Metformin With Neoadjuvant Chemoradiation to Improve Pathologic Responses in Rectal Cancer

Official Title

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


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.

Trial Description

Primary Outcome:

  • Pathological Complete Response (pCR) rate
Secondary Outcome:
  • Tumour Proliferation Reduction
  • Tumour Hypoxia
This study is a phase II, single arm, controlled, open label internal pilot.

The study hypothesis is that metformin improves rates of pathological complete response in patients with rectal cancer treated with neoadjuvant chemoradiation by mitigating tumour proliferation and hypoxia. The hypothesis will be tested with this phase II trial, where metformin will be administered prior to, during and after CRT. The primary end‐point is the pCR rate. The study will also examine tumour proliferation and hypoxia longitudinally in tumour biopsies obtained at diagnosis as well as after metformin but prior to CRT. This study will, for the first time, provide proof‐of‐principle whether non‐diabetic patients with rectal cancer can benefit from metformin prior to, during and after CRT. These results may guide future trials across sites and provide biomarkers for future patient stratification and personalized radiation medicine.

Study Schedule: Each participant will be consented prior to enrollment. At baseline, eligibility will be assessed based on the inclusion/exclusion criteria. Once eligibility is confirmed and documented, participants are enrolled in the study. Eligible and consented participants are dispensed the study drug, metformin.

Intervention Period
Phase 1: (2 weeks prior to CRT)
Participants will begin and self‐administer 500 mg of metformin twice daily by mouth for 2 weeks prior to CRT. After 2 weeks of metformin administration and prior to CRT, an optional sigmoidoscopy will be performed for research purposes, if consented by the participant.

Phase 2 (During CRT)
Participants will continue metformin at a dose of 500 mg twice daily throughout the course of CRT. Participants will be followed weekly at usual SOC visits, which will include weekly blood tests to determine blood counts and liver and kidney function. Information about the occurrence of adverse events and updates in concomitant medications will be collected.

Phase 3 (Post‐CRT)
Participants will continue metformin at a dose of 500 mg twice daily, and complete the last dose the day prior to TME surgery.

Enrolled participants are to be followed approximately 1 month after surgery coinciding with the SOC visit. If an enrolled participant, for any reason, becomes ineligible for surgery the participant will be required to be seen for two follow‐up visits approximately 4 and 8 weeks (+/‐ 1 week) after chemoradiation.

End of Study Visit (3 Months)
An end of study visit will be conducted 3 months after completion of surgical resection of the rectal tumour. Participants who become clinically ineligible for surgery will have an End of Study visit 3 months after completion of chemoradiation.

Statistical analysis:
The primary endpoint is the pCR rate. The pCR rate and its associated 95% confidence intervals will be estimated using unadjusted normal approximation for binomial proportions (z approximation). A responder will be defined as any participant who exhibits a complete response (total regression, no tumour cells, only fibrotic mass with or without mucin). pCR rate = sum of number of complete responders/number of participants qualified for efficacy analysis.

The null hypothesis to be tested is that the pCR rate of all evaluable participants is ≤15% and the alternative hypothesis is the pCR rate is greater than or equal to 25%. A pCR of ≥ 25% would justify further evaluation of study therapy in phase III testing. The null hypothesis will be tested using a one‐sample binomial test of proportions.

All participants will be evaluable for toxicity from the time of their first treatment with metformin, and all participants who have received at least one week of CRT and had surgery will be considered evaluable for response.

Assessment of Tumour Proliferation and Hypoxia
Proliferation, hypoxia and markers of metformin activity will be monitored longitudinally in the same participants using the diagnostic biopsy, a research biopsy taken at the start of CRT, and at time of surgery in cases without pCR. Markers will be quantified by immunohistochemistry (IHC) and include Ki67 (proliferation), CA9 (hypoxia), IRS‐P and S6‐P (metformin activity). A Colon Cancer Hypoxia Score (CCHS) from the expression of six genes was recently published and demonstrated to confer poor prognosis in stage II and III colon cancer patients. Hypoxia will also be assessed longitudinally by the CCHS score measured by qPCR. Furthermore, since previous study results suggest that p53 mutations exacerbates the anti‐proliferative effects of metformin, DNA will be isolated from the research biopsies and p53 DNA binding domain, in which 93% of mutations occur, will be sequenced.

Sample Size considerations
The study will be an internal pilot study. The initial goal is to complete the internal pilot study with the view to accrue 15 participants. Twelve participants have been shown to be the minimum number required to build a confidence interval. The sample of 15 will therefore be sufficient to construct a confidence interval and allow for the potential of drop outs. Upon completion of this internal pilot study, the data from the 15 participants will be used to derive a formal sample size calculation for a larger clinical trial. The data from these 15 individuals will also be incorporated into the final analysis for this larger trial, hence the choice of the 'internal' pilot design.

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