| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small-cell-lung-cancer |
|
| 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 |
|
| 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 III study is to evaluate the efficacy of combining bevacizumab with Tarceva (erlotinib) relative to Tarceva monotherapy in patients receiving second-line therapy for advanced NSCLC. Efficacy will be assessed by measuring overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
•Evaluate the safety of combining bevacizumab with Tarceva in patients with previously treated advanced NSCLC, including patients with squamous cell carcinoma, treated brain metastases, and patients receiving full-dose anticoagulation with low-molecular-weight heparin or fondaparinux.
•Evaluate the efficacy of combining bevacizumab with Tarceva relative to Tarceva monotherapy in patients with previously treated advanced NSCLC, as measured by PFS, objective response rate, disease control rate and duration of response
•Evaluate the pharmacokinetic behavior of Tarceva and the combination of bevacizumab with Tarceva in a subset of patients with previously treated advanced NSCLC
•Evaluate the association of survival, PFS, and treatment effect with markers of EGFR expression, as measured by immunohistochemistry (IHC), EGFR gene copy number measured by fluorescence in situ hybridization (FISH) and other molecular markers of EGFR pathway activity in archival tissue samples |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The sub-study is included in the main protocol in Appendix C (page 126). At least 17 patients in each treatment arm from selected institutions will be consented to participate in the intensive pharmacokinetic analysis and will undergo extensive sampling according to the schedule outlined below. Patients at participating institutions must sign the Pharmacokinetic Sample Informed Consent Form to indicate whether or not they consent to participate in the optional pharmacokinetic sampling. |
|
| E.3 | Principal inclusion criteria |
Patients are eligible for this second-line therapy study if they have recurrent or refractory (progression through at least two cycles of a given chemotherapeutic
regimen) NSCLC following standard first-line chemotherapy or chemoradiotherapy.
• Signed written informed consent
• Cytologically or histologically confirmed NSCLC
Patients must have histologically or cytologically confirmed NSCLC. Tumors of mixed histology will be categorized by the predominant cell type unless small cell elements are present, in which case the patient will not be eligible for study participation. Cytologic or histologic elements may be established on metastatic tumor aspirates or biopsy. Patients 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 > 2 cm from the trachea, main, and lobar bronchi. Squamous cell carcinoma patients are eligible for study participation irrespective of the proximity of their adenopathy to the costal or diaphragmatic pleura or major airways. Patients with hilar adenopathy are eligible for study participation. Patients with squamous cell carcinoma must have a copy of the screening computed tomography (CT) or magnetic resonance imaging (MRI) scans (either as copy films or digital images) reviewed by Genentech or its designee prior to randomization. Patients will not be randomized until Genentech or its designee provides confirmation of eligibility. Patients 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 WBRT (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 0 (see Section 4.3.2). Neurosurgery must be completed at least 24 weeks prior to Day 0, and brain biopsy must be completed at least 12 weeks prior to Day 0.
• Clinical or radiographic progression during or after first-line chemotherapy
or chemoradiotherapy for NSCLC. Patients receiving neo-adjuvant and adjuvant therapy for Stage I–IIIa disease prior to their first-line regimen are eligible for study participation provided they have also received first-line therapy (for unresectable, metastatic disease) and have demonstrated progression during or after that first-line therapy.
• Consent to provide archival tissue for analysis is required for participation in this study. Patients who consent to provide tissue but whose archival tissue is found to be inadequate (e.g., stained slides) remain eligible for study participation (see Appendix E).
• ECOG performance status of 0, 1, or 2 (see Appendix F)
• Age ≥ 18 years
• Use of an acceptable means of contraception for men and women of childbearing potential
• INR no greater than 1.3 and an aPTT no greater than the upper limits of normal within 28 days prior to enrollment for patients not on low-molecular-weight heparin or fondaparinux. Patients on low-molecular-weight heparin or fondaparinux are not required to meet INR or aPTT limits. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be ineligible for study entry:
• Squamous cell carcinoma, except for patients with no intrathoracic disease or small peripheral lesions only.
• Prior treatment with an investigational or marketed inhibitor of the EGFR pathway or anti-angiogenesis agent Angiogenesis inhibitors include (but are not limited to) bevacizumab, thalidomide, CP 547632, SU 11248, and PTK 787.
• Systemic chemotherapy, radiotherapy, or investigational treatment within 28 days prior to randomization. Local palliative radiotherapy within 14 days prior to randomization or persistent adverse effects from radiotherapy that have not resolved to Grade 2 or less following completion of treatment
• Whole brain radiotherapy or stereotactic radiosurgery for brain metastases within 4 weeks of Day 0
• Neurosurgery for brain metastases within 24 weeks of Day 0
• Brain biopsy within 12 weeks of Day 0
• Current use of dexamethasone for treatment associated with brain metastases
• History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or 2.5 mL per episode) within 3 months prior to randomization unless definitively treated with surgery or radiation
• History of any of the following within 6 months prior to Day 0: serious systemic disease, including myocardial infarction, uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg taken per the JNC 7 guidelines, unstable angina, New York Heart Association (NYHA) Grade 2 or greater CHF, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess. Patients with evidence of hypertension during study screening should be evaluated for uncontrolled hypertension in accordance with the JNC 7 guidelines.
• Evidence of bleeding diathesis or coagulopathy or other serious or acute internal bleeding within 6 months prior to randomization
• CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months
• Progressive neurologic symptoms in patients with a history of brain metastases
• Full-dose anticoagulation with warfarin. Patients who require full-dose anticoagulation may be treated with low-molecular-weight heparin or fondaparinux. Patients fully anticoagulated with warfarin during the study will be discontinued from bevacizumab/placebo.
• Chronic daily use of aspirin (> 325 mg/day) or other full-dose NSAIDs with anti-platelet activity. Treatment with other antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, and/or cilostazol) is permitted.
• In-patient surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization (placement of a central line is not considered surgery, and can be placed on the same day as study drug administration)
• Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior to randomization
• Anticipation of need for a major surgical procedure during the course of the study
• Serious, non-healing wound, ulcer, or bone fracture
• Inability to take oral medication or requirement for IV alimentation or total parenteral nutrition with lipids, or prior surgical procedures affecting absorption
• Any of the following abnormal hematologic values (within 1 week prior to
randomization: ANC ≤ 1000 cells/μL; Platelet count ≤ 100,000 cells/μL; Hemoglobin ≤ 9.0 g/dL; INR ≥ 1.5 × upper limit of normal (ULN)
• Any of the following abnormal liver function tests (within 1 week prior to randomization): Serum bilirubin ≥ 1.5 × ULN; Albumin ≤ 2.5 g/dL; Serum ALT ≥ 2 × ULN (unless clearly due to liver metastases, then 5 × ULN); Serum AST ≥ 2 × ULN (unless clearly due to liver metastases, then 5 × ULN)
• Other baseline laboratory values: Uncontrolled hypercalcemia (≥ 11.5 mg/dL); Urinary protein/creatinine ratio ≥ 1 (spot urine); Serum creatinine ≥ 2.0 × ULN
• Pregnancy or breast-feeding. Because of the possible teratogenic effect. All women of childbearing potential must have a negative pregnancy test within 1 week prior to randomization.
• Presence of another invasive cancer within 5 years prior to randomization, except for adequately treated basal or squamous cell skin cancer, or carcinoma in situ of the cervix
• Evidence of confusion or disorientation, or history of major psychiatric illness that may impair the patient’s understanding of the Informed Consent Form or their ability to comply with study requirements |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is overall survival, defined as the period from the date of randomization (as entered in the IVRS) until the date of patient death from any cause. All deaths will be included, regardless of whether they occur during treatment or following treatment discontinuation. For patients who have not died, survival data will be censored at the date of last contact.
The two-sided log-rank test, stratified by the randomization stratification factors, will be used to perform hypothesis testing for assessing the primary study objective. The randomization stratification factors are ECOG performance status (0/1 vs. 2), smoking history (never vs. current/previous), sex (male vs. female), and study site; however, because of the large number of study sites in this trial, study sites will not be included in any efficacy analyses adjusted for randomization stratification factors. Levels of the stratification factors reported on the CRF will be used in the analysis. A sensitivity analysis stratified using levels reported on the IVRS will be performed. Both analyses will be based on the treatment arm to which the patients have been randomized.
An interim efficacy analysis will be conducted when approximately 67% of the required deaths (280 deaths) have occurred. Overall survival will be tested at the significance level determined using the Lan-DeMets alpha spending function with an
O’Brien-Fleming boundary so that the overall type I error rate will be maintained at
the 0.05 level.
The unstratified log-rank test will be performed as a sensitivity analysis. The Kaplan-Meier methods will be used to estimate median overall survival for each treatment arm. Cox proportional hazard models, using two models (with and without stratification by the randomization stratification factors), will be employed to estimate the hazard ratio (i.e., the magnitude of treatment effect and 95% CI). |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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