Testing ONC201 to Prevent Colorectal Cancer

Phase 1 Trial of ONC201 for Chemoprevention of Colorectal Cancer

This phase I trial tests the safety, side effects, and best dose of Akt/ERK Inhibitor ONC201 (ONC201) in preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) or a history of multiple polyps. ONC201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Not yet recruiting
• Conditions: Familial Adenomatous Polyposis; Colorectal Carcinoma; Colorectal Adenomatous Polyp; Multiple Adenomatous Polyps
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Biopsy; Other: Questionnaire Administration; Procedure: Colonoscopy; Procedure: Sigmoidoscopy; Drug: Dordaviprone

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the optimal cancer preventive dose of ONC201 defined as the lowest dose with less than or equal to 16.67% of participants experiencing unacceptable toxicity and simultaneously resulting in a statistically significant increase in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression.

SECONDARY OBJECTIVES:

I. To determine the lowest dose of ONC201 with less than or equal to 16.67% of participants experiencing unacceptable toxicity and simultaneously resulting in a statistically significant increase in normal human mucosa TRAIL expression.

II. To evaluate the safety and tolerability of multiple ascending doses of ONC201 when administered weekly and every 3 weeks in participants with familial adenomatous polyposis (FAP) or with multiple adenomas.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of ONC201 on:

Ia. Cytokine/immune response profiles (with attention to IL-10, IL-17A, 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 killers (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 12 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.

After completion of study treatment, patients are followed up for 4 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
      • Contact: Elena M. Stoffel; Phone Number: 734-936-0781; Email: estoffel@med.umich.edu
      • Principal Investigator: Elena M. Stoffel
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • 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
      • 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
      • 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
      • 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 endoscopy 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 (pathologic confirmation of adenoma in non-FAP participants is required prior to starting therapy) 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

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 12 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.

Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Other: Questionnaire Administration; Complete questionnaire; Procedure: Colonoscopy; Undergo colonoscopy; Procedure: Sigmoidoscopy; Undergo sigmoidoscopy; Other Names: Proctosigmoidoscopy; Drug: Dordaviprone; Given PO; Other Names: TIC10; ONC201; Akt/ERK Inhibitor ONC201

What is the study measuring?

Primary 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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Proportion and severity of treatment emergent adverse events	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

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
Mean change in TRAIL expression between those who experience TEAEs versus those who do not	Will be compared qualitatively.	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alexander G Raufi, Rhode Island Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): October 8, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 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 (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Genetic Diseases, Inborn; Colonic Diseases; Intestinal Diseases; Pathological Conditions, Anatomical; Intestinal Neoplasms; Rectal Diseases; Neoplastic Syndromes, Hereditary; Adenoma; Intestinal Polyposis; Colorectal Neoplasms; Polyps; Adenomatous Polyposis Coli; Adenomatous Polyps; Antineoplastic Agents; TIC10 compound
• Other Study ID Numbers: NCI-2022-09737 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); Pending17 (Other Identifier: University of Michigan Comprehensive Cancer Center); UMI22-09-02 (Other Identifier: DCP); P30CA046592 (U.S. NIH Grant/Contract); UG1CA242632 (U.S. NIH Grant/Contract)

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