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

NCT ID: NCT00640471

Last Updated: 2023-08-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 750 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-05-12
• Study Completion Date: 2013-01-10

Brief Summary

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.

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Brivanib

Group Type: ACTIVE_COMPARATOR

cetuximab

Intervention Type: BIOLOGICAL

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

brivanib alaninate

Intervention Type: DRUG

brivanib (BMS-582664) 800 mg po, QD

Placebo

Group Type: ACTIVE_COMPARATOR

cetuximab

Intervention Type: BIOLOGICAL

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

Interventions

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

Intervention Type: BIOLOGICAL

brivanib alaninate

brivanib (BMS-582664) 800 mg po, QD

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

PATIENT CHARACTERISTICS:

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

NCIC Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lillian L. Siu, MD, FRCPC

Role: STUDY_CHAIR

Princess Margaret Hospital, Canada

Locations

Tom Baker Cancer Centre

Calgary, Alberta, Canada

Cross Cancer Institute

Edmonton, Alberta, Canada

BCCA - Abbotsford Centre

Abbotsford, British Columbia, Canada

BCCA - Cancer Centre for the Southern Interior

Kelowna, British Columbia, Canada

BCCA - Fraser Valley Cancer Centre

Surrey, British Columbia, Canada

BCCA - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

CancerCare Manitoba

Winnipeg, Manitoba, Canada

The Moncton Hospital

Moncton, New Brunswick, Canada

The Vitalite Health Network - Dr. Leon Richard

Moncton, New Brunswick, Canada

Atlantic Health Sciences Corporation

Saint John, New Brunswick, Canada

Dr. H. Bliss Murphy Cancer Centre

St. John's, Newfoundland and Labrador, Canada

The Royal Victoria Hospital

Barrie, Ontario, Canada

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, Canada

Cancer Centre of Southeastern Ontario at Kingston

Kingston, Ontario, Canada

Grand River Regional Cancer Centre

Kitchener, Ontario, Canada

London Regional Cancer Program

London, Ontario, Canada

Stronach Regional Health Centre at Southlake

Newmarket, Ontario, Canada

Lakeridge Health Oshawa

Oshawa, Ontario, Canada

Ottawa Health Research Institute - General Division

Ottawa, Ontario, Canada

Algoma District Cancer Program

Sault Ste. Marie, Ontario, Canada

Niagara Health System

St. Catharines, Ontario, Canada

Thunder Bay Regional Health Science Centre

Thunder Bay, Ontario, Canada

Toronto East General Hospital

Toronto, Ontario, Canada

Odette Cancer Centre

Toronto, Ontario, Canada

St. Michael's Hospital

Toronto, Ontario, Canada

Univ. Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

PEI Cancer Treatment Centre,Queen Elizabeth Hospital

Charlottetown, Prince Edward Island, Canada

Hopital Charles LeMoyne

Greenfield Park, Quebec, Canada

L'Hotel-Dieu de Levis

Lévis, Quebec, Canada

CHUM - Hopital Notre-Dame

Montreal, Quebec, Canada

McGill University - Dept. Oncology

Montreal, Quebec, Canada

Hopital du Sacre-Coeur de Montreal

Montreal, Quebec, Canada

CHUQ-Pavillon Hotel-Dieu de Quebec

Québec, Quebec, Canada

CHA-Hopital Du St-Sacrement

Québec, Quebec, Canada

Centre hospitalier universitaire de Sherbrooke

Sherbrooke, Quebec, Canada

Allan Blair Cancer Centre

Regina, Saskatchewan, Canada

Saskatoon Cancer Centre

Saskatoon, Saskatchewan, Canada

Countries

Canada

References

Quality of life (QoL) assessment in patients (pts) with K-RAS wild-type (WT) chemotherapy refractory metastatic colorectal cancer (mCRC) treated with cetuximab (CET) plus brivanib alaninate (BRIV) or placebo: Results of the NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol 30, 2012 (suppl 4; abstr 542). Jolie Ringash, Heather-Jane Au, Lillian L. Siu, Jeremy D. Shapiro, Derek J. Jonker, John Raymond Zalcberg, Malcolm J. Moore, Andrew H. Strickland, Rami Kotb, Mark Jeffery, Thierry Alcindor, Siobhan Ng, Muhammad Salim, Sabe S. Sabesan, Jacob C. Easaw, Jennifer Anne Shannon, Fabyolla El-Tahche, Ian B. Walters, Dongsheng Tu, Christopher J. O'Callaghan.

Reference Type: BACKGROUND

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.

Reference Type: RESULT

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.

Reference Type: RESULT

Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A 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). J Clin Oncol 30, 2012 (suppl; abstr 3572). Jeremy David Shapiro, Lillian L. Siu, Christopher J O'Callaghan, John Raymond Zalcberg, Malcolm J. Moore, Timothy Jay Price, Catherine Doyle, John Simes, Brian Peter Findlay, Michelle F. Cronk, Asif Shaikh, Warren Lance Joubert, Benoit Samson, Antonino Bonaventura, Craig Underhill, David Wyld, Ian B. Walters, Penny Phillips, Dongsheng Tu, Derek J. Jonker.

Reference Type: RESULT

Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. doi: 10.1200/JCO.2012.46.0543. Epub 2013 May 20.

Reference Type: RESULT

PMID: 23690424 (View on PubMed)

Nicholls DL, Xu MC, Zhan L, Sharma D, Hueniken K, Chiasson K, Wahba M, Brown MC, Grant B, Shapiro J, Karapetis CS, Simes J, Jonker D, Tu D, O'Callaghan C, Chen E, Liu G. Machine Learning Models of Early Longitudinal Toxicity Trajectories Predict Cetuximab Concentration and Metastatic Colorectal Cancer Survival in the Canadian Cancer Trials Group/AGITG CO.17/20 Trials. JCO Clin Cancer Inform. 2025 Apr;9:e2400114. doi: 10.1200/CCI.24.00114. Epub 2025 Apr 11.

Reference Type: DERIVED

PMID: 40215447 (View on PubMed)

Hay AE, Pater JL, Corn E, Han L, Camacho X, O'Callaghan C, Chong N, Bell EN, Tu D, Earle CC. Pilot study of the ability to probabilistically link clinical trial patients to administrative data and determine long-term outcomes. Clin Trials. 2019 Feb;16(1):14-17. doi: 10.1177/1740774518815653. Epub 2018 Nov 22.

Reference Type: DERIVED

PMID: 30466310 (View on PubMed)

Other Identifiers

CAN-NCIC-CO20

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000590316

Identifier Type: OTHER

Identifier Source: secondary_id

CO20

Identifier Type: -

Identifier Source: org_study_id