FOLFOXIRI With or Without Intensification for Rectal Cancer

Study Overview
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Brief Summary
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Pathologic complete response rate

Official Title
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A Randomized Study of Neoadjuvant Chemoradiotherapy With or Without Intensification With the FOLFOXIRI Chemo-regimen for High-risk Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Control arm
* Drug: Experimental arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written informed consent Age >= 18 years of either sex. ECOG performance status 0-1 Measurable disease by RECIST 1.1 criteria. Histologically confirmed rectal adenocarcinoma (defined as either mid- or low rectal cancer that is located within 12 cm from the anal verge OR below the peritoneal reflection) that is previously untreated. 'High risk' rectal cancer, or rectal cancers that are considered marginally perable where there is a significant risk of positive surgical margin: T3 or T4, and / or Tumour infiltrating perirectal fat and/ or mesorectal fascia, and / or Involvement of pelvic lymph nodes, and/or Tumour invading surrounding structures or peritoneum or vasculature. Adequate bone marrow, renal and hepatic function as defined by: absolute neutrophil count >= 1.5 x 109/L, hemoglobin >= 9 g/L, platelets >= 100 x 109/L, serum creatinine level < 1.5 x ULN (or calculated creatinine clearance >=50 ml/min, whichever is worse), total bilirubin <=1.5 x the upper limit of normal, alanine aminotransferase (ALT) < 3 upper limit of normal. Exclusion Criteria: Known distant metastasis, even if the metastasis has been resected. History of another invasive malignancy within the last 5 years, except for treated basal cell carcinoma of the skin, cervical intraepithelial neoplasia, or breast DCIS. Upper rectal cancer that is located above the peritoneal reflection. Patients with synchronous colon and rectal cancers are not excluded as long as: (1) these tumors are considered as two separate primaries (i.e. not metastasis or a contiguous part of a large primary), (2) both tumors are not causing imminent obstruction; (3) pelvic radiotherapy is not considered a contraindication. Primary tumour associated with any one of the following features:Frank intestinal obstruction, or Endoscope unable to pass through the tumour's lumen plus worsening local obstructive symptoms. Note: Patients with such features should be assessed by the surgical team regarding stomal bypass prior to study enrolment. Such patients can still be considered for study enrolment after undergoing stomal bypass. Known hypersensitivity reaction to the study drugs (i.e. fluoropyrimidine, irinotecan, oxaliplatin) Known peripheral neuropathy of grade 2 or more in severity.\ -Patients who have received an experimental anticancer therapy within the last 28 days. Previous pelvic radiotherapy Previous oxaliplatin or irinotecan for the treatment of colon or rectal cancer. Patient with hip prosthesis Major surgery (i.e. requiring general anaesthetics) within the last 28 days. Exception: Any patient who underwent stomal bypass for obstructing primary tumour within the last 14 days are still eligible, as long as the patient has sufficiently recovered from the surgery at the investigator's discretion. Known cardiac disease that is symptomatic or poorly controlled, including cardiac failure, arrhythmia or ischemic heart disease. Myocardial infarction or cerebrovascular accident within the last 12 months. Intercurrent infections or medical illnesses that are serious/ potentially life-threatening and require ongoing treatment. Patients who are unable to take capecitabine tablets uncrushed by the oral route (e.g. enteral feeding). Patients with significantly impaired gastrointestinal integrity and absorption are excluded. Patients with known and untreated bilateral hydronephrosis and/or hydroureters (or unilateral hydronephrosis and/or hydroureters in any patient with a single kidney) are excluded. The obstruction should be treated with ureteric stent(s) or percutaneous nephrostomy(s) prior to study enrolment. Patients with unilateral hydronephrosis and/or hydroureters and adequate renal function (i.e. as stated in the eligibility criteria: serum creatinine level < 1.5 x ULN, or calculated creatinine clearance >=50 ml/min - whichever is worse) are not excluded. Patients on warfarin therapy. Patients on low molecular weight heparin are not excluded. Pregnant or lactating women. Patients with reproductive potential who are not willing to use barrier method of birth control. Patients who are unable to provide written informed consent, or to comply with study requirements as judged by the investigator. Patients who refuse surgical treatment of the rectal cancer.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control arm<br>neoadjuvant concurrent capecitabine-radiotherapy followed by surgery and postoperative chemotherapy | Drug: Control arm<br>* neoadjuvant concurrent capecitabine-radiotherapy followed by surgery and postoperative chemotherapy.<br>|
| Experimental: Experimental arm<br>Neoadjuvant FOLFOXIRI x4 cycles, then capecitabine-radiotherapy and postoperative chemotherapy | Drug: Experimental arm<br>* Neoadjuvant FOLFOXIRI x4 cycles, then capecitabine-radiotherapy and postoperative chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic complete response |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of tumour regression grade |  | 2 years | 
| Number of objective tumour response |  | 2 years | 
| Rate of circumferential resection margin (CRM) clearance |  | 2 years | 
| Rate of tumour downstaging |  | 2 years | 
| Number of Participants with Adverse Events |  | 2 years | 
| Rate of overall survival |  | 5 years | 
| Rate of disease-free survival, relapse-free survival |  | 5 years | 
| Time to local (and distant) recurrence |  | 5 years | 
| Number of patients with 30-days post-operative mortality |  | 1 month | 
| Rate of compliance to study treatment |  | 2 years | 
| Number of response to neoadjuvant therapy |  | 2 years |