Testing for Safety and Colorectal Cancer Preventive Effects of ONC201

Phase I Trial of ONC201 for Chemoprevention of Colorectal Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Familial Adenomatous Polyposis; Colorectal Carcinoma; Colorectal Adenomatous Polyp; Multiple Adenomatous Polyps
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Procedure: Colonoscopy; Procedure: Sigmoidoscopy; Procedure: Biopsy Procedure; Drug: Dordaviprone Hydrochloride

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the safety and toxicity of dordaviprone (ONC201) for the indication of cancer prevention in a healthy population of individuals who are at high risk (FAP and/or history of multiple adenomas [excluding hereditary nonpolyposis colorectal cancer (HNPCC)]) for recurrent colorectal adenomas.

SECONDARY OBJECTIVES:

I. To determine the dose(s) of ONC201 that yield(s) a statistically significant increase in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression.

II. To determine the dose(s) of ONC201 that yield(s) a statistically significant increase in normal human mucosa TRAIL expression.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of ONC201 on:

Ia. Cytokine/immune response profiles (with attention to interleukin [IL]-10, IL-17A, tumor necrosis factor [TNF]-alpha, IL-6, granzyme A, and perforin) in sera, normal colonic mucosa, and adenomas; Ib. Serum TRAIL concentration; Ic. Serum prolactin concentration; Id. Proliferation markers (Ki67), cell death markers (BCL2, Caspase 3), stemness markers (LGR5, CD44, CD133, ALDH), and natural killer (NK) cell infiltration in adenomas and in normal colonic mucosa; Ie. To evaluate for associations between observed toxicity and TRAIL expression; If. To establish organoids ex vivo and compare adenoma-derived organoid take rates between samples obtained prior to and following treatment.

OUTLINE: This is a dose-escalation study.

Patients receive ONC201 orally (PO) once weekly (QW) or once every 3 weeks (Q3W) for 13 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.

After completion of study treatment, patients are followed up at 21-35 days.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Rogel Cancer Center
      • Contact: Elena M. Stoffel; Phone Number: 734-936-0781; Email: estoffel@med.umich.edu
      • Principal Investigator: Elena M. Stoffel
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Not yet recruiting
      • Washington University School of Medicine
      • Contact: Paul E. Wise; Phone Number: 314-454-7177; Email: wisepe@wustl.edu
      • Principal Investigator: Paul E. Wise
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Foundation
      • Contact: Carol A. Burke; Phone Number: 216-444-6864; Email: BURKEC1@ccf.org
      • Principal Investigator: Carol A. Burke
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Contact: Peter P. Stanich; Phone Number: 614-293-6255; Email: peter.stanich@osumc.edu
      • Principal Investigator: Peter P. Stanich
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Not yet recruiting
      • Rhode Island Hospital
      • Contact: Alexander G. Raufi; Phone Number: 401-787-0988; Email: alexander_raufi@brown.edu
      • Principal Investigator: Alexander G. Raufi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Colonoscopy; Undergo colonoscopy; Procedure: Sigmoidoscopy; Undergo sigmoidoscopy; Other Names: Proctosigmoidoscopy; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Drug: Dordaviprone Hydrochloride; Given PO; Other Names: Modeyso

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in polyps induced by ONC201	The TRAIL expression in polyps obtained during pre-treatment colonoscopy and again during sigmoidoscopy after 12 weeks of treatment will be measured. The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	Baseline up to week 13 end of treatment
Mean change in normal human mucosa TRAIL expression induced by ONC201	The TRAIL expression in polyps obtained during pre-treatment colonoscopy and again during sigmoidoscopy after 12 weeks of treatment will be measured. The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	Baseline up to week 13 end of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	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	The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	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	The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	Baseline up to week 13 end of treatment
Changes in Ki67, BCL2, Caspase 3, LGR5, CD44, CD133, and ALDH staining and NK cell infiltration in adenomas and in normal colonic mucosa obtained from participants prior to and following treatment with escalating doses of ONC201	The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	Baseline up to week 13 end of treatment
Adenoma-derived organoid take rates between samples obtained prior to and following treatment	The mean difference in this change is compared between time points by means of a paired t-test. For skewed outcomes, the nonparametric Wilcoxon signed-rank test will be employed.	Baseline up to week 13 end of treatment
Mean change in TRAIL expression between those who experience adverse events versus those who do not	Will be compared qualitatively.	Baseline up to week 13 end of treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alexander G Raufi, MD, Brown University Health/ Rhode Island Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: November 29, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms, Glandular and Epithelial; Colonic Diseases; Adenoma; Neoplastic Syndromes, Hereditary; Adenomatous Polyps; Intestinal Polyposis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Colorectal Neoplasms; Adenomatous Polyposis Coli; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Endoscopy; Digestive System Surgical Procedures; Biopsy; Specimen Handling; Colonoscopy; Sigmoidoscopy
• Other Study ID Numbers: NCI-2022-09737 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UMI22-09-02 (Other Identifier: DCP); P30CA046592 (U.S. NIH Grant/Contract); UG1CA242632 (U.S. NIH Grant/Contract); UMCC 2022.038 (Other Identifier: University of Michigan Rogel Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No