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Cetuximab With or Without Brivanib in Treating Patients With Metastatic Colorectal Cancer

Information source: NCIC Clinical Trials Group
Information obtained from ClinicalTrials.gov on October 04, 2010
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Colorectal Cancer

Intervention: cetuximab (Biological); brivanib alaninate (Drug); laboratory biomarker analysis (Other)

Phase: Phase 3

Status: Recruiting

Sponsored by: NCIC Clinical Trials Group

Official(s) and/or principal investigator(s):
Lillian L. Siu, MD, FRCPC, Study Chair, Affiliation: Princess Margaret Hospital, Canada

Overall contact:
Chris O'Callaghan, Phone: 613-533-6430, Email: cocallaghan@ctg.queensu.ca

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.

Clinical Details

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 Tumors Previously Treated With Combination Chemotherapy for Metastatic Colorectal Carcinoma

Study design: Allocation: Randomized, Control: Placebo Control, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Overall survival

Secondary outcome:

Progression-free survival

Objective response rate

Duration of response

Quality of life (using EORTC QLQ-C30 and Skindex-16 Dermatology Survey)

Health utilities (using HUI3 Health Utilities Index)

Economic evaluation

Safety profile

Molecular markers

Detailed description: OBJECTIVES:

Primary

- To compare the overall survival of patients with previously treated 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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Chris O'Callaghan, Phone: 613-533-6430, Email: cocallaghan@ctg.queensu.ca

Tom Baker Cancer Centre - Calgary, Calgary, Alberta T2N 4N2, Canada; Recruiting
Jacob Easaw, Phone: 403-521-3446

Cross Cancer Institute at University of Alberta, Edmonton, Alberta T6G 1Z2, Canada; Recruiting
Michael Sawyer, Phone: 780-432-8248

BC Cancer Agency - Abbotsford Centre, Abbotsford, British Columbia V2S 0C2, Canada; Recruiting
Thuan Do, Phone: 604-851-4710

British Columbia Cancer Agency - Centre for the Southern Interior, Kelowna, British Columbia V1Y 5L3, Canada; Recruiting
Sanjay Chandar Rao, Phone: 250-712-3930

BCCA - Fraser Valley Cancer Centre, Surrey, British Columbia V3V 1Z2, Canada; Recruiting
Balvindar S. Johal, Phone: 604-587-4306

British Columbia Cancer Agency - Vancouver Cancer Centre, Vancouver, British Columbia V5Z 4E6, Canada; Recruiting
Hagen Kennecke, Phone: 604-877-6000

CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada; Recruiting
Ralph P.W. Wong, Phone: 204-237-2006

Moncton Hospital, Moncton, New Brunswick E1C 6Z8, Canada; Recruiting
Asif Shaikh, Phone: 506-860-2269

Doctor Leon Richard Oncology Centre, Moncton, New Brunswick E1C 8X3, Canada; Recruiting
Pierre Whitlock, Phone: 506-862-4030

Doctor H. Bliss Murphy Cancer Centre, St. John's, Newfoundland and Labrador AIB 3V6, Canada; Recruiting
Muhammad Zulfiqar, Phone: 709-777-7802

Royal Victoria Hospital of Barrie, Barrie, Ontario L4M 6M2, Canada; Recruiting
Robert El-Maraghi, Phone: 705-728-9090

Margaret and Charles Juravinski Cancer Centre, Hamilton, Ontario L8V 5C2, Canada; Recruiting
Elaine McWhirter, Phone: 905-387-9495

Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, Ontario K7L 5P9, Canada; Recruiting
Anna Tomiak, Phone: 613-549-6666

Grand River Regional Cancer Centre at Grand River Hospital, Kitchener, Ontario N2G 1G3, Canada; Recruiting
Gregory J. Knight, Phone: 519-749-4370

London Regional Cancer Program at London Health Sciences Centre, London, Ontario N6A 4L6, Canada; Recruiting
Mary J. MacKenzie, Phone: 519-685-8640

Southlake Regional Health Centre, Newmarket, Ontario L3Y 2P9, Canada; Recruiting
Janet A. MacKinnon, Phone: 905-895-4521

R. S. McLaughlin Durham Regional Cancer Centre at Lakeridge Health Oshawa, Oshawa, Ontario L1G 2B9, Canada; Recruiting
Rafal Wierzbicki, Phone: 905-576-8711

Ottawa Hospital Regional Cancer Centre - General Campus, Ottawa, Ontario K1H 8L6, Canada; Recruiting
Derek Jonker, Phone: 613-737-7700

Algoma District Cancer Program at Sault Area Hospital, Sault Ste. Marie, Ontario P6A 2C4, Canada; Recruiting
Bruce D. Keith, Phone: 705-759-3434

St. Catharines General Hospital at Niagara Health System, St. Catharines, Ontario L2R 7C6, Canada; Recruiting
Brian Findlay, Phone: 905-684-7271

Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario P3E 5J1, Canada; Recruiting
Jonathan Noble, Phone: 705-522-6237

Cancer Care Program at Thunder Bay Regional Health Sciences, Thunder Bay, Ontario P7B 6V4, Canada; Recruiting
Dorie-Anna Dueck, Phone: 807-684-7204

Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada; Recruiting
Lillian Siu, Phone: 416-946-2911

Edmond Odette Cancer Centre at Sunnybrook, Toronto, Ontario M4N 3M5, Canada; Recruiting
Yoo-Joung Ko, Phone: 416-480-4928

Toronto East General Hospital, Toronto, Ontario M4C 3E7, Canada; Recruiting
Richard H-F Shao, Phone: 416-469-6580

Prince Edward Island Cancer Centre at Queen Elizabeth Hospital, Charlottetown, Prince Edward Island C1A 8T5, Canada; Recruiting
Philip Champion, Phone: 902-894-2027

Hotel-Dieu de Levis, Levis, Quebec G6V 3Z1, Canada; Recruiting
Felix Couture, Phone: 418-691-5225

McGill Cancer Centre at McGill University, Montreal, Quebec H2W 1S6, Canada; Recruiting
Thierry Alcindor, Phone: 514-934-1934

Hopital Notre-Dame du CHUM, Montreal, Quebec H2L 4M1, Canada; Recruiting
Danielle Charpentier, Phone: 514-890-8200

Hopital du Saint-Sacrement - Quebec, Quebec City, Quebec G1S 4L8, Canada; Recruiting
Catherine Doyle, Phone: 418-649-5726

Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec G1R 2J6, Canada; Recruiting
Felix Couture, Phone: 418-691-5225

CHUS-Hopital Fleurimont, Sherbrooke, Quebec J1H 5N4, Canada; Recruiting
Rami R. Kotb, Phone: 819-346-1110

Allan Blair Cancer Centre at Pasqua Hospital, Regina, Saskatchewan S4T 7T1, Canada; Recruiting
Muhammad Salim, Phone: 306-766-2691

Saskatoon Cancer Centre at the University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada; Recruiting
Kamal Haider, Phone: 306-655-2710

Additional Information

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: May 2008
Last updated: May 31, 2010

Page last updated: October 04, 2010

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