NCT00265850|CompletedPhase 3ResultsDMC

Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer

A Phase III Trial of Irinotecan / 5-FU / Leucovorin or Oxaliplatin / 5-FU/ Leucovorin With Bevacizumab, or Cetuximab (C225), or With the Combination of Bevacizumab and Cetuximab for Patients With Untreated Metastatic Adenocarcinoma of the Colon or Rectum

Alliance for Clinical Trials in Oncology ClinicalTrials.gov

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4 other identifiers

CALGB 80405U10CA037447CDR0000455161NCI-2009-00434

Study Type

interventional

Target

2,334

Locations

2 countries

Sites

683

Timeline

RegisteredDec 2005

StartedNov 2005

CompletionJan 2018

Brief Summary

PURPOSE: This randomized phase III trial is studying cetuximab and/or bevacizumab when given together with combination chemotherapy to compare how well they work in treating patients with metastatic colorectal cancer. RATIONALE: Monoclonal antibodies, such as cetuximab and 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. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, leucovorin, oxaliplatin, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibodies together with combination chemotherapy may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with cetuximab and/or bevacizumab in treating patients with colorectal cancer.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

2,334

participants targeted

Target at P75+ for phase_3 colorectal-cancer

Timeline

Completed

Started Nov 2005

Longer than P75 for phase_3 colorectal-cancer

Geographic Reach

2 countries

683 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

12.2 years study duration

Study Start

First participant enrolled

November 1, 2005

Completed

1 month until next milestone

First Submitted

Initial submission to the registry

December 14, 2005

Completed

1 day until next milestone

First Posted

Study publicly available on registry

December 15, 2005

Completed

9.1 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 1, 2015

Completed

2.2 years until next milestone

Results Posted

Study results publicly available

April 26, 2017

Completed

8 months until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2018

Completed

Last Updated

May 7, 2020

Status Verified

April 1, 2020

Enrollment Period

9.3 years

First QC Date

December 14, 2005

Results QC Date

March 13, 2017

Last Update Submit

April 28, 2020

Conditions

Colorectal Cancer

Keywords

recurrent colon cancerstage III colon cancerstage III rectal cancerstage IV colon cancerrecurrent rectal cancerstage IV rectal canceradenocarcinoma of the colonadenocarcinoma of the rectum

Outcome Measures

Primary Outcomes (1)

Overall Survival
Survival time will be defined as the time from registration to death. Time to event distributions will be estimated using the Kaplan-Meier method. Overall Survival (OS) will be compared between Arm A and Arm B.
Up to 5 years post-treatment

Secondary Outcomes (3)

Progression-free Survival (PFS)
Up to 5 years post-treatment
Time to Treatment Failure
Up to 5 years post-treatment
Duration of Tumor Response
Up to 5 years post-treatment

Study Arms (3)

Arm A: FOLFOX or FOLFIRI + bevacizumab

ACTIVE COMPARATOR

Patients receive bevacizumab 5 mg/kg IV every two weeks and then receive either FOLFOX or FOLFIRI every two weeks as described in the intervention section. One cycle is defined as 8 weeks of treatment. Treatment continues until disease progression, unacceptable toxicity or surgery with curative intent as planned.

Biological: bevacizumabDrug: FOLFOX orDrug: FOLFIRI

Arm B: FOLFOX or FOLFIRI + cetuximab

EXPERIMENTAL

Patients receive cetuximab 400mg/m\^2 IV over 2 hours on the first day of treatment, then 250 mg/m\^2 IV over 1 hour weekly thereafter. Patients also receive either FOLFOX or FOLFIRI every two weeks as described in the intervention section. One cycle is defined as 8 weeks of treatment. Treatment continues until disease progression, unacceptable toxicity or surgery with curative intent as planned.

Biological: cetuximabDrug: FOLFOX orDrug: FOLFIRI

Arm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab

EXPERIMENTAL

Patients receive cetuximab 400mg/m\^2 IV over 2 hours on the first day of treatment, then 250 mg/m\^2 IV over 1 hour weekly thereafter. Also, patients receive bevacizumab 5 mg/kg IV every two weeks and then receive either FOLFOX or FOLFIRI every two weeks as described in the intervention section. One cycle is defined as 8 weeks of treatment. Treatment continues until disease progression, unacceptable toxicity or surgery with curative intent as planned.

Biological: bevacizumabBiological: cetuximabDrug: FOLFOX orDrug: FOLFIRI

Interventions

bevacizumabBIOLOGICAL

Given IV

Arm A: FOLFOX or FOLFIRI + bevacizumabArm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab

cetuximabBIOLOGICAL

Given IV

Arm B: FOLFOX or FOLFIRI + cetuximabArm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab

FOLFOX orDRUG

Patients receive oxaliplatin 85 mg/m\^2 IV infused over two hours followed by leucovorin 400 mg/m\^2 IV over 2 hours followed by 5-FU 400 mg/m\^2 IV bolus, then 2400 mg/m\^2 continuous IV infusion over 46-48 hours

Also known as: Eloxatin (oxaliplatin), leucovorin (folinic acid) and 5-Fluorouracil (5-FU)

Arm A: FOLFOX or FOLFIRI + bevacizumabArm B: FOLFOX or FOLFIRI + cetuximabArm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab

FOLFIRIDRUG

Patients receive irinotecan 180 mg/m\^2 IV infused over 90 minutes followed by leucovorin 400 mg/m\^2 IV over 2 hours followed by 5-FU 400 mg/m\^2 IV bolus following leucovorin then 2400 mg/m\^2 continuous IV infusion over 46-48 hours.

Also known as: CPT-11 (irinotecan), leucovorin (folinic acid), and 5-Fluorouracil (5-FU)

Arm A: FOLFOX or FOLFIRI + bevacizumabArm B: FOLFOX or FOLFIRI + cetuximabArm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab

Eligibility Criteria

Age18 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

1. Locally Advanced or Metastatic Colorectal Cancer 1. Eligible patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have either locally advanced (unresectable) or metastatic disease. Patients with resected primary tumors who have documented metastases are eligible. Documentation of residual disease by CT scan or surgeon's notes is required for all patients, and histologic confirmation of metastases is strongly encouraged. 2. Patients with a history of colorectal cancer treatment by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless: * Either an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease or * The primary cancer was stage I. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature or source of apparent metastases. 3. At the time of randomization, the intent of this treatment must be indicated palliative or neoadjuvant chemotherapy with the potential for resection of all sites of metastatic disease. 2. Only patients with a wildtype K-ras gene as determined by the laboratory at the SWOG Solid Tumor Repository or by a local CLIA-certified laboratory are eligible. Patients with a mutation in the K-ras gene are ineligible. All patients must have available for analysis of K-ras status at least one H and E slide and one paraffin block of the previously resected primary colorectal tumor and/or a tumor deposit. For patients registered and randomized based on local CLIA-certified laboratory results, SWOG analysis will be confirmatory only. 3. Prior Treatment 1. No prior systemic treatment for advanced or metastatic colorectal cancer is allowed. Prior regional chemotherapy (eg, hepatic arterial infusion) is also not allowed. * Patients may have received prior adjuvant chemotherapy that included fluorouracil alone or in combination with fluorouracil and oxaliplatin or irinotecan (no more than 6 months); or radiation with radiosensitizing chemotherapy. * The last course of adjuvant chemotherapy must have concluded \> 12 months prior to colorectal cancer recurrence. * Patients may have received neoadjuvant chemo-radiation with capecitabine or 5-fluorouracil. * Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to randomization. * No prior exposure to any tyrosine kinase inhibitors or other agents (including protein products, monoclonal antibodies, antisense, etc.) that target VEGF or EGF receptors is allowed. * No prior treatment with bevacizumab or cetuximab. 2. Patients may not have had prior radiotherapy to greater than 25% of bone marrow. (Standard adjuvant rectal cancer chemoradiation will not exclude patient from protocol entry.) Radiation must have concluded ≥ 4 weeks prior to randomization. 3. Patients should have completed any major surgery ≥ 4 weeks from randomization. Patients must have completed any minor surgery ≥ 2 weeks prior to randomization. Patients must have fully recovered from the procedure. (Insertion of a vascular access device is not considered major or minor surgery.) 4. No previous or concurrent malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years. 5. For patients who are to receive FOLFIRI: No evidence of Gilbert's Syndrome or of homozygosity for the UGT1A1\*28 allele. 1. Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome would include a prior finding of an isolated elevation of indirect bilirubin. 2. UGT1A1 genotyping is not required on this study. However, patients known to be homozygous for the UGT1A1\*28 allele are not to receive FOLFIRI for this study. Patients with Gilbert's Syndrome or who are found to be homozygous for the UGT1A1 allele who will receive FOLFOX are eligible. 6. No sensory peripheral neuropathy of ≥ grade 2 at baseline for patients who are to receive FOLFOX. 7. No known central nervous system metastases or carcinomatous meningitis. 8. No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung. 9. No pleural effusion or ascites that causes ≥ grade 2 dyspnea. 10. No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of \> 3 watery or soft stools daily in patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy may entered at investigator discretion. 11. Patients must not have an uncontrolled seizure disorder, or active neurological disease. 12. No current congestive heart failure (New York Heart Association Class II, III or IV) 13. Patients with history of hypertension must be well controlled ( \< 160/90) on a regimen of anti-hypertensive therapy. 14. Patients on full-dose anticoagulation (eg, warfarin) are eligible provided that both of the following criteria are met: 1. The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or be on a stable dose of low molecular weight heparin. 2. The patient has no active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices). 15. Patients receiving anti-platelet agents are eligible. In addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible. 16. No significant history of bleeding events or GI perforation: 1. Patients with a history of significant bleeding episodes (eg, hemoptysis, upper or lower GI bleeding ) within 6 months of randomization are not eligible unless the source of bleeding has been resected. 2. Patients with a history of GI perforation within 12 months of randomization are not eligible. 17. No arterial thrombotic events within 6 months before randomization, including transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI). Patients with clinically significantly peripheral artery disease (eg, claudication on less than one block) or any other arterial thrombotic event are also ineligible. 18. No serious or non-healing wound, ulcer or bone fracture 19. Patients with known hypersensitivity to Chinese hamster ovary cell products or to recombinant human or murine antibodies are not eligible. 20. Non-pregnant and not nursing: 1. Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to randomization. 2. DNA alkylating agents are known to be teratogenic, and the effects of irinotecan, oxaliplatin, 5-FU, bevacizumab, and cetuximab on a developing fetus at the recommended therapeutic doses are unknown. 3. Women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal. 4. Postmenopausal is defined as amenorrhea ≥ 12 consecutive months or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL. 5. Women of child-bearing potential also include women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (eg, vasectomy), should be considered to be of child bearing potential. 21. ECOG Performance Status of 0-1 22. Age ≥ 18 years 23. Required Initial Laboratory Values: 1. Granulocytes ≥ 1500 µL 2. Hemoglobin ≥ 9.0 grams/dL (patient may be transfused to meet this criterion) 3. Platelet count ≥ 100,000/µL 4. Creatinine ≤ 1.5 x Upper limits of normal 5. Bilirubin ≤ 1.5 mg/dL 6. Albumin ≥ 2.5 g/dL 7. Urinalysis ≤ 1 + protein\* * \*Patients discovered to have ≥ 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate \< 1 g of protein/24 hour or have a UPC \< 1.0 to allow participation in the study.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

Alliance for Clinical Trials in Oncologylead
National Cancer Institute (NCI)collaborator
SWOG Cancer Research Networkcollaborator
Bristol-Myers Squibbcollaborator
Aptuitcollaborator

Study Sites (683)

Providence Cancer Center at Providence Hospital

Mobile, Alabama, 36608, United States

Location

Alaska Regional Hospital Cancer Center

Anchorage, Alaska, 99508, United States

Location

Providence Cancer Center

Anchorage, Alaska, 99508, United States

Location

Hembree Mercy Cancer Center at St. Edward Mercy Medical Center

Fort Smith, Arkansas, 72903, United States

Location

NEA Medical Center - Stadium Boulevard

Jonesboro, Arkansas, 72401, United States

Location

Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center

Burbank, California, 91505, United States

Location

East Bay Radiation Oncology Center

Castro Valley, California, 94546, United States

Location

Valley Medical Oncology Consultants - Castro Valley

Castro Valley, California, 94546, United States

Location

North Bay Cancer Center

Fairfield, California, 94533, United States

Location

Kaiser Permanente - Fremont

Fremont, California, 94538, United States

Location

Valley Medical Oncology

Fremont, California, 94538, United States

Location

Glendale Memorial Hospital Comprehensive Cancer Center

Glendale, California, 91204, United States

Location

California Cancer Care, Incorporated - Greenbrae

Greenbrae, California, 94904, United States

Location

Kaiser Permanente Medical Center - Hayward

Hayward, California, 94545, United States

Location

Veterans Affairs Medical Center - Loma Linda (Pettis)

Loma Linda, California, 92357, United States

Location

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, 90089-9181, United States

Location

Contra Costa Regional Medical Center

Martinez, California, 94553-3156, United States

Location

Tibotec Therapeutics - Division of Ortho Biotech Products, LP

Marysville, California, 95901, United States

Location

Camino Medical Group - Treatment Center

Mountain View, California, 94040, United States

Location

El Camino Hospital Cancer Center

Mountain View, California, 94040, United States

Location

Alta Bates Summit Medical Center - Summit Campus