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.
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%)
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
Single group
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood
Colonoscopy
Procedure/SurgeryUndergo colonoscopy
Dordaviprone Hydrochloride
DrugGiven PO
Endoscopic Procedure
Procedure/SurgeryUndergo lower endoscopic evaluation
Questionnaire Administration
Other interventionAncillary studies
Sigmoidoscopy
Procedure/SurgeryUndergo sigmoidoscopy
Proportion of participants with unacceptable toxicity
Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
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.
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.
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.
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.
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.
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.
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