Testing for Safety and Colorectal Cancer Preventive Effects of ONC201

NCT05630794 | Recruiting Phase 1 DMC FDA Drug

• 5 other identifiers: NCI-2022-09737UMCC 2022.038UMI22-09-02P30CA046592UG1CA242632
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 5

Brief Summary

The purpose of this phase I trial is to test the safety and cancer preventive effects of different doses of ONC201 in people with familial adenomatous polyposis (FAP) or a history of multiple polyps. People with familial adenomatous polyposis (FAP) or a history of multiple polyps are at higher than average risk of developing colorectal cancer. ONC201, now known as dordaviprone, is a drug that may stop cancer cells from growing. This drug has been shown in previous studies to cause cancer cell death but not harm normal cells. If successful, this study may help us develop a new option for colorectal cancer prevention.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Proportion of participants with unacceptable toxicity

  Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

  Up to 35 days post last dose of ONC201

Secondary Outcomes (2)

• Mean change in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in polyps induced by ONC201

  Baseline up to week 13 end of treatment

• Mean change in normal human mucosa TRAIL expression induced by ONC201

  Baseline up to week 13 end of treatment

Other Outcomes (6)

• Changes in mean cytokine/immune response levels (with attention to IL-10, IL-17A, TNFalpha, IL-6, granzyme A, and perforin) in sera, normal colonic mucosa, and adenomas between pre-, on-, and post-ONC201 treatment samples

  Baseline up to week 13 end of treatment

• Changes in mean serum TRAIL concentrations in pre-, on-, and post-treatment samples obtained from participants treated with escalating doses of ONC201

  Baseline up to week 13 end of treatment

• Changes in mean serum prolactin concentrations in pre-, on-, and post-treatment samples obtained from participants treated with escalating doses of ONC201

  Baseline up to week 13 end of treatment

Study Arms (1)

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

EXPERIMENTAL

Patients receive ONC201 PO QW or Q3W for 13 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Colonoscopy; Drug: Dordaviprone Hydrochloride; Other: Questionnaire Administration; Procedure: Sigmoidoscopy

Interventions

Dordaviprone Hydrochloride DRUG

Given PO

Also known as: Modeyso

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Colonoscopy PROCEDURE

Undergo colonoscopy

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Questionnaire Administration OTHER

Ancillary studies

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Sigmoidoscopy PROCEDURE

Undergo sigmoidoscopy

Also known as: Proctosigmoidoscopy

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

RECRUITING

Washington University School of Medicine

St Louis, Missouri, 63110, United States

RECRUITING

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

RECRUITING

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

RECRUITING

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms; Adenomatous Polyposis Coli

Interventions

Biopsy; Specimen Handling; Colonoscopy; Sigmoidoscopy

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Adenomatous Polyps; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplastic Syndromes, Hereditary; Intestinal Polyposis; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Endoscopy; Digestive System Surgical Procedures; Minimally Invasive Surgical Procedures

Study Officials

• Alexander G Raufi, MD

  Brown University Health/ Rhode Island Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2022
• First Posted: November 30, 2022
• Study Start: October 6, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): March 1, 2028
• Last Updated: April 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (5)