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.
- Pathological Complete Response (pCR) rate
- 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.
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.
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.
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
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.
View this trial on ClinicalTrials.gov