Testing ONC201 to Prevent Colorectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 1 Trial of ONC201 for Chemoprevention of Colorectal Cancer

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

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Colonoscopy
* Drug: Dordaviprone
* Other: Questionnaire Administration
* Procedure: Sigmoidoscopy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)<br>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: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Colonoscopy<br>* Undergo colonoscopy<br>Drug: Dordaviprone<br>* Given PO<br>* Other names: TIC10;Other: Questionnaire Administration<br>* Complete questionnaire<br>Procedure: Sigmoidoscopy<br>* Undergo sigmoidoscopy<br>* Other names: Proctosigmoidoscopy;|

What is the study measuring?
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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 |