
* Any of the following cardiac criteria:

  * Prolongation of corrected QT (QTc) interval (QTc interval \> 480 milliseconds, preferably using Frederica's QT correction formula), confirmed on electrocardiogram (ECG) tracings performed during screening
  * A history of Torsades de pointes, heart failure, or family history of prolonged QT Syndrome
* Concomitant use of drugs that are known to prolong QT and have a known risk of torsade de pointes (TdP) unless they are willing to stop these medications and possibly change to an alternative non-excluded medication to treat the same condition at least 72 hours prior to beginning ONC201

Where this trial is running

Ann Arbor, Michigan and 4 other locations

• University of Michigan Rogel Cancer Center — Ann Arbor, Michigan, United States (Recruiting)
• Washington University School of Medicine — St Louis, Missouri, United States (Recruiting)
• Cleveland Clinic Foundation — Cleveland, Ohio, United States (Recruiting)
• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (Recruiting)
• Rhode Island Hospital — Providence, Rhode Island, United States (Not_yet_recruiting)

Study contacts

• Principal investigator: Alexander G Raufi, MD — Brown University Health/ Rhode Island Hospital

Conditions Colorectal Adenomatous Polyp; Colorectal Carcinoma; Familial Adenomatous Polyposis; Multiple Adenomatous Polyps