Combination Chemotherapy and Bevacizumab With or Without Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer

A Pilot Study of Neoadjuvant Chemotherapy With Selective Use of Radiation for Locally Advanced Rectal Cancer

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, 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. Bevacizumab may also stop the growth of rectal cancer by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy and bevacizumab together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy and bevacizumab with or without radiation therapy works in treating patients with locally advanced rectal cancer

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Drug: oxaliplatin; Procedure: conventional surgery; Biological: bevacizumab

Detailed Description

OBJECTIVES:

Primary

• Determine whether neoadjuvant chemotherapy comprising oxaliplatin, fluorouracil, leucovorin calcium (FOLFOX), and bevacizumab can be substituted for pelvic radiotherapy without compromising R0 resection rates in patients with locally advanced rectal cancer.

Secondary

• Determine whether a 3-year local recurrence rate of ≤ 10% can be achieved in patients treated with this regimen.
• Determine the proportion of patients who achieve a complete pathologic response after treatment with this regimen.

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

• Neoadjuvant chemotherapy: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over 10 minutes on day 1 and fluorouracil IV continuously over 48 hours on days 1 and 2 in weeks 1, 3, 5, and 7. Patients then receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 48 hours on days 1 and 2 in weeks 9 and 11. Treatment continues in the absence of disease progression or unacceptable toxicity.

Within 3 weeks after completion of neoadjuvant chemotherapy, patients undergo restaging evaluation. Patients with no evidence of disease progression by endorectal ultrasound (ERUS), pelvic MRI, and CT scan of the chest/abdomen AND who remain candidates for R0 resection may proceed directly to surgical resection within 4-6 weeks after completion of neoadjuvant chemotherapy. Patients with progressive disease who are not candidates for an R0 resection, proceed to neoadjuvant chemoradiotherapy.

• Neoadjuvant chemoradiotherapy: Patients undergo pelvic radiotherapy 5 days a week and receive concurrent fluorouracil IV continuously for 5½ weeks. Within 4-7 weeks after completion of chemoradiotherapy, patients undergo surgical resection.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically or pathologically confirmed adenocarcinoma of the rectum

  • Clinical stage T1, N1; T2, N1; T3, N0; or T3, N1 by endorectal ultrasonography (ERUS)

    • No bulky N2 disease by either ERUS or MRI

    • No primary fixed or unresectable (clinical stage T4) rectal cancer or recurrent colorectal cancer limited to the pelvis

      • Primary unresectable rectal cancer is defined as a primary rectal tumor which on the basis of either physical exam, ERUS or pelvic MRI is deemed to be adherent or fixed to adjacent pelvic structures

• Must be a candidate for all of the following:

  • Neoadjuvant chemoradiotherapy
  • Systemic therapy with fluorouracil, leucovorin calcium, oxaliplatin (FOLFOX), and bevacizumab
  • Complete surgical resection via low anterior resection prior to administration of any therapy
• No low-lying tumors deemed to require an abdominal perineal resection
• No large or bulky tumors that require a diverting colostomy or placement of an endorectal stent prior to treatment initiation
• No clinical evidence of metastatic disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count > 150,000/mm^3
• Hemoglobin > 8.0 g/dL
• Creatinine ≤ 1.5 times upper limit of normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 weeks after completion of study therapy
• 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 arterial thrombotic event within the past 6 months, including stable or unstable angina, myocardial infarction (MI), or cerebral vascular accident (CVA)

  • Deep venous thrombosis, pulmonary embolus, MI, CVA, atrial fibrillation, or any other conditions occurring more than 6 months ago allowed provided patient is on stable doses of anticoagulant therapy
• No other medical or psychiatric condition or disease that would preclude study therapy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy or surgery for rectal cancer
• No prior pelvic radiotherapy

• No other concurrent experimental therapy, including any of the following:

  • Chemotherapy
  • Radiotherapy
  • Hormonal therapy
  • Antibody therapy
  • Immunotherapy
  • Gene therapy
  • Vaccine therapy
  • Angiogenesis inhibitors
  • Matrix metalloprotease inhibitors
  • Thalidomide
  • Anti-vascular endothelial growth factor/Flk-1 monoclonal antibody
  • Any 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

Experimental: Chemotherapy and Bevacizumab With or Without Radiation; FOLFOX/Bevacizumab will be given for 4 cycles over 8 weeks; FOLFOLX6 without Bevacizumab will be given for an additional 2 cycles over 4 weeks. Oxaliplatin will be given on Day 1 of each cycle over 2 hours at 85 mg/m2 IV. Leucovorin will be given Day 1 of each cycle over 2 hours at 400 mg/m2 IV. Fluorouracil will be given on Day 1 of each cycle at 400 mg/m2 IVP, then Fluorouracil will be given at 1200 mg/m2 IVCI over Day 1 and 2. Bevacizumab will be given at 5mg/kg over 10 minutes on day 1. Patients will undergo re-staging within 3 weeks of completing their 6th cycle of FOLFOX. If the reassessment reveals that there has been no disease progression as compared to the pre-treatment evaluation and the patient remains a candidate for an R0 resection. If the surgical oncologist's reassessment is that the patient is not a candidate for an R0 resection, the patient will proceed to standard pre-operative radiation with synchronous infusional 5-fluorouracil.

Drug: fluorouracil; Drug: leucovorin calcium; Radiation: radiation therapy; Drug: oxaliplatin; Procedure: conventional surgery; Biological: bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Pathologic Response	This will be assessed on the basis of the surgical pathology report.	3 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI); Genentech, Inc.
• Investigators: Principal Investigator: Martin Weiser, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Leonard B. Saltz, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Karyn A. Goodman, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: April 18, 2007
• First Submitted That Met QC Criteria: April 18, 2007
• First Posted (Estimate): April 19, 2007

Study Record Updates

• Last Update Posted (Estimate): January 20, 2016
• Last Update Submitted That Met QC Criteria: December 15, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; 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; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: 07-021; P30CA008748 (U.S. NIH Grant/Contract); MSKCC-07021