E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or recurrent non-squamous non-small cell lung cancer. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | PT |
E.1.2 | Level | 7.0 |
E.1.2 | Classification code | 10061873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
STAGE 1 •To evaluate early safety and efficacy of 2 bevacizumab doses in combination with cisplatin and gemcitabine and select the optimal bevacizumab dose, both based on: •Toxicity in patients treated with cisplatin/gemcitabine +/- 2 different doses of bevacizumab •Comparison of response rate, progression-free and overall survival in patients treated with cisplatin/gemcitabine + 2 different doses of bevacizumab or placebo
STAGE 2 •To demonstrate superiority in overall survival when bevacizumab is added to cisplatin and gemcitabine |
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E.2.2 | Secondary objectives of the trial |
STAGE 1 •To study coagulation parameters •To characterize the pharmacokinetics of the combination bevacizumab, cisplatin and gemcitabine •To evaluate the relationship between baseline VEGF and clinical outcome parameters
STAGE 2 •To compare progression-free survival and time to treatment failure •To compare response rate and assess duration of response •To evaluate and compare the safety profile of patients treated with bevacizumab + cisplatin/gemcitabine versus cisplatin/gemcitabine •To evaluate the relationship between baseline VEGF and clinical outcome parameters •To assess quality of life in the two treatment arms •To analyze pharmacoeconomics in both treatment arms |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
•Age 18 years or over •Able to comply with the protocol •Histologically or cytologically documented inoperable, locally advanced (stage IIIb with supraclavicular lymph node metastases or malignant pleural or pericardial effusion), metastatic (stage IV) or recurrent non-squamous NSCLC (NOTE: In cases where the diagnosis is based on cytology only, representative samples have to be sent to Roche for central review. Results of the review do not have to be awaited for randomization and treatment of the patient. Sputum cytology alone is not acceptable). Mixed tumors should be categorized according to the predominant cell type. •ECOG performance status 0-1 •Life expectancy > 12 weeks •Adequate hematological function : ANC greater than or equal to 1.5 x 10^9/L; platelets greater than or equal to 100 x 10^9/L, Hb greater than or equal to 9 g/dL •INR less than or equal to 1.5 and PTT less than or equal to 1.5 x ULN within 7 days prior to starting study treatment •Adequate liver function: Serum bilirubin less than or equal to 1.5 x ULN; transaminases less than or equal to 2.5 x ULN (in case of liver metastases < 5 x ULN) •Adequate renal function: oCreatinine clearance, calculated according to the formula of Cockroft and Gault greater than or equal to 60 ml/min AND oUrine dipstick for proteinuria < 2+. If urine dipstick is greater than or equal to 2+, 24- hour urine must demonstrate less than or equal to 1 g of protein in 24 hours •Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women < 2 years after the onset of menopause •Written informed consent |
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E.4 | Principal exclusion criteria |
•Prior chemotherapy or treatment with another systemic anti-cancer agent (for example monoclonal antibody, tyrosine kinase inhibitor) NOTE: prior surgery and irradiation is permitted •Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component •History of ≥ grade 2 hemoptysis (bright red blood of at least ½ teaspoon) •Brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to randomization) •Evidence of tumor invading or abutting major blood vessels •Surgery (including open biopsy), significant traumatic injury or radiotherapy within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment •Pregnant or lactating women •Fertile men or woman of childbearing potential not using adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) •Malignancies other than NSCLC within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, DCIS treated surgically with curative intent •Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study •Known hypersensitivity to any of the study drugs •Non healing wound, ulcer or bone fracture •History of thrombotic or hemorrhagic disorders •Uncontrolled hypertension •Clinically significant cardiovascular disease for example CVA (less than or equal to 6 months before randomization), myocardial infarction (less than or equal to 6 months before randomization), unstable angina, NYHA greater than or equal to grade 2 CHF, arrhythmia requiring medication •Current or recent (within 10 days of first dose of study treatment) use of aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel and cilostazol. •Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes •Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications |
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E.5 End points |
E.5.1 | Primary end point(s) |
Duration of overall survival defined as the time between randomisation and death. The primary analysis will compare the duration of overall survival between the placebo group and the bevacizumab group with the dose chosen for stage 2 of the study, for all patients randomised in stage 2 of the study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Randomized (1:1:1), 3 arm, 2 stage study with a comparison of 2 doses of IMP |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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This is an event driven trial. The final analysis will be done when approximately 525 deaths have occurred, at which point randomization into the study will be stopped. The study will then continue for another two years in order to collect survival follow-up information, after which time the study will end and a follow-up analysis will be performed. The end of the trial is considered the end of the follow-up period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |