Metformin With Neoadjuvant Chemoradiation to Improve Pathologic Responses in Rectal Cancer

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

This study is a phase II, single arm, controlled, open label internal pilot.

Study Overview

• Status: Completed
• Conditions: Rectal Neoplasm Carcinoma in Situ Adenocarcinoma
• Intervention / Treatment: Drug: Metformin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre, Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Plan for care inclusive of:

   i. standard of care neoadjuvant chemoradiation ii. planned total mesorectal excision (TME)

2. Histologically confirmed adenocarcinoma of the rectum

3. 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

4. ECOG performance status of 0 or 1
5. Provide written informed consent
6. 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:

1. Diagnosis of diabetes
2. Current use of metformin
3. Prior pelvic radiation
4. Life expectancy < 6 months.
5. Active infection
6. Creatinine > 1.5X ULN, within 1 month prior to baseline
7. AST, ALT > 2.5X ULN, within 1 month prior to baseline
8. Bilirubin > 1.5 ULN, within 1 month prior to baseline
9. Pregnant or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Metformin; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: University of Toronto; Sunnybrook Research Institute
• Investigators: Principal Investigator: Shun Wong, MD, Sunnybrook Health Sciences Centre; Principal Investigator: Marianne Koritzinsky, MD, Princess Margaret Hospital, Canada

Study record dates

Study Major Dates

• Study Start: December 8, 2016
• Primary Completion (ACTUAL): June 26, 2019
• Study Completion (ACTUAL): June 26, 2019

Study Registration Dates

• First Submitted: December 20, 2016
• First Submitted That Met QC Criteria: February 10, 2017
• First Posted (ACTUAL): February 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2019
• Last Update Submitted That Met QC Criteria: September 25, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; rectal cancer; metformin; neoadjuvant chemoradiation; node positive rectal tumors
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Carcinoma in Situ; Adenocarcinoma; Rectal Neoplasms; Adenocarcinoma in Situ; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 472-2015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Results from this internal pilot will be disseminated to participants and stakeholders by means of publication and presentation where appropriate.