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

Colorectal Cancer Clinical Trial

— COPERNICUS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01263171
• Other study ID #: CDR0000691166
• Secondary ID: WCTU-COPERNICUS2
• Status: Completed
• Phase: Phase 2
• First received: December 17, 2010
• Last updated: September 20, 2016
• Start date: April 2012
• Est. completion date: November 2015

Study information

• Verified date: September 2016
• Source: Cardiff University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 120 Years

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Rectal Neoplasms

Intervention

Drug:
• Leucovorin

• fluorouracil

• leucovorin calcium

• oxaliplatin

Procedure:
• adjuvant therapy

• neoadjuvant therapy

• therapeutic conventional surgery

Radiation:
• radiation therapy

Locations

Country	Name	City	State
United Kingdom	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales
United Kingdom	Walsgrave Hospital	Coventry	England
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Rosemere Cancer Centre at Royal Preston Hospital	Preston	England
United Kingdom	Glan Clwyd Hospital	Rhyl, Denbighshire	Wales
United Kingdom	Royal Marsden - Surrey	Sutton	England

Sponsors (2)

Lead Sponsor	Collaborator
Cardiff University	Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who commence neoadjuvant chemotherapy and radiotherapy and then undergo surgical resection		Two years	No
Secondary	Feasibility in terms of achieved dose intensity for chemotherapy and radiotherapy		Two years	No
Secondary	Safety in terms of NCI CTCAE v 4 toxicities up to 30 days postoperatively and late toxicity at 1 year after surgery		Two years	Yes
Secondary	Complete response		Two years	No
Secondary	Efficacy in terms of down-staging rectal cancer		Two years	No
Secondary	Local recurrence-free, distant metastasis-free, and overall survival at 1 year after surgery		Two years	No