Neoadjuvant Cetuximab, Fluorouracil, and Pelvic Irradiation in Treating Patients With Locally Advanced or Locally Recurrent Rectal Cancer

A Pilot Clinical Trial of Preoperative Cetuximab With Concurrent Continuous Infusion Fluorouracil and Pelvic Radiation in Patients With Local-Regionally Advanced Rectal Cancer

RATIONALE: Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy such as fluorouracil work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving cetuximab with fluorouracil and radiation therapy may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Radiation: radiation therapy; Procedure: neoadjuvant therapy; Biological: cetuximab

Detailed Description

OBJECTIVES:

Primary

• Determine the safety profile of neoadjuvant cetuximab, fluorouracil, and pelvic irradiation in patients with locally advanced or locally recurrent rectal cancer.

Secondary

• Determine the activity of this regimen, in terms of pathological complete response rate, in these patients.

OUTLINE: This is a non-randomized, open-label, pilot study.

Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 and fluorouracil IV continuously on days 1-42. Patients undergo whole-pelvic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Treatment continues in the absence of disease progression or unacceptable toxicity.

Approximately 1-3 weeks after completion of study treatment, patients undergo surgical resection followed by adjuvant chemotherapy off-study.

Patients are followed for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center

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:

• Histologically confirmed rectal adenocarcinoma meeting 1 of the following staging criteria:

  • Locally advanced disease

    • Resectable (uT3) disease

      • Primary gross transmural tumor that is not adherent to adjacent pelvic structures by endorectal ultrasound

    • Primary tethered or unresectable (cT4 or uT4) disease

      • Primary tumor is contiguous with or adherent or fixed to adjacent pelvic structures by clinical exam and CT scan
      • Primary surgery would likely leave residual tumor
    • Small volume extrapelvic metastases allowed

  • Recurrent disease after definitive resection

    • Disease limited to the pelvis
• Requires combined modality treatment
• Epidermal growth factor receptor status-positive, -negative, or -unknown
• If previously treated with adjuvant fluorouracil-based chemotherapy, no disease recurrence during or within 12 months after completion of adjuvant therapy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0 -1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Hemoglobin > 8.0 g/dL
• Platelet count > 150,000/mm^3

Hepatic

• Not specified

Renal

• Creatinine ≤ 1.5 times upper limit of normal

Cardiovascular

• No myocardial infarction within the past 6 months
• No evidence of uncontrolled congestive heart failure requiring therapy

Other

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No known severe hypersensitivity to cetuximab or any of its excipients
• No uncontrolled infection
• No high-grade bowel obstruction (bowel lumen ≤ 1 cm) unless patient has undergone protective surgical diversion or endoscopic stenting procedure
• No other concurrent medical or psychiatric condition or disease that would preclude study participation
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior cetuximab
• No prior murine or chimeric monoclonal antibody therapy
• No prior biological response modifiers for metastatic colorectal cancer
• No concurrent anti-vascular endothelial growth factor/Flk-1 monoclonal antibody therapy
• No other concurrent antibody therapy or immunotherapy
• No concurrent gene therapy
• No concurrent vaccine therapy
• No concurrent angiogenesis inhibitors, including thalidomide

Chemotherapy

• See Disease Characteristics
• No prior chemotherapy for metastatic colorectal cancer
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• No prior radiotherapy for metastatic colorectal cancer
• No prior pelvic radiotherapy
• No other concurrent radiotherapy

Surgery

• See Disease Characteristics
• Fully recovered from prior oncologic or other major surgery

Other

• No other prior therapy that targets the epidermal growth factor receptor pathway
• No other concurrent experimental therapy or drugs
• No concurrent matrix metalloprotease inhibitors
• No concurrent participation in another clinical study

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

Experimental: Cetuximab, Fluorouracil, and Pelvic Irradiation; Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 and fluorouracil IV continuously on days 1-42. Patients undergo whole-pelvic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Treatment continues in the absence of disease progression or unacceptable toxicity. Approximately 1-3 weeks after completion of study treatment, patients undergo surgical resection followed by adjuvant chemotherapy off-study. Patients are followed for up to 5 years.

Drug: fluorouracil; Radiation: radiation therapy; Procedure: neoadjuvant therapy; Biological: cetuximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety profile	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Activity in terms of pathological complete response rate	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Leonard B. Saltz, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): January 1, 2007
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Estimate): December 22, 2015
• Last Update Submitted That Met QC Criteria: December 21, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; recurrent rectal cancer; stage II rectal cancer; stage III 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; Antineoplastic Agents, Immunological; Fluorouracil; Cetuximab
• Other Study ID Numbers: 04-006; MSKCC-04006