Clinical trial NCT00640471: Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
First posted: 2008-03-21
Enrollment: 750
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Overall survival
timeFrame: 3 years
Secondary outcomes:
measure: Progression-free survival
timeFrame: 3 years
measure: Objective response rate
timeFrame: 3 years
measure: Duration of response
timeFrame: 3 years
measure: Quality of life (using EORTC QLQ-C30 and Skindex-16 Dermatology Survey)
timeFrame: 3 years
measure: Health utilities (using HUI3 Health Utilities Index)
timeFrame: 3 years
measure: Economic evaluation
timeFrame: 3 years
measure: Safety profile
timeFrame: 3 years
measure: Molecular markers
timeFrame: 3 years
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Abbotsford
country: Canada
facility: BCCA - Abbotsford Centre
state: British Columbia
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Barrie
country: Canada
facility: The Royal Victoria Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto East General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
state: Prince Edward Island
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Levis
country: Canada
facility: L'Hotel-Dieu de Levis
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Princess Margaret Hospital, Canada
name: Lillian L. Siu, MD, FRCPC
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.