Neoadjuvant Chemotherapy in Patients With Moderate Risk Mid Rectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether 3 months of neoadjuvant CapOx is non-inferior to neoadjuvant radiotherapy in patients with moderate risk CRM- mid rectal cancer.

Detailed Description
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This trial aims to investigate the efficacy of neoadjuvant chemotherapy compared to 5x5 Gy neoadjuvant radiotherapy in moderate risk CRM-negative rectal cancer patients. This is a prospective multicenter open-label non-inferiority randomized phase III clinical trial. Patients will be randomized using an online randomization system to receive either 4 cycles of neoadjuvant CapOx (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 per os bid days 1-14) chemotherapy, surgery and 4 cycles of adjuvant CapOx chemotherapy or 5x5 Gy radiotherapy, surgery and 8 cycles of adjuvant CapOx chemotherapy. A stratification will be performed based on сN stage and clinical center. Patients with сT3c-T3dN0-1M0, cT1-T3dN2M0 cancer in the middle rectum are included. Chemoradiotherapy (50 Gy with concomitant capecitabine 825 mg/m2 per os bid on radiation days) will be performed for patients with tumor progression after neoadjuvant chemotherapy. The main hypothesis is that the 2-year local recurrence rate is non-inferior after neoadjuvant chemotherapy and neoadjuvant radiotherapy in moderate risk mid rectal cancer patients. The target accrual is 158 patients in each treatment arm (including 10% potential data loss) based on non-recurrence rate of 98% in investigated and 96% in the control group with a non-inferiority margin of 3%, α=0,05, power 80%. An interim analysis is planned after 50% of the patients will reach a 2-year followup. Pelvic Magnetic Resonance Imaging (MRI) is performed in all patients for staging before and after neoadjuvant chemotherapy and before surgery. Pelvic MRI is subject to central review. Conduction of this study and data collection are controlled by a local institutional board.

Official Title
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A Multicenter Prospective Phase III Clinical Trial of Neoadjuvant CapOx in Patients With Intermediate Risk CRM-negative Middle Rectal Cancer

Conditions
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Rectal Neoplasms Malignant, Rectum Carcinoma, Rectal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Capecitabine
* Radiation: Radiotherapy
* Procedure: Rectal cancer surgery
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent Histologically verified colon rectal adenocarcinoma сT3c-T3dN0-1M0, cT1-T3dN2M0. cancer of the middle rectum (based on pelvic MRI) Tumor more than 2 mm from mesorectal fascia (based on pelvic MRI) Eastern Cooperative Oncology Group (ECOG) status 0-2 Haemoglobin (HGB) > 90 g/L Platelet Count (PLT) > 120x10*9/L Serum creatinine < 150 µmol/L Total bilirubin < 25 µmol/L Exclusion Criteria: inability to obtain informed consent distant metastases synchronous or metachronous tumors previous chemotherapy or radiotherapy clinically significant cardiovascular disorders (myocardial infarction < 6 months before visit, stroke < < 6 months before visit, instable angina < 3 months before visit, arrhythmia, uncontrolled hypertension > 160/100 mm hg clinically significant neurological disorders previous neuropathy 2 or higher current infection or heavy systemic disease pregnancy, breastfeeding ulcerative colitis individual intolerance to treatment components proven dihydropyrimidine dehydrogenase (DPD) deficiency participation in other clinical trials psychiatric disorders, which render patient unable to follow instructions or understand his/her condition technical inability to perform pelvic MRI inability of long-term followup of the patient HIV

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Neoadjuvant chemotherapy<br>Patients will receive 4 cycles of neoadjuvant CapOx chemotherapy (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 bid per os days 1-14 every 3 weeks). In case of partial response or stable disease (based on pelvic MRI) patients proceed to surgery within 2 weeks. In case of disease progression patients receive 50 Gy pelvic chemoradiotherapy with capecitabine 825 mg/m2 bid per os on radiation days and then surgery following 8-10 weeks. After surgery patients receive 4 cycles of adjuvant CapOx chemotherapy (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 bid per os days 1-14 every 3 weeks). | Drug: Capecitabine<br>* 2000 mg/m2, bid, per os, days 1-14, 4 cycles<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 130 mg/m2 iv day 1, 4 cycles<br>Drug: Capecitabine<br>* 825 mg/m2, bid, per os, only on days of radiation (Monday through Friday)<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* Pelvic radiotherapy dose: 44 Gy on regional nodes, 50 Gy on primary tumor<br>Procedure: Rectal cancer surgery<br>* Laparoscopic or open total mesorectal excision<br>|
| Active Comparator: Neoadjuvant radiotherapy<br>Patients will receive 5x5 Gy radiotherapy and then surgery following 6-8 weeks. After surgery patients receive 8 cycles of adjuvant CapOx chemotherapy (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 bid per os days 1-14 every 3 weeks). | Drug: Capecitabine<br>* 2000 mg/m2, bid, per os, days 1-14, 4 cycles<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 130 mg/m2 iv day 1, 4 cycles<br>Procedure: Rectal cancer surgery<br>* Laparoscopic or open total mesorectal excision<br>Radiation: Radiotherapy<br>* Pelvic radiotherapy dose: 25 Gy in 5 Gy fractions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year local recurrence rate |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjuvant chemotherapy compliance | Proportion of patients who receive a complete course of adjuvant chemotherapy | 6 months | 
| Acute chemotherapy toxicity | Toxicity measured according to NCI-CTCAE v.5.0 | 6 months | 
| pathologic complete response rate (pCR) |  | 1 month | 
| 2-year overall survival |  | 2 years | 
| 2-year disease-free survival |  | 2 years | 
| Operative morbidity | Morbidity measured according to Clavien-Dindo classification | 30 days | 
| Neoadjuvant chemotherapy disease progression rate | Proportion of patients with disease progression during neoadjuvant chemotherapy | 3 months | 
| Preoperative tumor-associated complications rate | The rate of tumor-associated complications (bowel obastruction, bleeding etc) during neoadjuvant chemotherapy | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, neoadjuvant chemotherapy, neoadjuvant radiotherapy