Neoplasms

All Conditions

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Adenomatous Polyposis Coli

Polyps

Adenomatous Polyps

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Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

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Pathological Conditions, Anatomical

Adenoma

Neoplasms, Glandular and Epithelial

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TIC10 compound

Patients receive ONC201 PO QW or Q3W for 12 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.

Biopsy

Biospecimen Collection

Colonoscopy

Dordaviprone

Questionnaire Administration

Sigmoidoscopy

Elena M. Stoffel

Paul E. Wise

Carol A. Burke

Peter P. Stanich

Alexander G. Raufi

Alexander G Raufi

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.

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.

Testing ONC201 to Prevent Colorectal Cancer

Phase 1 Trial of ONC201 for Chemoprevention of Colorectal Cancer

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.

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.

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.

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

National Cancer Institute (NCI)

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