Oxaliplatin, Capecitabine, and Radiation Therapy With or Without Cetuximab in Treating Patients Undergoing Surgery for High-Risk Rectal Cancer

Colorectal Cancer Clinical Trial

— EXPERT-C  

Official title:

A Multicentre Randomised Phase II Clinical Trial Comparing Oxaliplatin (Eloxatin), Capecitabine (Xeloda) and Pre-Operative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision for the Treatment of Patients With Magnetic Resonance Imaging (MRI) Defined High Risk Rectal Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00383695
• Other study ID #: CDR0000503948
• Secondary ID: RMNHS-RMH-CCR-25
• Status: Active, not recruiting
• Phase: Phase 2
• First received: September 29, 2006
• Last updated: January 12, 2010
• Start date: September 2005

Study information

• Verified date: January 2010
• Source: Royal Marsden NHS Foundation Trust
• 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 and capecitabine, 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. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy and radiation therapy with or without cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether giving oxaliplatin, capecitabine, and radiation therapy is more effective with or without cetuximab when given before surgery in treating rectal cancer.

PURPOSE: This randomized phase II trial is studying oxaliplatin, capecitabine, and radiation therapy to compare how well they work with or without cetuximab in treating patients undergoing surgery for high-risk rectal cancer.

Description:

OBJECTIVES:

• Compare the pathological complete response rate at total mesorectal excision in patients with high-risk rectal cancer treated with neoadjuvant therapy comprising oxaliplatin, capecitabine, and radiotherapy with or without cetuximab.

OUTLINE: This is a multicenter, open-label, randomized, controlled study. Patients are stratified according to participating center and presence of T4 disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I:

• Neoadjuvant chemotherapy: Patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77.

• Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy once daily on days 85-89, 92-96, 99-103, 106-110, 113-117, and 120-124 and receive oral capecitabine twice daily on days 85-126.

• Surgery: Four to six weeks after completion of chemoradiotherapy, patients undergo total mesorectal excision (TME).

• Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77.

• Arm II:

• Neoadjuvant therapy: Patients receive oxaliplatin and capecitabine as in arm I neoadjuvant chemotherapy and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

• Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy and receive capecitabine as in arm I neoadjuvant chemoradiotherapy and cetuximab IV over 1 hour on days 85, 92, 99, 106, 113, and 120.

• Surgery: Four to six weeks after completion of chemoradiotherapy patients undergo TME as in arm I.

• Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin and capecitabine as in arm I adjuvant chemotherapy and cetuximab IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

PROJECTED ACCRUAL: A total of 164 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 164
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma or undifferentiated non-small cell carcinoma of the rectum

• MRI-defined high-risk, operable disease, defined by = 1 of the following:

• Tumors within 1 mm of mesorectal fascia (i.e., circumferential resection margin threatened or involved)

• T3 tumors at or below levators

• Tumors extending = 5 mm into perirectal fat

• T4 tumors

• Presence of extramural venous invasion (primary tumor is therefore at least T3)

• No evidence of metastatic disease by CT scan of the chest and abdomen or, if required, by positron emission tomography scan or biopsy

• No rectal cancer that is unlikely to be operable even after neoadjuvant treatment (i.e., tumor involving the internal iliac vessels)

• No T1-2 rectal cancer, in the absence of other high-risk factors

• T2 tumors within 1 mm of mesorectal fascia allowed

• No recurrent disease

PATIENT CHARACTERISTICS:

• WHO performance status 0-2

• Life expectancy > 3 months

• WBC > 3,000/mm³

• Absolute neutrophil count > 1,500/mm³

• Platelet count > 100,000/mm³

• Bilirubin < 1.5 times upper limit of normal (ULN)

• Transaminases < 2.5 times ULN

• Creatinine normal OR creatinine clearance > 50 mL/min

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No concurrent uncontrolled medical condition

• No other active malignant disease within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix

• No contraindications to MRI (e.g., pacemaker)

• No medical or psychiatric conditions that would preclude informed consent

• No known malabsorption syndrome or lack of physical integrity of the upper gastrointestinal tract

• No clinically significant (i.e., active) cardiac disease, including any of the following:

• Congestive heart failure

• Symptomatic coronary artery disease

• Cardiac dysrhythmia (e.g., atrial fibrillation, even if controlled with medication)

• Myocardial infarction within the past 12 months

• No symptoms or history of peripheral neuropathy

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or investigational treatment for rectal cancer

• No other concurrent cytotoxic agents or investigational drugs

• No concurrent sorivudine or sorivudine analogues (e.g., brivudine)

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer

Intervention

Biological:
• cetuximab

Drug:
• capecitabine

• oxaliplatin

Procedure:
• adjuvant therapy

• conventional surgery

• neoadjuvant therapy

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Clinico Universitario de Valencia	Valencia
Sweden	Karolinska University Hospital - Solna	Stockholm
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Royal Bournemouth Hospital NHS Trust	Bournemouth	England
United Kingdom	Sussex Cancer Centre at Royal Sussex County Hospital	Brighton	England
United Kingdom	Eastbourne District General Hospital	Eastbourne	England
United Kingdom	Cancer Research UK Clinical Groups at Guy's King's & St. Thomas' Hospitals	London	England
United Kingdom	Mid Kent Oncology Centre at Maidstone Hospital	Maidstone	England
United Kingdom	Dorset Cancer Centre	Poole Dorset	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Royal Marsden - Surrey	Sutton	England

Sponsors (1)

Lead Sponsor	Collaborator
Royal Marsden NHS Foundation Trust

Countries where clinical trial is conducted

Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete response rate at time of total mesorectal excision (TME)			No
Secondary	Radiological response rates after completion of neoadjuvant therapy			No
Secondary	Complete resection rate (R0 resection) with microscopic clear resection margin (tumor observed > 1 mm from the resection margin), especially circumferential resection margin			No
Secondary	Perioperative measures, including operation time, duration of in-patient stay, perioperative transfusion requirement, and mortality, within 30 days of TME			No
Secondary	Postoperative complications, including wound infection, wound dehiscence, and fistula formation			No
Secondary	Quality of TME as assessed by audit of photographed surgical specimens			No
Secondary	Rate of abdominoperitoneal excision			No
Secondary	Rate of permanent defunctioning colostomies			No
Secondary	Clinical and radiological anastomotic leak rate			No
Secondary	Progression-free survival and patterns of failure			No
Secondary	Overall survival			No
Secondary	Safety			Yes
Secondary	Quality of life, including long-term bowel function			No