Metformin With Neoadjuvant Chemoradiation to Improve Pathologic Responses in Rectal Cancer

Study Overview
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Brief Summary
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This study is a phase II, single arm, controlled, open label internal pilot.

Detailed Description
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This internal pilot will be the first prospective study to assess the feasibility and efficacy of adding metformin in non-diabetic rectal patients who undergo standard of care neoadjuvant chemoradiation therapy (CRT). The translational aim of the study will inform on predictive factors (such as p53) and mechanism of action (hypoxia, proliferation). Metformin has been used for decades in patients with type 2 diabetes and has an extremely safe toxicity profile. With current interest in the use of metformin as a cancer therapeutic in non-diabetics, this study is expected to provide proof-of principle data for a larger study.

Official Title
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Metformin With Neoadjuvant Chemoradiation to Improve Pathologic Responses in Rectal Cancer: An Internal Pilot Study

Conditions
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Rectal Neoplasm Carcinoma in Situ Adenocarcinoma

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Plan for care inclusive of: i. standard of care neoadjuvant chemoradiation ii. planned total mesorectal excision (TME) Histologically confirmed adenocarcinoma of the rectum At least one of the following: i. T3 or T4 lesions ii. T2 lesions ≤ 1 mm to the mesorectal fascia iii. Node positive rectal tumor ECOG performance status of 0 or 1 Provide written informed consent Female participants of childbearing potential agree to use adequate methods of contraception from the start of metformin administration until the start of CRT. Contraception will not be required to be continued during or after CRT as this treatment renders participants infertile. Clinically acceptable methods of birth control for this study include intrauterine devices (IUD), birth control pills, hormonal implants, injectable contraceptives, and using barrier methods such as condoms, vaginal diaphragm with spermicide, or sponge. Exclusion Criteria: Diagnosis of diabetes Current use of metformin Prior pelvic radiation Life expectancy < 6 months. Active infection Creatinine > 1.5X ULN, within 1 month prior to baseline AST, ALT > 2.5X ULN, within 1 month prior to baseline Bilirubin > 1.5 ULN, within 1 month prior to baseline Pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 19 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Participants will self-administer 500mg metformin twice daily by mouth: 1) beginning 1 to 2 weeks prior to standard of care CRT, 2) during standard of care CRT and 3) until 30 days after the end of standard of care CRT. | Drug: Metformin<br>* Participants will self-administer 500mg metformin twice daily by mouth: 1) beginning 1-2 weeks prior to standard of care CRT, 2) during standard of care CRT and 3) until 30 days after the end of standard of care CRT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) rate | The primary outcome is to evaluate the use of metformin to improve pathological complete response (pCR) rates in non-diabetic participants undergoing standard of care neoadjuvant CRT for rectal cancer. The primary outcome will be measured by the pathological complete response rate after completion of the study treatment. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Proliferation Reduction | The secondary outcome is to determine if metformin reduces tumor proliferation in this study population. The secondary outcome will be determined by examining tumor cell proliferation from longitudinal biopsy specimens. | 1 year | 
| Tumor Hypoxia | The secondary outcome is to determine if metformin reduces tumor hypoxia in this study population. The secondary outcome will be determined by examining tumor cell hypoxia from longitudinal biopsy specimens. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, adenocarcinoma of the rectum, node positive rectal tumors, metformin, neoadjuvant chemoradiation