Bevacizumab in Extensive Small Cell Lung Cancer

Study Overview
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Brief Summary
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Despite the fact that a substantial response rate may be obtained in small-cell lung cancers (using double-drug chemotherapy: cisplatin-etoposide, PE), a cure remains an exception. More aggressive regimens remain controversial and recent attempts at increasing dose-intensity have been restricted to patients with a more favourable presentation. Bevacizumab is a humanized monoclonal antibody which binds to VEGF (Vascular Endothelial Growth Factor). In association with double-drug standard chemotherapies, it has been proven that bevacizumab can improve survival of previously untreated advanced non-small-cell lung cancers (NSCLC), compared to chemotherapy without bevacizumab). Such promising effects on NSCLC deserve to be tested on small-cell lung cancers. In this trial (IFCT-0802), standard chemotherapy (PCDE or PE) will be compared to experimental treatment (PCDE or PE + bevacizumab 7.5 mg/kg) for previously untreated SCLC patients.

Official Title
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Randomized Phase II-III Study of Bevacizumab 7,5 mg/kg in Combination With Chemotherapy Versus Chemotherapy in Extensive-Disease Small-Cell Lung Cancer After Response to Chemotherapy : PCDE (cisPlatin - Cyclophosphamide - epiDoxorubicin - Etoposide) or PE (cisPlatin - Etoposide)

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Standard Chemotherapy (PCDE or PE)
* Drug: Experimental Treatment (PCDE or PE + bevacizumab)
* Drug: Prerandomization Chemotherapy (PCDE or PE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (must be checked at the inclusion, week -8): Small-Cell Lung Cancer histologically or cytologically proved Extended disease as defined by Veteran's Administration Lung Cancer Group (VALG) At least one unidimensionally measurable lesion (RECIST criterion) Age between 18 and 75 years Weight loss < 10% for the last three month Performance Status (PS)≤ 2 Creatininemia < 110 µmol/L and creatinin clearance > 60 mL/min Neutrophils ≥ 1,500/µL and platelets ≥ 100,000/µL Bilirubin ≤ 1.5 x normal value Transaminases, Alkaline Phosphatase ≤ 2.5 x ULN excepted in case of liver metastasis (5xULN) Left ventricular ejection fraction (measured by echocardiographic or isotopic method) > 50% if PCDE is planned Electrocardiogram without uncontrolled coronaropathy Signed informed consent Randomization Criteria (to be checked during the randomization (week 0)): Partial or complete tumoral response as defined by RECIST All chemotherapy-induced toxicities decreased to level ≤ 2 as defined by NCI CTC VS 3 (except for alopecia) Inclusion criteria concerning creatininemia, clearance, neutrophils, platelets, transaminases, alkaline phosphatases and left ventricular ejection fraction must be checked again Exclusion Criteria: Non-Small-Cell Lung Cancer or mixed cancer (small-cell / non-small-cell) Previous antitumoral treatment of the small-cell lung cancer (chemotherapy, radiotherapy, immunotherapy, surgery) Non-extended disease as defined by VALG Natremia < 125 mmol/L Hypercalcemia whereas a corrective treatment Pathology contra-indicating the hyper-hydration Hemoptysis in the last three months Tumor invading large vessels or invading the proximal trachea-bronchial tree (visible at the medical imagery). Investigator or radiologist must reject tumors adjoining, merging or extending to large vessel's lumen (for example : pulmonary artery, superior vena cava) Symptomatic cerebral or meningeal metastasis Other cancer in progress or medical history of cancer in the five last years (excepted basal cell carcinoma or in situ cervical cancer of the uterus. Important surgical intervention (including surgical biopsy), traumatic lesion during 28 days before starting the treatment, or anticipation of an important surgical intervention during the study Minor surgical intervention, including implanting permanent catheter during the 24 hours before the first administration of bevacizumab Unhealed wound, evolutive gastroduodenal ulcer, fractured bone Medical history of abdominal fistula, trachea-oesophageal fistula, of another type with a severity rank of 4, gastrointestinal perforation or intraabdominal abscess during 6 month before inclusion Ongoing or recent use of aspirin (during 10 days before the first administration of bevacizumab) (>325 mg/day) or use of another platelet aggregation inhibitor (dipyridamole, ticlopidine, clopidogrel > 75 mg/day), or ongoing or recent use of a therapeutic dose (during 10 days before the first administration of bevacizumab) of anticoagulant or thrombolytic drugs per os or in parenteral injection. Prophylactic use of anticoagulant drug is allowed Medical history or genetic predisposition to bleeding or coagulopathy Clinically significative cardiac disease: infarct or CVA during 6 month before inclusion, unstable angina, congestive cardiac failure level > II as defined by New York Heart Association (NYHA) or cardiac arrythmia needing a specific treatment which risk to interfere with the study, or uncontrolled arrythmia. Known allergy or hypersensibility to monoclonal antibodies (bevacizumab), to chinese hamster ovary cells or to any humanized or recombinant antibody Uncontrolled high blood pressure (systolic pressure > 150 mm Hg and/or diastolic pressure > 100 mm Hg), with or without hypotension treatment. Patients presenting an high blood pressure are eligibles if their treatment can decrease their blood pressure to the values required by the protocol. Severe ongoing infectious disease or fever > 38.5°C or evidence of any other pathology, organic or neurologic functions deterioration, physical examination or laboratory result which cause suspicion of a disease which contra-indicate use of any studied treatment. Woman with a positive pregnancy test or who has not made a pregnancy test (unless pregnancy risk can be excluded) Lactating woman Sexually active woman who don't use hormonal or mechanical contraceptive method or sexually active man who has a sexually active partner who don't want to use an effective contraceptive method during the course of the study and during the 6 months after last treatment administration Patient who as already been included and treated in the present study Patient who participate or who has participated in another study during 4 weeks before treatment administration Patient who receive a previous antiangiogenic treatment (experimental or commercial : bevacizumab, thalidomide, CP-547632, sunitinib, sorafenib...) Geographical or psychological condition which not allowed a good comprehension or compliance to protocol Liberty deprived patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>4 additional cycles of chemotherapy | Drug: Standard Chemotherapy (PCDE or PE)<br>* PCDE: cisPlatin 75 mg/m² D2 ; Cyclophosphamide 300 mg/m² D1 to D3; 4'-epiDoxorubicin 30 mg/m² D1; Etoposide 75 mg/m² D1 to D3, 4 cycles PE: cisPlatin 80 mg/m², D2; Etoposide 120 mg/m² D1 to D3, 4 cycles<br>Drug: Prerandomization Chemotherapy (PCDE or PE)<br>* PCDE: cisPlatin 75 mg/m² D2; Cyclophosphamide 300 mg/m² D1 to D3; 4'-epiDoxorubicin 30 mg/m² D1; Etoposide 75 mg/m² D1 to D3, 2 cycles PE: cisplatin 80 mg/m², D2; Etoposide 120 mg/m² D1 to D3, 2 cycles<br>|
| Experimental: Arm B<br>4 additional cycles of chemotherapy + bevacizumab | Drug: Experimental Treatment (PCDE or PE + bevacizumab)<br>* PCDE: cisPlatin 75 mg/m² D2; Cyclophosphamide 300 mg/m² D1 to D3; 4'-epiDoxorubicin 30 mg/m² D1; Etoposide 75 mg/m² D1 to D3, 4 cycles Bevacizumab 7.5 mg/kg, D1, until progression PE: cisPlatin 80 mg/m², D2; Etoposide 120 mg/m² D1 to D3, 4 cycles Bevacizumab 7.5 mg/kg, D1, until progression<br>Drug: Prerandomization Chemotherapy (PCDE or PE)<br>* PCDE: cisPlatin 75 mg/m² D2; Cyclophosphamide 300 mg/m² D1 to D3; 4'-epiDoxorubicin 30 mg/m² D1; Etoposide 75 mg/m² D1 to D3, 2 cycles PE: cisplatin 80 mg/m², D2; Etoposide 120 mg/m² D1 to D3, 2 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (complete response + partial response) |  | 6 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 12 weeks | 
| Complete response length |  | 12 weeks | 
| Quality of life |  | 12 weeks | 
| Toxicities |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extensive-Disease Small-Cell Lung Cancer