Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Biomarker/Laboratory analysis, Treatment Active 18 and over Other CAN-NCIC-CO20 CO20, CAN-NCIC-CA182009, NCT00640471

Objectives

Primary

1. 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

1. To compare the progression-free survival of these patients.
2. To compare the objective response rate and duration of response in these patients.
3. To compare the quality of life of these patients.
4. To compare the health utilities of these patients.
5. To conduct a comparative economic evaluation of these patients.
6. To evaluate the safety profile of this regimen in these patients.
7. To explore an association between FGF-2, K-RAS 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.
8. 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.
9. To establish a comprehensive tumor bank linked to a clinical database for the further study of molecular markers in colorectal cancer.

Entry Criteria

Disease Characteristics:

• Histologically confirmed primary colorectal cancer
  • Metastatic disease



• 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

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

Patient Characteristics:

Inclusion criteria:

• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1.5 x 10⁹/L
• Platelet count ≥ 75 x 10⁹/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

Expected Enrollment

Outcomes

Overall survival

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

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 K-ras mutations status) and correlation with response.

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

Trial Contact Information

Trial Lead Organizations

NCIC-Clinical Trials Group

Lillian Siu, MD, FRCPC, Protocol chair		Ph: 416-946-2911

Canada
Ontario
	Ottawa
	Ottawa Hospital Regional Cancer Centre - General Campus
		Derek Jonker	Ph:  613-737-7700
	Toronto
	Princess Margaret Hospital
		Lillian Siu	Ph:  416-946-2911
Quebec
	Quebec City
	Centre Hospitalier Universitaire de Quebec
		Felix Couture	Ph:  418-691-5225
Saskatchewan
	Regina
	Allan Blair Cancer Centre at Pasqua Hospital
		Muhammad Salim	Ph:  306-766-2691

Registry Information
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 Previously Treated with Combination Chemotherapy for Metastatic Colorectal Carcinoma
Trial Start Date		2008-05-01 (estimated)
Trial Completion Date		2010-12-01 (estimated)
Registered in ClinicalTrials.gov		NCT00640471
Date Submitted to PDQ		2008-03-17
Information Last Verified		2008-05-20