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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: cetuximab; Drug: brivanib alaninate

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.

• Study Type: Interventional
• Enrollment (Actual): 750
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S 0C2
      • BCCA - Abbotsford Centre
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA - Vancouver Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • The Moncton Hospital
    • Moncton, New Brunswick, Canada, E1C 8X3
      • The Vitalite Health Network - Dr. Leon Richard
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Atlantic Health Sciences Corporation
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
      • Dr. H. Bliss Murphy Cancer Centre
  • Ontario
    • Barrie, Ontario, Canada, L4M 6M2
      • The Royal Victoria Hospital
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Regional Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Newmarket, Ontario, Canada, L3Y 2P9
      • Stronach Regional Health Centre at Southlake
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Oshawa
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Health Research Institute - General Division
    • Sault Ste. Marie, Ontario, Canada, P6B 0A8
      • Algoma District Cancer Program
    • St. Catharines, Ontario, Canada, L2R 7C6
      • Niagara Health System
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Science Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M4C 3E7
      • Toronto East General Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 8T5
      • PEI Cancer Treatment Centre,Queen Elizabeth Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Levis, Quebec, Canada, G6V 3Z1
      • L'Hotel-Dieu de Levis
    • Montreal, Quebec, Canada, H4J 1C5
      • Hôpital du Sacré-Coeur de Montréal
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
    • Quebec City, Quebec, Canada, G1R 2J6
      • CHUQ-Pavillon Hotel-Dieu de Quebec
    • Quebec City, Quebec, Canada, G1S 4L8
      • CHA-Hopital Du St-Sacrement
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	3 years
Objective response rate	3 years
Duration of response	3 years
Quality of life (using EORTC QLQ-C30 and Skindex-16 Dermatology Survey)	3 years
Health utilities (using HUI3 Health Utilities Index)	3 years
Economic evaluation	3 years
Safety profile	3 years
Molecular markers	3 years

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Investigators: Study Chair: Lillian L. Siu, MD, FRCPC, Princess Margaret Hospital, Canada

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2008
• Primary Completion (Actual): September 6, 2011
• Study Completion (Actual): January 10, 2013

Study Registration Dates

• First Submitted: March 20, 2008
• First Submitted That Met QC Criteria: March 20, 2008
• First Posted (Estimated): March 21, 2008

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: CO20; CAN-NCIC-CO20 (Registry Identifier: NCI US - Physician Data Query); CDR0000590316 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No