Neoadjuvant Metformin in Association to Chemoradiotherapy for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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A phase II, randomized study of placebo versus metformin in association to chemotherapy with capecitabine and radiation in the neoadjuvant treatment of locally advanced (T3-4N0M0 or TxN1-2M0) rectal carcinomas.

Detailed Description
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NEOMETRE is a randomized, double blind trial aiming to evaluate the efficacy and tolerability of metformin in association to chemoradiotherapy for the preoperative treatment of locally advanced (T3-4N0M0 or TxN1-2M0) rectal carcinomas. Patients eligible for this study will be submitted to neoadjuvant 3D radiotherapy with 50,4 Gray (Gy) divided in 25 applications, in association to capecitabine, 825mg/m2 bid for five days every week. The participants will be randomized to daily metformin or placebo during the chemoradiotherapy period. The primary end-point is pathological complete response. The secondary end-points are recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), local recurrence rate, overall response rate, sphincter preservation rate, quality of life (QoL) and toxicity.

Official Title
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Metformin in Association to Chemoradiotherapy for the Neoadjuvant Treatment of Locally Advanced Rectal Cancer: a Randomized, Placebo-controlled Phase II Study

Conditions
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Rectal Neoplasms, Adenocarcinoma, Carcinoma

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Metformin
* Radiation: Radiotherapy
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older; biopsy proven poorly differentiated carcinoma or adenocarcinoma of the rectum; lesions located within 12 cm of the anal verge (from colonoscopy assessment); ability to tolerate oral treatment; locally advanced tumor, classified by the presence of positive regional lymph nodes or primary tumor invasion beyond the serosa (T3 or T4), assessed by MRI; eligibility for curative surgery (no distant metastasis or invasion of bony structures of the pelvis); Performance Status (PS) Eastern Cooperative Oncology Group (ECOG) 0-2; adequate hematologic functions (hemoglobin ≥ 10 g / dL [5.6 mmol / L]; neutrophil count ≥ 1,500 / mm3 and platelet count ≥ 100,000 / mm3), adequate renal function (serum creatinine less than 1.5 times the UNL) and adequate hepatic function (bilirubin less than 1.5 times the UNL; aspartate aminotransferase and alanine aminotransferase less than 2.5 times the UNL); Exclusion Criteria: known hypersensitivity to metformin or its excipients; squamous carcinomas of the rectum or anal canal; chronic treatment with corticosteroids or other immunosuppressive agents; treatment with oral antidiabetic products; distant metastasis at diagnosis or tumor invasion of pelvic bone structures that may proscribe curative intent surgery; chronic or acute infections; use of drugs under study up to four weeks prior to randomization; pregnant or nursing patients; prior radiotherapy to the pelvic region; myocardial infarction up to six months prior to randomization, or uncontrolled ischemic heart disease; congestive heart insufficiency New York Heart Association (NYHA) III-IV.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant capecitabine and metformin<br>Capecitabine 825 mg/m2 bid D1-5, q7d, for five weeks; Metformin 2500mg/d for five weeks; 3D radiotherapy 50,4Gy divided in 25 fractions | Drug: Capecitabine<br>* Capecitabine 825mg/m2 bid, D1-D5 q7d<br>* Other names: Xeloda;Drug: Metformin<br>* Metformin up to 2500mg/d<br>* Other names: Glifage, Dimefor, Glucoformin, Glucophage;Radiation: Radiotherapy<br>* 3D radiotherapy 50,4Gy divided in 25 fractions<br>* Other names: RDT;|
| Placebo Comparator: Neoadjuvant capecitabine and placebo<br>Capecitabine 825 mg/m2 bid D1-5, q7d, for five weeks; Placebo 2500mg/d for five weeks; 3D radiotherapy 50,4Gy divided in 25 fractions | Drug: Capecitabine<br>* Capecitabine 825mg/m2 bid, D1-D5 q7d<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* 3D radiotherapy 50,4Gy divided in 25 fractions<br>* Other names: RDT;Drug: Placebo<br>* Placebo up to 2500mg/d<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response | Pathological evaluation of the surgical specimen. Complete response will be defined as absence of neoplastic tissue upon pathological exam. | 8 to 16 weeks after neoadjuvant treatment completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Magnetic Resonance Imaging (MRI) assessment to compare the response of chemoradiotherapy+metformin versus chemoradiotherapy+placebo. | 4 to 6 weeks after neoadjuvant treatment completion | 
| Sphincter Preservation Rate | Rate of anal sphincter preservation during curative intent surgery. | 8 to 16 weeks after neoadjuvant treatment completion | 
| Toxicity will be assessed using National Cancer Institute Common Toxicity Criteria for Adverse Effects (NCI CTCAE) v4.03 | Safety and tolerability will be assessed using National Cancer Institute Common Toxicity Criteria for Adverse Effects (NCI CTCAE) v4.03. The number of patients in each arm experiencing grade 3-5 adverse events ou AE (for each AE) over the total number of subjects will be measured, and the proportion of patients experiencing AE in each arm will be compared using uncorrected chi-square test. AE will be recorded in baseline and in each visit, and the worst grade AE will be considered. | up to 4 weeks after neoadjuvant treatment completion | 
| Local Recurrence Rate | Rate of local or pelvic recurrence during follow up. | up to 5 years | 
| Local Recurrence Free Survival | The number of subjects without local relapse will be measured 6mo after the start of therapy, also after 1, 3 and 5 years from the start of therapy. Local recurrence free survival will be analysed with log-rank test, and reported as Hazard Ratio (HR) with respective 95% Confidence Interval (CI) and p value, and its median value will be estimated with kaplan-meyer method. | up to 5 years | 
| Disease Free Survival | The number of subjects without relapse will be measured 6mo after the start of therapy, also after 1, 3 and 5 years from the start of therapy. Disease free survival will be analysed with log-rank test, and reported as HR with respective 95% CI and p value, and its median value will be estimated with kaplan-meyer method. | up to 5 years | 
| Overall Survival | The number of subjects without death (any cause) will be measured 6mo after the start of therapy, and also after 1, 3 and 5 years from the start of therapy. Overall survival will also be analysed with log-rank test, and reported as HR with respective 95% CI and p value, and median OS will be estimated with kaplan-meyer method. All calculations will be performed 6 months after the last patient recruited. Also, the survival rate at year one, three and five will be calculated. | up to 5 years | 
| Quality of Life | European Organization for Research and Treatment of Cancer Quality of Life Questionaire (EORTC QLQ)-C30 and EORTC QLQ-CR29 will be assessed on screening, at the last day of neoadjuvant treatment, 4 weeks after neoadjuvant treatment completion and up to 4 weeks after surgery. | up to 20 weeks after neoadjuvant treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Capecitabine, Neoadjuvant, Adenocarcinoma, Carcinoma, Metformin, Rectal Cancer, Rectum, Radiotherapy