Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00640471
First received: March 20, 2008
Last updated: July 16, 2013
Last verified: November 2012
  Purpose

RATIONALE: Brivanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Monoclonal antibodies, such as cetuximab, 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. It is not yet known whether giving brivanib together with cetuximab is more effective than cetuximab alone in treating patients with metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying cetuximab to see how well it works compared with cetuximab given together with brivanib in treating patients with metastatic colorectal cancer.


Condition Intervention Phase
Colorectal Cancer
Biological: cetuximab
Drug: brivanib alaninate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III Randomized Study of Brivanib Alaninate (BMS-582664) in Combination With Cetuximab (Erbitux®) Versus Placebo in Combination With Cetuximab (Erbitux®) in Patients With K-RAS Wild Type Tumors Previously Treated With Combination Chemotherapy for Metastatic Colorectal Carcinoma

Resource links provided by NLM:


Further study details as provided by NCIC Clinical Trials Group:

Primary Outcome Measures:
  • Overall survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Objective response rate [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Quality of life (using EORTC QLQ-C30 and Skindex-16 Dermatology Survey) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Health utilities (using HUI3 Health Utilities Index) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Economic evaluation [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Safety profile [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Molecular markers [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Enrollment: 750
Study Start Date: May 2008
Study Completion Date: January 2013
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Brivanib Biological: cetuximab
cetuximab (Erbitux®) - Initial dose - Day 1 (Week 1): 400 mg/m2 IV over 120 minutes Maintenance Infusions (subsequent weeks): 250 mg/m2 IV over 60 minutes
Drug: brivanib alaninate
brivanib (BMS-582664) 800 mg po, QD
Active Comparator: Placebo Biological: cetuximab
cetuximab (Erbitux®) - Initial dose - Day 1 (Week 1): 400 mg/m2 IV over 120 minutes Maintenance Infusions (subsequent weeks): 250 mg/m2 IV over 60 minutes

Detailed Description:

OBJECTIVES:

Primary

  • To compare the overall survival of patients with previously treated K-Ras wild type metastatic colorectal carcinoma treated with brivanib alaninate in combination with cetuximab versus placebo in combination with cetuximab.

Secondary

  • To compare the progression-free survival of these patients.
  • To compare the objective response rate and duration of response in these patients.
  • To compare the quality of life of these patients.
  • To compare the health utilities of these patients.
  • To conduct a comparative economic evaluation of these patients.
  • To evaluate the safety profile of this regimen in these patients.
  • To explore an association between FGF-2, BRAF mutations, amphiregulin (AREG) and epiregulin (EREG) as determined from paraffin embedded tumor specimens and the potential for clinical benefit from the addition of brivanib alaninate or placebo to cetuximab in terms of overall survival, progression-free survival and objective response rate compared to cetuximab alone.
  • To explore associations with mRNA and/or protein expression and/or variations in genes associated with epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), angiogenesis, and other related pathways and the potential for clinical benefit from the addition of brivanib alaninate to cetuximab in terms of overall survival, progression-free survival, and objective response rate compared to cetuximab alone.
  • To explore an association with changes of Collagen IV in the blood and the potential for clinical benefit from the addition of brivanib alaninate to cetuximab in terms of overall survival, progression-free survival and objective response rate compared to cetuximab alone.
  • To establish a comprehensive tumor bank linked to a clinical database for the further study of molecular markers in colorectal cancer.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center and ECOG performance status (0-1 vs 2). Patients are randomized to 1 of 2 arms.

  • Arm I: Patients receive oral brivanib alaninate once daily and cetuximab IV over 60-120 minutes once weekly.
  • Arm II: Patients receive oral placebo once daily and cetuximab IV over 60-120 minutes once weekly.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Tumor tissue and blood samples are collected for correlative studies. Samples are analyzed for biomarker levels (Collagen IV, FGF-2, and epiregulin, amphiregulin, and BRAF mutation status) and correlation with response.

After completion of study treatment, patients are followed at 4 weeks and then every 8 weeks thereafter.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed primary colorectal cancer

    • Metastatic disease
  • Tumor must be confirmed to be K-Ras wild type (i.e., No K-Ras mutation found) by means of mutation analysis performed on representative samples of diagnostic tumor tissue by a central reference laboratory (archival tumor samples are acceptable for K-Ras mutation analysis)
  • Must have received a prior thymidylate synthase inhibitor (e.g., fluorouracil, capecitabine, raltitrexed, or tegafur-uracil) for adjuvant and/or metastatic disease

    • Thymidylate synthase inhibitor may have been given in combination with oxaliplatin or irinotecan hydrochloride
  • Must meet one of the following criteria:

    • Received and failed* an irinotecan hydrochloride-containing regimen (i.e., single-agent or in combination) for treatment of metastatic disease
    • Relapsed within 6 months of completion of an irinotecan hydrochloride-containing adjuvant therapy
    • Has documented unsuitability** for an irinotecan hydrochloride-containing regimen NOTE: *Failure is defined as either progression of disease or intolerance to the irinotecan-containing regimen, where intolerance is defined as discontinuation due to any of the following: severe allergic reaction or delayed recovery from toxicity preventing retreatment NOTE: **Documented unsuitability for irinotecan includes known hypersensitivity to irinotecan, abnormal glucuronidation of bilirubin, Gilbert's syndrome, previous pelvic/abdominal irradiation, or elderly with comorbid conditions
  • Must meet one of the following:

    • Received and failed* an oxaliplatin-containing regimen (i.e. single-agent or in combination) for treatment of metastatic disease
    • Relapsed within 6 months of completion of an oxaliplatin containing adjuvant therapy
    • Has documented unsuitability** for an oxaliplatin-containing regimen NOTE: *Failure is defined as either progression of disease or intolerance to the oxaliplatin-containing regimen, where intolerance is defined as discontinuation due to any of the following: severe allergic reaction, persistent severe neurotoxicity or delayed recovery from toxicity preventing retreatment

NOTE: **Documented unsuitability for oxaliplatin includes known hypersensitivity to oxaliplatin or other platinum compounds, pre-existing renal impairment, or Grade 2 or greater neurosensory neuropathy

  • Measurable or evaluable disease
  • Patient must consent to provision of, and investigator(s) must confirm access to and agree to submit at the request of the NCIC CTG Central Tumor Bank, a representative formalin fixed paraffin block of tumour tissue
  • Patient must consent to provision of a sample of blood
  • No symptomatic CNS metastases

    • Patients with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI scans

PATIENT CHARACTERISTICS:

Inclusion criteria:

  • ECOG performance status 0-2
  • Absolute granulocyte count ≥ 1.5 x 10^9/L
  • Platelet count ≥ 75 x 10^9/L
  • Hemoglobin ≥ 80 g/L
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (2.0 times ULN with documented liver metastases)
  • ALT and AST ≤ 2.5 times ULN (5.0 times ULN with documented liver metastases)
  • Serum creatinine ≤ 1.5 times ULN or creatinine clearance > 50 mL/min
  • Magnesium > 0.5 mmol/L (1.2 mg/dL)
  • LVEF > 45% by ECHO or MUGA scan
  • No proteinuria ≥ 2+ on dipstick or ≥ 1 g on 24 hour urine collection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to, during, and for 12 weeks after completion of study treatment
  • Able (i.e., sufficiently fluent) and willing to complete the quality of life (EORTC QLQ-C30 and Skindex-16) and health utilities questionnaires (HUI3) in either English or French

Exclusion criteria:

  • A history of other malignancies, except: adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
  • Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy
  • Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with the protocol
  • Uncontrolled or significant cardiovascular disease including any of the following:

    • Myocardial infarction within 12 months
    • Uncontrolled angina within 6 months
    • Clinically significant congestive heart failure
    • Stroke, transient ischemic attack, or other ischemic event within 12 months
    • Severe cardiac valve dysfunction
  • Uncontrolled hypertension (consistent elevation of systolic BP > 150 and diastolic BP > 100 mmHg)
  • History of a thromboembolic event in the last 6 months despite being treated with anticoagulation

    • Patients are eligible if they have experienced a thromboembolic event greater than 6 months previously and have initiated and are stable on anticoagulation or if they have previously initiated and are stable on anticoagulation for prevention of thromboembolic events
  • Severe restrictive lung disease or radiological pulmonary findings of "interstitial lung disease" on the baseline chest x-ray which, in the opinion of the investigator, represents significant pathology
  • Serious non-healing wounds, ulcers, or bone fractures
  • History of allergy to brivanib (alaninate or related drug class
  • Unable to swallow tablets

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Adequately recovered from recent surgery, chemotherapy and/or radiation therapy
  • At least 4 weeks must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or prior radiation therapy
  • No prior cetuximab or other therapy* with targets the EGFR pathway (e.g., erlotinib hydrochloride, gefitinib hydrochloride, panitumumab)
  • May have received a single prior regimen which targets the VEGFR pathway (e.g., bevacizumab , vatalanib, AZD2171, sorafenib tosylate, sunitinib malate, or others)
  • No prior murine monoclonal antibody therapy (e.g., edrecolomab)
  • No other concurrent chemotherapy
  • No other concurrent therapies targeting the EGFR pathway (e.g., erlotinib, gefitinib, panitumumab, or others) or other therapies targeting the VEGFR pathway (e.g., bevacizumab , vatalanib, AZD2171, sorafenib tosylate, sunitinib malate, or others)
  • Concurrent antihypertensive therapies allowed
  • Concurrent aspirin allowed
  • No other concurrent noncytotoxic experimental agents
  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: NCT00640471

  Hide Study Locations
Locations
Canada, Alberta
Tom Baker Cancer Centre
Calgary, Alberta, Canada, T2N 4N2
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
BCCA - Abbotsford Centre
Abbotsford, British Columbia, Canada, V2S 0C2
BCCA - Cancer Centre for the Southern Interior
Kelowna, British Columbia, Canada, V1Y 5L3
BCCA - Fraser Valley Cancer Centre
Surrey, British Columbia, Canada, V3V 1Z2
BCCA - Vancouver Cancer Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Manitoba
CancerCare Manitoba
Winnipeg, Manitoba, Canada, R3E 0V9
Canada, New Brunswick
The Moncton Hospital
Moncton, New Brunswick, Canada, E1C 6Z8
The Vitalite Health Network - Dr. Leon Richard
Moncton, New Brunswick, Canada, E1C 8X3
Atlantic Health Sciences Corporation
Saint John, New Brunswick, Canada, E2L 4L2
Canada, Newfoundland and Labrador
Dr. H. Bliss Murphy Cancer Centre
St. John's, Newfoundland and Labrador, Canada, AIB 3V6
Canada, Ontario
The Royal Victoria Hospital
Barrie, Ontario, Canada, L4M 6M2
Juravinski Cancer Centre at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8V 5C2
Cancer Centre of Southeastern Ontario at Kingston
Kingston, Ontario, Canada, K7L 5P9
London Regional Cancer Program
London, Ontario, Canada, N6A 4L6
Stronach Regional Health Centre at Southlake
Newmarket, Ontario, Canada, L3Y 2P9
Lakeridge Health Oshawa
Oshawa, Ontario, Canada, L1G 2B9
Ottawa Health Research Institute - General Division
Ottawa, Ontario, Canada, K1H 8L6
Algoma District Cancer Program
Sault Ste. Marie, Ontario, Canada, P6B 0A8
Niagara Health System
St. Catharines, Ontario, Canada, L2R 7C6
Thunder Bay Regional Health Science Centre
Thunder Bay, Ontario, Canada, P7B 6V4
St. Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8
Toronto East General Hospital
Toronto, Ontario, Canada, M4C 3E7
Odette Cancer Centre
Toronto, Ontario, Canada, M4N 3M5
Univ. Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Canada, Prince Edward Island
PEI Cancer Treatment Centre,Queen Elizabeth Hospital
Charlottetown, Prince Edward Island, Canada, C1A 8T5
Canada, Quebec
Hopital Charles LeMoyne
Greenfield Park, Quebec, Canada, J4V 2H1
L'Hotel-Dieu de Levis
Levis, Quebec, Canada, G6V 3Z1
CHUM - Hopital Notre-Dame
Montreal, Quebec, Canada, H2L 4M1
McGill University - Dept. Oncology
Montreal, Quebec, Canada, H2W 1S6
Hopital du Sacre-Coeur de Montreal
Montreal, Quebec, Canada, H4J 1C5
CHA-Hopital Du St-Sacrement
Quebec City, Quebec, Canada, G1S 4L8
CHUQ-Pavillon Hotel-Dieu de Quebec
Quebec City, Quebec, Canada, G1R 2J6
Centre hospitalier universitaire de Sherbrooke
Sherbrooke, Quebec, Canada, J1H 5N4
Canada, Saskatchewan
Allan Blair Cancer Centre
Regina, Saskatchewan, Canada, S4T 7T1
Saskatoon Cancer Centre
Saskatoon, Saskatchewan, Canada, S7N 4H4
Sponsors and Collaborators
NCIC Clinical Trials Group
Investigators
Study Chair: Lillian L. Siu, MD, FRCPC Princess Margaret Hospital, Canada
  More Information

Additional Information:
Publications:
Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol 30, 2012 (suppl 4; abstr 386). Lillian L. Siu, Jeremy D. Shapiro, Derek J. Jonker, Christos Stelios Karapetis, John Raymond Zalcberg, John Simes, Felix Couture, Malcolm J. Moore, Timothy Jay Price, Jehan Siddiqui, Louise M. Nott, Danielle Charpentier, Winston S. Liauw, Michael B. Sawyer, Michael Jefford, Nadine M Magoski, Andrew Mark Haydon, Ian B. Walters, Dongsheng Tu, Christopher J. O'Callaghan.
Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, K-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol 30, 2012 (suppl; abstr 3504). Lillian L. Siu, Jeremy David Shapiro, Derek J. Jonker, Christos Stelios Karapetis, John Raymond Zalcberg, John Simes, Felix Couture, Malcolm J. Moore, Timothy Jay Price, Jehan Siddiqui, Louise M. Nott, Danielle Charpentier, Winston S. Liauw, Michael B. Sawyer, Michael Jefford, Nadine M Magoski, Andrew Mark Haydon, Ian B. Walters, Dongsheng Tu, Christopher J. O'Callaghan.

Responsible Party: NCIC Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00640471     History of Changes
Other Study ID Numbers: CO20, CAN-NCIC-CO20, CAN-NCIC-CA182009, CDR0000590316
Study First Received: March 20, 2008
Last Updated: July 16, 2013
Health Authority: Canada: Health Canada

Keywords provided by NCIC Clinical Trials Group:
recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014