E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small-cell-lung-cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066490 |
E.1.2 | Term | Progression of non small cell lung cancer |
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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 |
The primary objective of this Phase IIIb study is to compare PFS in subjects randomized to bevacizumab + erlotinib versus bevacizumab + erlotinib-placebo in subjects with NSCLC who have completed four cycles of chemotherapy and bevacizumab without disease progression or significant toxicity. For the primary objective, PFS is defined as the length of time from randomization until documented disease progression (as assessed according to the Response Evaluation Criteria in Solid Tumors [RECIST; see Appendix C of the protocol]) or death on study treatment, whichever occurs earlier. Death on study treatment is defined as death from any cause within 30 days of the last dose of study treatment. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of bevacizumab during the chemotherapy phase by chemotherapy regimen and overall as measured by the incidence of selected Grade ≥ 3 adverse events. •To evaluate the safety of bevacizumab for both phases of therapy by chemotherapy regimen and overall as measured by the incidence of selected Grade ≥ 3 adverse events • To evaluate the incidence of treatment discontinuation for reasons other than disease progression during both phases of therapy • Among subjects who complete four cycles of chemotherapy and bevacizumab and undergo randomization; to evaluate the safety of bevacizumab + erlotinib versus bevacizumab + erlotinib-placebo during the post-chemotherapy phase, as measured by the incidence of all adverse events; to compare the overall survival of the group receiving bevacizumab + erlotinib versus bevacizumab + erlotinib-placebo. • To estimate overall survival in the two arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must have advanced NSCLC without prior systemic treatment for locally advanced, recurrent, or metastatic disease. This includes subjects with Stage IIIB with malignant pleural effusion or Stage IV or recurrent disease. • Signed Informed Consent Form • Histologically or cytologically confirmed NSCLC. Mixed tumors will be categorized by the predominant cell type. Cytologic or histologic elements may be established on metastatic tumor aspirates or biopsy • Advanced NSCLC (Stage IIIB with malignant pleural effusion or Stage IV) or recurrent disease Subjects with squamous cell carcinoma are eligible provided that their disease is extrathoracic or that their intrathoracic disease consists of peripheral lesions only. A peripheral lesion is defined as a lesion (or lesions), in which the epicenter of the tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a 3-dimensional orientation based on each lobe of the lung and is > 2 cm from the trachea, main, and lobar bronchi. Subjects with a history of brain metastases are eligible for study participation as long as their brain metastases have been treated, and they do not have an ongoing requirement for treatment with dexamethasone at screening. Treatment must be with whole-brain radiotherapy (e.g., 3000 cGy over 2 weeks) and may include neurosurgery or stereotactic radiosurgery. Radiotherapy and stereotactic radiosurgery must be completed at least 4 weeks prior to Day 1 (chemotherapy phase). Neurosurgery must be completed at least 24 weeks prior to Day 1 (chemotherapy phase), and brain biopsy must be completed at least 12 weeks prior to Day 1 (chemotherapy phase). Note: All subjects require a brain imaging (MRI or CT with contrast) within 28 days of enrollment. • INR no greater than 1.3 and aPTT no greater than upper limits of normal (ULN) within 28 days prior to enrollment for subjects not on low molecular weight heparin or fondaparinux. Subjects on low molecular weight heparin or fondaparinux are not required to meet INR or aPTT limits. Chronic full-dose anticoagulation with warfarin is not permitted. • ECOG performance status of 0 or 1 • 18 years of age or older • For women of childbearing potential and sexually active men, use of an accepted and effective method of contraception (hormonal or barrier methods, abstinence) prior to enrollment and for the duration of the study |
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E.4 | Principal exclusion criteria |
• Prior systemic chemotherapy in the metastatic setting. Prior adjuvant therapy and prior combined modality therapy is allowed provided that there is an interval of at least 6 months prior to recurrence. • Treatment with an investigational or marketed agent that acts by either EGFR inhibition or anti-angiogenesis mechanisms EGFR inhibitors include (but are not limited to) erlotinib, gefitinib, cetuximab, and CI-1033. Angiogenesis inhibitors include (but are not limited to) bevacizumab, thalidomide, CP-547632, sunitinib, and sorafinib. • Pregnancy or lactation • Any other medical condition, including mental illness or substance abuse, deemed by the clinician to be likely to interfere with a subject’s ability to provide informed consent, cooperate, and participate in the study, or to interfere with the interpretation of the results • Active infection or a fever > 38.5°C (>101.3°F) within 3 days of enrollment • Active malignancy other than lung cancer • Radiation therapy to sites other than whole brain within 14 days prior to enrollment Those who have not recovered from adverse events because of radiation therapy remain ineligible until resolution of all radiation-related toxicities to Grade ≤ 1. • History of gross hemoptysis (defined as bright-red blood of a half-teaspoon or more) within 3 months prior to enrollment • Known hypersensitivity to any of the components of cytotoxic chemotherapy combinations, bevacizumab, or tyrosine kinase inhibitors • Inadequately controlled hypertension (blood pressure systolic > 150 mmHg or diastolic >100 mmHg) (Refer to http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm for JNC 7guidelines regarding suggestions on measurement.) • Unstable angina or New York Heart Association Grade II or greater CHF • Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment • History of myocardial infarction within 6 months prior to enrollment • History of stroke within 6 months prior to enrollment • Symptomatic peripheral vascular disease within 6 months prior to enrollment • Evidence of bleeding diathesis or coagulopathy • Urine protein/creatinine ratio ≥ 1.0 at screening Microalbuminuria assay or urine dipstick assays are not permitted as a substitute for the urine protein assay. • Serious, non-healing wound, ulcer, or bone fracture • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment; anticipation of need for major surgical procedure during the course of the study • Exclusionary laboratories: Neutrophils < 1500/mm3; platelet count < 100,000/mm3; hemoglobin < 9 g/dL AST > 2.5 × ULN; ALT > 2.5 × ULN in the absence of liver metastasis or > 5 × ULN in case of liver metastasis Alkaline phosphatase > 2.5 × ULN; if alkaline phosphatase is > 2.5 × ULN, then AST and ALT must be < 1.5 × ULN Total bilirubin > 1.5 × ULN Creatinine > 1.5 × ULN • Current, recent (within 4 weeks of the first infusion of bevacizumab), or planned participation in an experimental drug study other than this Genentech-sponsored bevacizumab/erlotinib study • Progressive neurologic symptoms in subjects with a history of brain metastases
• History of significant vascular disease (e.g., aortic aneurysm) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is post-chemotherapy PFS, defined as the length of time from randomization to either disease progression (as assessed by RECIST) or death on study treatment. Death on study treatment is defined as death from any cause within 30 days of the last dose of study treatment. Pre-randomization tumor assessments at the end of Cycle 4 of chemotherapy will be used as the baseline for establishing disease progression thereafter. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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) | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | Yes |
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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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 | 3 |
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 | 3 |