Oxaliplatin, Leucovorin, and Fluorouracil Before and After Radiation Therapy and Surgery in Treating Patients With Rectal Cancer That Can Be Removed by Surgery (COPERNICUS)

A Stratified Phase II Study of Neoadjuvant Chemotherapy Given Before SCPRT as Treatment for Patients With MRI-Staged Operable Rectal Cancer at High Risk of Metastatic Relapse

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying giving oxaliplatin, leucovorin, and fluorouracil together, before and after radiation therapy and surgery in treating patients with rectal cancer that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Procedure: therapeutic conventional surgery; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Drug: Leucovorin; Drug: oxaliplatin

Detailed Description

OBJECTIVES:

Primary

• To assess the feasibility of introducing 8 weeks of neoadjuvant oxaliplatin and fluorouracil followed by radiotherapy and immediate surgical resection in patients with resectable adenocarcinoma of the rectum.

Secondary

• Determine feasibility of achieving dose intensity for chemotherapy and radiotherapy in these patients.
• Determine the safety, in terms of NCI CTCAE version 4 toxicities, including postoperative complication rate (up to 30 days postoperatively), and late toxicity assessment at 1 year following surgery, in these patients.
• Determine how active is the neoadjuvant chemotherapy, in terms of down staging the rectal cancer, local recurrence-free, distant metastasis-free, and overall survival at 1 year following surgery in these patients.

Neoadjuvant therapy: Patients receive oxaliplatin and leucovorin (L-leucovorin or leucovorin calcium) IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Radiotherapy/Surgery: Beginning 1 week after completion of chemotherapy, patients undergo radiotherapy, followed by surgical resection of their primary tumor, within 7-14 days after completion of radiotherapy. Between 6-8 weeks following surgery, patients begin adjuvant therapy.

Adjuvant therapy: Patients receive oxaliplatin and leucovorin (L-leucovorin or leucovorin calcium) IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 2 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Blood and biopsy specimens are collected at baseline and periodically for translational research studies.

After completion of study therapy, patients are followed up periodically for 1 year.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Coventry, England, United Kingdom, CV2 2DX
      • Walsgrave Hospital
    • Leeds, England, United Kingdom, LS9 7TF
      • Leeds Cancer Centre at St. James's University Hospital
    • Manchester, England, United Kingdom, M20 4BX
      • Christie Hospital
    • Preston, England, United Kingdom, PR2 9HT
      • Rosemere Cancer Centre at Royal Preston Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden - Surrey
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Center at Velindre Hospital
    • Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
      • Glan Clwyd Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histopathologically confirmed rectal adenocarcinoma meeting the following criteria:

  • Inferior aspect of tumor is > 4 cm from anal verge on digital examination and pelvic MRI scan
  • Superior aspect of tumor is not higher than the anterior aspect of the S1/S2 interspace on pelvic MRI scan
  • Mesorectal fascia is not threatened or involved (tumor > 1 mm from mesorectal fascia)

  • Primary tumor meets 1 of the following criteria:

    • T3a-b (mesorectal primary tumor invasion seen ≤ 5 mm beyond muscularis propria) in the presence of 1 of the following:

      • Extra-mural vascular invasion
      • Mesorectal lymph node(s)/tumor deposit(s) with irregular border and mixed signal intensity
    • Any T3c (primary tumor invasion seen > 5 mm beyond muscularis propria)-T4a (invasion of visceral peritoneum for tumors with a component above peritoneal reflection)
  • Low tumors should not involve levator ani (> 1 mm gap between tumor and levator ani) or anal sphincters
• No evidence of distant metastases or stage T4b cancer with invasion into adjacent organs or structures
• Must have measurable disease at the baseline visit
• Impending rectal obstruction is permitted if relieved by a non-functioning ileostomy or colostomy
• No disease threatening mesorectal fascia (disease ≤ 1 mm from mesorectal fascia whether this is primary tumor, extra-mural vascular invasion, or tumor deposit with irregular border and mixed signal intensity)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Hemoglobin ≥ 9 g/dL
• WBC ≥ 3 x 10^9/L
• Absolute neutrophil count ≥ 1.5 x10^9/L
• Platelet count ≥ 100 x10^9/L
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 5 x ULN
• AST or ALT ≤ 2.5 x ULN
• Creatinine clearance ≥ 50 mL/min
• Magnesium and calcium normal
• Candidate for systemic therapy, in the opinion of the primary oncologist
• No known significant impairment of intestinal absorption (e.g., chronic diarrhea, inflammatory bowel disease)
• No evidence of established or acute ischemic heart disease (e.g., left bundle branch block, pathological q-waves, ST elevation, or ST-segment depression) and normal clinical cardiovascular assessment by ECG
• No enlarged pelvic sidewall lymph nodes
• No severe local bowel symptoms of tenesmus or irregularity or frequency of bowel habit precluding accurate assessment of diarrhea
• No pelvic sepsis
• No uncontrolled infection
• Not pregnant or nursing
• Fertile patients must use effective contraception during treatment and for 6 months after completion of treatment
• No other prior or current malignant disease that, in the judgement of the treating investigator, is likely to interfere with study treatment or assessment of response

• No clinically significant cardiovascular disease, including any of the following within the past year:

  • Myocardial infarction
  • Unstable angina
  • Symptomatic congestive heart failure
  • Serious uncontrolled cardiac arrhythmia
• No history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease)

PRIOR CONCURRENT THERAPY:

• No prior pelvic radiotherapy
• No metallic colon stent or rectal stent in situ
• More than 30 days since prior chemotherapy, radiotherapy, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloproteinase inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibodies, or other experimental drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Neo-adjuvant chemotherapy; Neo-adjuvant chemotherapy prior to short course pre-operative radiotherapy followed by adjuvant chemotherapy.	Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Procedure: therapeutic conventional surgery; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy; Drug: Leucovorin; Drug: oxaliplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients who commence neoadjuvant chemotherapy and radiotherapy and then undergo surgical resection	Two years

Secondary Outcome Measures

Outcome Measure	Time Frame
Feasibility in terms of achieved dose intensity for chemotherapy and radiotherapy	Two years
Safety in terms of NCI CTCAE v 4 toxicities up to 30 days postoperatively and late toxicity at 1 year after surgery	Two years
Complete response	Two years
Efficacy in terms of down-staging rectal cancer	Two years
Local recurrence-free, distant metastasis-free, and overall survival at 1 year after surgery	Two years

Collaborators and Investigators

• Sponsor: Cardiff University
• Collaborators: Cancer Research UK
• Investigators: Principal Investigator: Simon Gollins, MD, Glan Clwyd Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: December 17, 2010
• First Submitted That Met QC Criteria: December 17, 2010
• First Posted (Estimate): December 20, 2010

Study Record Updates

• Last Update Posted (Estimate): September 21, 2016
• Last Update Submitted That Met QC Criteria: September 20, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IIIB rectal cancer; stage IIIC rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000691166; WCTU-COPERNICUS (Other Identifier: Cardiff University); 2010-023083-40 (EudraCT Number); C23134/A11537 (Other Grant/Funding Number: Cancer Research UK); CARDIFF-SPON830-10 (Other Identifier: Cardiff University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No