Bevacizumab, Radiation Therapy, and Combination Chemotherapy in Treating Patients Who Are Undergoing Surgery for Locally Advanced Nonmetastatic Rectal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00321685
First received: May 2, 2006
Last updated: May 1, 2013
Last verified: May 2013
  Purpose

This phase II trial is studying how well giving bevacizumab together with radiation therapy and combination chemotherapy works in treating patients who are undergoing surgery for locally advanced nonmetastatic rectal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as capecitabine, 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. Giving bevacizumab together with radiation therapy and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab together with combination chemotherapy after surgery may kill any tumor cells that remain after surgery.


Condition Intervention Phase
Adenocarcinoma of the Rectum
Stage II Rectal Cancer
Stage III Rectal Cancer
Radiation: 3-dimensional conformal radiation therapy
Drug: capecitabine
Drug: oxaliplatin
Biological: bevacizumab
Procedure: therapeutic conventional surgery
Drug: leucovorin calcium
Drug: fluorouracil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Pathological complete response rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    A two-stage design will be used and 90% confidence intervals will be provided.


Secondary Outcome Measures:
  • Grade 3 or higher toxicities according to NCI CTCAE v3.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    A two-stage monitoring plan will be used and 90% confidence intervals will be provided.

  • Resection rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    There will be 82% power to detect a 45% absolute difference in resection rate between 95% in T3 rectal cancer patients and 50% in T4 rectal cancer patients at significance level of 0.10 using Fisher's exact test. The expected versus actual types of resection (APR or LAR or LAR/coloanal anastomosis) will be summarized and reported in an exploratory fashion.

  • Overall survival [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Will be estimated using Kaplan-Meier method.

  • Time to recurrence [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Will be estimated using Kaplan-Meier method. The patterns of recurrence in terms of timing of recurrence and locations of recurrence will be explored and summarized.


Estimated Enrollment: 58
Study Start Date: July 2006
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
See detailed description.
Radiation: 3-dimensional conformal radiation therapy
Undergo radiotherapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Drug: capecitabine
Given orally
Other Names:
  • CAPE
  • Ro 09-1978/000
  • Xeloda
Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Procedure: therapeutic conventional surgery
Undergo surgical resection
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Detailed Description:

PRIMARY OBJECTIVES:

I. Evaluate the pathological complete response rate in patients with T3 or T4 rectal cancer treated with neoadjuvant bevacizumab in combination with radiotherapy, capecitabine, and oxaliplatin followed by surgical resection and adjuvant bevacizumab in combination with fluorouracil, leucovorin calcium, and oxaliplatin.

SECONDARY OBJECTIVES:

I. Evaluate the resection rate for T3 and T4 rectal cancers. II. Evaluate the expected versus actual type of resection (abdominoperineal resection [APR] vs low anterior resection [LAR] vs LAR/coloanal anastomosis) performed on these patients.

III. Determine, preliminarily, survival and patterns of recurrence in patients treated with this regimen.

IV. Determine the toxicity and tolerability of this preoperative and postoperative regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to primary tumor size (T3 vs T4).

PREOPERATIVE CHEMORADIOTHERAPY: Patients undergo radiotherapy once daily 5 days a week and receive oral capecitabine twice daily 5 days a week for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29 during radiotherapy.

SURGERY: Approximately 6-8 weeks after completion of chemoradiotherapy, patients undergo surgical resection. Patients whose tumors are not completely resected or who have metastatic disease discontinue protocol therapy.

POSTOPERATIVE CHEMOTHERAPY: Approximately 4-8 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive fluorouracil (5-FU) IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. Patients then receive up to 3 additional courses of leucovorin calcium, 5-FU, and bevacizumab.

After completion of study treatment, patients are followed periodically for 10 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the rectum

    • Locally advanced disease
  • Must have primary T3 or T4 tumor

    • Transmural penetration of tumor through the muscularis propria by CT scan plus endorectal ultrasound or MRI

      • An endorectal coil or pelvic MRI is allowed
    • Distal border of the tumor must be at or below the peritoneal reflection, defined as within12 cm of the anal verge by proctoscopic examination
    • Tumors that are clinically fixed, clinical stage T4, N0-2, M0 are eligible if it is believed that the tumors are potentially resectable after chemoradiotherapy, based on the following:

      • Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum

        • Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane will be considered evidence of fixation
      • Hydronephrosis on CT scan or intravenous pyelogram or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into the prostate
      • Vaginal or uterine involvement
  • Nonmetastatic disease

    • No evidence of tumor outside of the pelvis
    • No liver metastases
    • No peritoneal seeding
    • No metastatic inguinal lymphadenopathy
  • Resectable disease, defined as completely resectable disease with negative margins based on routine examination of the non-anesthetized patient

    • A surgeon must prospectively define the tumor as either initially resectable or potentially resectable after preoperative chemoradiotherapy
    • A surgical evaluation must confirm patient's ability to tolerate the proposed surgical procedure
  • Carcinoembryonic antigen must be determined prior to initiation of therapy
  • ECOG performance status 0-1
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Creatinine clearance ≥ 50 mL/min
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Bilirubin ≤ 1.5 times ULN
  • Alkaline phosphatase < 2 times ULN
  • SGOT < 2 times ULN
  • Urine protein: creatinine ratio < 1

    • Patients with a urine protein: creatinine ratio of ≥ 1 must demonstrate < 1 gm of protein by 24-hour urine collection
  • INR ≤ 1.5 unless patient is on full-dose anticoagulants and the following criteria is met:

    • In range INR (usually between 2 and 3)
    • On a stable dose of warfarin or on a stable dose of low molecular weight heparin
    • Must not have active bleeding or a pathological condition that is associated with a high risk of bleeding
  • Caloric intake > 1,500 kilocalories/day
  • Albumin > 2 gm/dL
  • No known dihydropyrimidine dehydrogenase deficiency
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 6 months after discontinuing bevacizumab
  • No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction, unless diverting colostomy has been performed
  • No active inflammatory bowel disease
  • No history of cerebrovascular accident/transient ischemic attack
  • No myocardial infarction or unstable angina within the past 12 months
  • No peripheral neuropathy > grade 1
  • No clinically significant peripheral vascular disease
  • Patients with a history of hypertension must have a blood pressure of < 150/90 mm Hg and be on a stable regimen of antihypertensive therapy
  • No New York Heart Association class II-IV congestive heart failure
  • No evidence of bleeding diathesis/coagulopathy
  • No serious nonhealing wound or bone fracture
  • No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
  • No significant traumatic injury within the past 28 days
  • No other malignancy within the past 5 years except for in situ carcinomas that were completely removed
  • No known allergy to study drugs
  • No other serious medical illness or disease that might limit the patient's ability to receive protocol therapy
  • At least 28 days since prior major surgical procedure or open biopsy
  • At least 7 days since prior core biopsy
  • No prior chemotherapy for rectal cancer
  • No prior pelvic irradiation
  • No prior intra-operative radiotherapy (IORT) or brachytherapy treatment to the pelvis
  • No concurrent intensity-modulated radiotherapy
  • No concurrent full-dose anticoagulants
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00321685

  Show 83 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Jerome Landry Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00321685     History of Changes
Other Study ID Numbers: NCI-2009-01081, E3204, CDR0000471148, ECOG-E3204, U10CA021115
Study First Received: May 2, 2006
Last Updated: May 1, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Rectal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Antibodies
Antibodies, Monoclonal
Fluorouracil
Capecitabine
Oxaliplatin
Bevacizumab
Leucovorin
Levoleucovorin
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 20, 2014