A Randomized Double-Blinded Phase II Study of Carboplatin/Paclitaxel/CT-322 versus Carboplatin/Paclitaxel/Bevacizumab as First-Line Treatment for Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology

• Register: REBEC
• Last refreshed on: 29 April 2013
• Main ID: RBR-48pb9h
• Date of registration: 13/06/2011
• Primary sponsor: Bristol-Myers Squibb - Brazil
• Public title: A Randomized Double-Blinded Phase II Study of Carboplatin/Paclitaxel/CT-322 versus Carboplatin/Paclitaxel/Bevacizumab as First-Line Treatment for Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology
• Scientific title: A Randomized Double-Blinded Phase II Study of Carboplatin/Paclitaxel/CT-322 versus Carboplatin/Paclitaxel/Bevacizumab as First-Line Treatment for Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology
• Date of first enrolment: 01/07/2010
• Target sample size: 254
• Recruitment status: recruiting
• URL: http://www.ensaiosclinicos.gov.br/rg/RBR-48pb9h/
• Study design: A therapeutic, phase 2, double-blind , parallel, randomized with 2 arms, multicenter study

Countries of recruitment

Brazil, France, Italy, Poland, Russian Federation, South Africa, United Kingdom

Contacts

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

Key inclusion & exclusion criteria

Inclusion criteria: Subjects must sign an informed consent prior to any study-related procedures.
Histologically or cytologically confirmed, stage IIIB (malignant pleural effusion), stage IV or recurrent Non Small Cell Lung Cancer;
Measurable disease by Response Evaluation Criteria In Solid Tumors guidelines, with at least 1 target lesion outside any previous radiotherapy field;
Eastern Cooperative Oncology Group performance status < 1;
Life expectancy of at least 3 months;
Accessible for treatment and follow-up. Subjects enrolled in this trial must be treated at the participating center(s).
Willing to give a whole blood sample for the study of proteins and genetic polymorphisms in genes related to the Vascular Endothelial Growth Factor signaling pathway.
Men and women, ages >18 years.
Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study [and for up to 6 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized.
Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Postmenopause is defined as:
Amenorrhea > 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone level > 35 International Units/mL
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 International Units/L or equivalent units of Human Chorionic Gonadotropin) within 72 hours prior to the start of investigational product.

Exclusion criteria: Women of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period [and for up to 6 weeks after the last dose of investigational product]
Women who are pregnant or breastfeeding
Women with a positive pregnancy test on enrollment or prior to investigational product administration
Sexually active fertile men not using effective birth control if their partners are Women of childbearing potential.
Evidence of predominantly squamous-cell histology (mixed cell type tumors only)
Known central nervous system metastasis
Less than 28 days elapsed following major surgery
Excessive risk of bleeding such as history of clinically significant bleeding diathesis or coagulopathy including platelet function disorder (eg, known hemophilia or von Willebrand disease) or acquired bleeding disorder within 12 months (eg, acquired anti-factor VIII antibodies)
Gross hemoptysis (>= 1/2 tablespoon of red blood)
Subjects receiving therapeutic anticoagulation
Thrombotic or embolic cerebrovascular accident including transient ischemic attacks within the past 12 months
Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg or diastolic > 90 mmHg, measured repeatedly at >=2 visits despite adequate treatment with >= 2 antihypertensive drugs)
Clinically significant cardiovascular disease, including (but not limited to) the following:
Myocardial infarction within the past 6 months
Unstable angina
New York Heart Association class II-IV congestive heart failure
Serious cardiac arrhythmia (eg ventricular arrhythmia, high-grade atrioventricular block), not controlled by medication or requiring medication which might interfere with regularity of study treatment
Left ventricular ejection fraction below institutional lower limit of normal as measured by 2-dimensional echocardiogram or cardiac MUGA scan.
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
Serious non-healing wound, active peptic ulcer, non-healing bone fracture, or bleeding skin metastases
Glomerulonephritis or other protein-wasting glomerulopathy
Active clinically significant infection(> Grade 2) requiring the use of antimicrobial agents, or that would otherwise, in the opinion of the investigator, interfere with the ability the subject to participate
Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in-situ of the cervix
Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent
Any serious uncontrolled medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive study therapy.
Hemoglobin <9.0 g/dL, Absolute Neutrophil Count <1500 cells/mm3, Platelets <100,000 cells/mm3
Serum creatinine >1.5 mg/dL
Calculated creatinine clearance <50 mL/min (using Cockcroft and Gault formula)
Urine protein/creatinine ratio > 1
Serum total bilirubin >1.5 times the institutional upper limit of normal, unless due to Gilbert’s disease
Alanine transaminase or aspartate aminotransferase >2.5 times the institutional upper limit of normal (>5 times upper limit of normal for subjects with documented liver metastases)
Serum amylase and lipase >1.5 times the upper limit of normal
Known hypersensitivity to any of the investigational products or excipients, including Cremophor EL®
Any prior antineoplastic s

Age minimum: 18Y
Age maximum: 0Y
Gender: -

Health Condition(s) or Problem(s) studied

C00-D48

Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology
C04.588.894.797.520.109.220.249

Intervention(s)

Comparison group: 127 patients receive paclitaxel (200 mg/m2) and carboplatin on day 1 of a cycle of 21 days and CT-322 administered in blinded (2 mg / kg) weekly. Control group: 127 patients receive paclitaxel (200 mg/m2) and carboplatin on day 1 of a 21-day cycle, and bevacizumab (15 mg / kg) on day 1 and placebo on days 8 and 15, a 21-day cycle, in blinded, to match the schedule of administration of CT-322.
All patients will receive carboplatin and paclitaxel for a maximum of 6 treatment cycles (each cycle 21 days) or until they have documented progressive disease or unacceptable toxic signs develop, or withdraw consent, whichever occurs first. Patients in arms A and B receive CT-322 (on days 1, 8 and 15 of the 21-day cycle) or placebo and bevacizumab (bevacizumab on day 1 of cycle and placebo on days 8 and 15 of the cycle), respectively, blinded, until they have documented progressive disease or until unacceptable toxic signs develop, or withdraw consent, whichever occurs first. Assessments of efficacy will be performed every 6 weeks until documented progressive disease, death or the introduction of a subsequent therapy for Lung Cancer Non-Small Cell. Security will be evaluated weekly for all patients treated.
The length of treatment is 6 cycles (each cycle 21 days). After the sixth cycle, patients enter the maintenance period and will only receive CT-322 (on days 1, 8 and 15 of the 21-day cycle) or placebo and bevacizumab (bevacizumab on day 1 and placebo in cycle 8 and 15 cycle) according to the arm of the study until they have documented progressive disease or until unacceptable toxic signs develop, or withdraw consent, whichever occurs first.

Primary Outcome(s)

The primary efficacy analysis will be performed for all randomized subjects. The primary analysis of progression-free survival will be performed when 170 progression free survival events have occurred. The difference between the 2 treatment arms will be tested using a one-sided, alpha = 0.15 level, log-rank test. This analysis is considered the primary analysis. In addition, a sensitivity analysis will be performed to test this difference using a one-sided alpha = 0.15 level, log-rank test stratified by Eastern Cooperative Oncology Group Performance Status (0 vs 1) and disease stage (Stage IIIB or IV).
Additional analyses of progression free survival will include the computation of hazard ratios and the estimation of survival functions. The progression free survival hazard ratio of CT-322 to bevacizumab, an associated one-sided 85% confidence interval, and a two-sided 95% confidence interval will be computed using unadjusted and adjusted Cox proportional hazards modeling. Cox models will include treatment only, treatment stratified by the above-mentioned stratification factors, and an adjusted model which will include a pre-defined list of covariates (listed below) as well as the abovementioned stratification factor, all as covariates. The progression free survival function for each treatment arm will be estimated using Kaplan-Meier methodology. In addition, one-sided 85% confidence bound and a 95% confidence interval for the median progression free survival will be computed by treatment arm.
The following are the prognostic factors to be included in the adjusted Cox proportional hazards models: age (> 65, <= 65 years), Eastern Cooperative Oncology Group Performance Status and disease stage.

The primary objective is to compare the Progressio Free Survival of CT-322 versus bevacizumab in combination with carboplatin and paclitaxel in chemonaive subjects with recurrent or advanced non-squamous Non Small Cell Lung Cancer.

Secondary Outcome(s)

• To compare overall survival between the two treatment arms
• To compare the objective tumor response rate between the two treatment arms
• To estimate the duration of response and time to response in each of the two treatment arms
• To evaluate the safety in the CT-322 plus carboplatin and paclitaxel arm
• To evaluate the pharmacokinetics of CT-322 and paclitaxel when administered in combination.

Secondary efficacy analyses will be performed for all randomized subjects. Overall survival and time to response will be compared for the two treatment arms using a two-sided alpha = 0.05 level, log-rank test. When 80% of the patients have died (n=203), this can detect a Hazard Ratio of 0.77 with 80% power and an alpha of 0.15.
The same unadjusted and adjusted Cox proportional hazards modeling as specified for progression free survival will be computed for overall survival and time to response. Kaplan Meier curves will be presented by treatment arm. In addition, the two-sided 95% confidence intervals for the median overall survival and time to response will be computed by treatment arm.

Secondary ID(s)

05013/2009

148/10

NCT00850577

Source(s) of Monetary Support

Bristol-Myers Squibb - Brazil