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

• ClinicalTrials.gov Identifier: NCT00265850
• Recruitment Status: Completed
• First Posted: December 15, 2005
• Results First Posted: April 26, 2017
• Last Update Posted: May 7, 2020
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); SWOG Cancer Research Network; Bristol-Myers Squibb; Aptuit
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: December 14, 2005
• First Posted Date: December 15, 2005
• Results First Submitted Date: March 13, 2017
• Results First Posted Date: April 26, 2017
• Last Update Posted Date: May 7, 2020
• Study Start Date: November 2005
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2017)

Overall Survival [ Time Frame: Up to 5 years post-treatment ]

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: March 13, 2017)

• Progression-free Survival (PFS) [ Time Frame: Up to 5 years post-treatment ]
  PFS will be measured from study entry until first documented progression or death from any cause. Time to event distributions will be estimated using the Kaplan-Meier method. PFS will be compared between Arm A and Arm B.
• Time to Treatment Failure [ Time Frame: Up to 5 years post-treatment ]
• Duration of Tumor Response [ Time Frame: Up to 5 years post-treatment ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer
• Official Title: 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

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.

Detailed Description

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to physician-selected chemotherapy (FOLFOX or FOLFIRI), prior adjuvant chemotherapy (yes vs no), and prior pelvic radiotherapy (yes vs no). Patients were randomized to 1 of 3 treatment arms.

Primary Objective:

• To determine if the addition of cetuximab to FOLFIRI or FOLFOX chemotherapy prolongs survival compared to FOLFIRI or FOLFOX with bevacizumab in patients with untreated, advanced or metastatic colorectal cancer who have K-ras wild type tumors.

Secondary Objectives:

• To evaluate response, progression-free survival (PFS), time to treatment failure (TTF), and duration of response (DR) among patients with unresectable advanced metastatic colon cancer treated with bevacizumab or cetuximab in addition to chemotherapy with FOLFIRI or FOLFOX
• To evaluate toxicity and, in particular, 60-day mortality among patients with unresectable advanced metastatic colon cancer treated with bevacizumab or cetuximab in addition to chemotherapy with FOLFIRI or FOLFOX
• To describe patients with unresectable locally advanced or metastatic colorectal cancer rendered "resectable" with chemotherapy

There are premedication guidelines that were established for patients assigned to receive cetuximab. All patients must be premedicated with diphenhydramine hydrochloride 50 mg (or a similar agent) IV prior to the first dose of cetuximab in an effort to prevent an infusion or hypersensitivity reaction. Premedication is also recommended prior to subsequent doses, but at the investigator's discretion the dose of diphenhydramine (or a similar agent) may be reduced. Pretreatment with acetaminophen may also be used.

There are bevacizumab administration instructions for patients for whom surgery is being contemplated or required. For patients for whom elective surgery is contemplated, bevacizumab is to be discontinued for at least 8 weeks prior to surgery. Bevacizumab may be resumed after at least 4 weeks following surgery. Patients who undergo complete resection of metastatic disease will discontinue protocol therapy and may receive further treatment at the treating physician's discretion. For patients for whom non-elective surgery is required, hold bevacizumab as long as possible prior to surgery and for at least 6 weeks following surgery.

Patients received a minimum of two cycles of therapy. Patients were allowed to receive ancillary therapy per protocol. Treatment continued until disease progression, unacceptable toxicity, or surgery with curative intent as planned. After completion of study treatment, patients are followed up to 5 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Cancer

Intervention

• Biological: bevacizumab
  Given IV
• Biological: cetuximab
  Given IV
• Drug: FOLFOX or
  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
  Other Name: Eloxatin (oxaliplatin), leucovorin (folinic acid) and 5-Fluorouracil (5-FU)
• Drug: FOLFIRI
  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.
  Other Name: CPT-11 (irinotecan), leucovorin (folinic acid), and 5-Fluorouracil (5-FU)

Study Arms

• Active Comparator: Arm A: FOLFOX or FOLFIRI + bevacizumab
  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.
  Interventions:

  • Biological: bevacizumab
  • Drug: FOLFOX or
  • Drug: FOLFIRI
• Experimental: Arm B: FOLFOX or FOLFIRI + cetuximab
  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.
  Interventions:

  • Biological: cetuximab
  • Drug: FOLFOX or
  • Drug: FOLFIRI
• Experimental: Arm C: FOLFOX or FOLFIRI + cetuximab + bevacizumab
  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.
  Interventions:

  • Biological: bevacizumab
  • Biological: cetuximab
  • Drug: FOLFOX or
  • Drug: FOLFIRI

Publications *

• Schrag D, Naughton M, Kesselheim A, et al.: Clinical trial participants' strategies for coping with prescription drug costs: A companion study to CALGB 80405. [Abstract] J Clin Oncol 27 (Suppl 15): A-9503, 2009.
• Venook AP, Blanke CD, Niedzwiecki D, Lenz HJ, Taylor JR, Hollis DR, Sutherland S, Goldberg RM. Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 Trial: a phase III trial of chemotherapy and biologic agents for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer. 2007 May;6(7):536-8. doi: 10.3816/CCC.2007.n.021. No abstract available.
• Venook AP, Blanke CD, Niedzwiecki D, Lenz HJ, Taylor JR, Hollis DR, Sutherland S, Goldberg RM. Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer. 2005 Nov;5(4):292-4. doi: 10.3816/ccc.2005.n.043. No abstract available.
• Yuan C, Sato K, Hollis BW, Zhang S, Niedzwiecki D, Ou FS, Chang IW, O'Neil BH, Innocenti F, Lenz HJ, Blanke CD, Goldberg RM, Venook AP, Mayer RJ, Fuchs CS, Meyerhardt JA, Ng K. Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance). Clin Cancer Res. 2019 Dec 15;25(24):7497-7505. doi: 10.1158/1078-0432.CCR-19-0877. Epub 2019 Sep 23.
• Guercio BJ, Zhang S, Ou FS, Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, O'Neil BH, Shaw JE, Polite BN, Hochster HS, Atkins JN, Goldberg RM, Sato K, Ng K, Van Blarigan E, Mayer RJ, Blanke CD, O'Reilly EM, Fuchs CS, Meyerhardt JA. Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405. J Clin Oncol. 2019 Oct 10;37(29):2620-2631. doi: 10.1200/JCO.19.01019. Epub 2019 Aug 13.
• Lenz HJ, Ou FS, Venook AP, Hochster HS, Niedzwiecki D, Goldberg RM, Mayer RJ, Bertagnolli MM, Blanke CD, Zemla T, Qu X, Wirapati P, Tejpar S, Innocenti F, Kabbarah O. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2019 Aug 1;37(22):1876-1885. doi: 10.1200/JCO.18.02258. Epub 2019 May 1. Erratum In: J Clin Oncol. 2020 Feb 20;38(6):656.
• Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. doi: 10.1001/jama.2017.7105.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 16, 2014): 2334
• Original Enrollment: Not Provided
• Actual Study Completion Date: January 2018
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States
• Removed Location Countries: Puerto Rico

Administrative Information

• NCT Number: NCT00265850
• Other Study ID Numbers: CALGB 80405; U10CA037447 ( U.S. NIH Grant/Contract ); CDR0000455161 ( Other Identifier: Physician Data Query ); NCI-2009-00434 ( Registry Identifier: NCI Clinical Trial Reporting Program Office )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Not Provided
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Cancer and Leukemia Group B

Collaborators

• National Cancer Institute (NCI)
• SWOG Cancer Research Network
• Bristol-Myers Squibb
• Aptuit

Investigators

• Study Chair: Alan Venook, MD; University of California, San Francisco

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: April 2020