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Testing ONC201 to Prevent Colorectal Cancer

Primary Purpose

Colorectal Adenomatous Polyp, Colorectal Carcinoma, Familial Adenomatous Polyposis

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Biopsy
Biospecimen Collection
Colonoscopy
Dordaviprone
Questionnaire Administration
Sigmoidoscopy
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Colorectal Adenomatous Polyp

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Michigan Comprehensive Cancer Center
  • Washington University School of Medicine
  • Cleveland Clinic Foundation
  • Ohio State University Comprehensive Cancer Center
  • Rhode Island Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Proportion and severity of treatment emergent adverse events
Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Full Information

First Posted
November 29, 2022
Last Updated
January 3, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05630794
Brief Title
Testing ONC201 to Prevent Colorectal Cancer
Official Title
Phase 1 Trial of ONC201 for Chemoprevention of Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
May 13, 2023 (Anticipated)
Primary Completion Date
February 1, 2025 (Anticipated)
Study Completion Date
February 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Adenomatous Polyp, Colorectal Carcinoma, Familial Adenomatous Polyposis, Multiple Adenomatous Polyps

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Prevention (ONC201, biopsy, sigmoidoscopy, colonoscopy)
Arm Type
Experimental
Arm Description
Patients receive ONC201 PO QW or Q3W for 12 weeks. Patients also undergo collection of blood, tissue biopsy, and sigmoidoscopy/colonoscopy throughout the study.
Intervention Type
Procedure
Intervention Name(s)
Biopsy
Other Intervention Name(s)
BIOPSY_TYPE, Bx
Intervention Description
Undergo biopsy
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo collection of blood
Intervention Type
Procedure
Intervention Name(s)
Colonoscopy
Intervention Description
Undergo colonoscopy
Intervention Type
Drug
Intervention Name(s)
Dordaviprone
Other Intervention Name(s)
Akt/ERK Inhibitor ONC201, ONC201, TIC10
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Questionnaire Administration
Intervention Description
Complete questionnaire
Intervention Type
Procedure
Intervention Name(s)
Sigmoidoscopy
Other Intervention Name(s)
Proctosigmoidoscopy
Intervention Description
Undergo sigmoidoscopy
Primary Outcome Measure Information:
Title
Mean change in human adenoma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in polyps induced by ONC201
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Secondary Outcome Measure Information:
Title
Mean change in normal human mucosa TRAIL expression induced by ONC201
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Title
Proportion and severity of treatment emergent adverse events
Description
Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time Frame
Up to 35 days post last dose of ONC201
Other Pre-specified Outcome Measures:
Title
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
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Title
Changes in mean serum TRAIL concentrations in pre-, on-, and post-treatment samples obtained from participants treated with escalating doses of ONC201
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Title
Changes in mean serum prolactin concentrations in pre-, on-, and post-treatment samples obtained from participants treated with escalating doses of ONC201
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Title
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
Description
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.
Time Frame
Baseline up to week 13 end of treatment
Title
Mean change in TRAIL expression between those who experience TEAEs versus those who do not
Description
Will be compared qualitatively.
Time Frame
Baseline up to week 13 end of treatment
Title
Adenoma-derived organoid take rates between samples obtained prior to and following treatment
Description
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.
Time Frame
Baseline up to week 13 end of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander G Raufi
Organizational Affiliation
Rhode Island Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elena M. Stoffel
Phone
734-936-0781
Email
estoffel@med.umich.edu
First Name & Middle Initial & Last Name & Degree
Elena M. Stoffel
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paul E. Wise
Phone
314-454-7177
Email
wisepe@wustl.edu
First Name & Middle Initial & Last Name & Degree
Paul E. Wise
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carol A. Burke
Phone
216-444-6864
Email
BURKEC1@ccf.org
First Name & Middle Initial & Last Name & Degree
Carol A. Burke
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter P. Stanich
Phone
614-293-6255
Email
peter.stanich@osumc.edu
First Name & Middle Initial & Last Name & Degree
Peter P. Stanich
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexander G. Raufi
Phone
401-787-0988
Email
alexander_raufi@brown.edu
First Name & Middle Initial & Last Name & Degree
Alexander G. Raufi

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing URL
https://grants.nih.gov/policy/sharing.htm

Learn more about this trial

Testing ONC201 to Prevent Colorectal Cancer

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