Clinical trial NCT00930891: Bevacizumab in Extensive Small Cell Lung Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Small Cell Lung Cancer
Keywords: Extensive-Disease Small-Cell Lung Cancer
Lead sponsor: Intergroupe Francophone de Cancerologie Thoracique
Sponsor class: OTHER
First posted: 2009-07-02
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Response rate (complete response + partial response)
timeFrame: 6 weeks after randomization
Secondary outcomes:
measure: Progression-free survival
timeFrame: 12 weeks
measure: Complete response length
timeFrame: 12 weeks
measure: Quality of life
timeFrame: 12 weeks
measure: Toxicities
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Ambilly
country: France
facility: Annemasse - CH
city: Angers
country: France
facility: Angers - CHU
city: Armentières
country: France
facility: Armentières - CH
city: Besancon
country: France
facility: CHU Besancon - Pneumologie
city: Caen
country: France
facility: Centre F. Baclesse
city: Caen
country: France
facility: CHU - Pneumologie
city: Cahors
country: France
facility: Cahors - CH
city: Chalons-en-Champagne
country: France
facility: Chalons-en-Champagne - CH
city: Chauny
country: France
facility: Chauny - CH
city: Clamart
country: France
facility: Hôpital Percy-Armées - Pneumologie
city: Clermont Ferrand
country: France
facility: Clermont Ferrand - CHU
city: Colmar
country: France
facility: Colmar - CH
city: Compiègne
country: France
facility: CH - Compiègne
city: Créteil
country: France
facility: Créteil - CHI
city: Dijon
country: France
facility: Dijon - CAC
city: Dijon
country: France
facility: Dijon - CHU
city: Draguignan
country: France
facility: Draguignan - CH
city: Grenoble
country: France
facility: CHU Grenoble - pneumologie
city: Harfleur
country: France
facility: Harfleur - Clinique du Petit Colmoulins
city: Helfaut
country: France
facility: Saint Omer - CHI
city: Jonzac
country: France
facility: Jonzac - CH
city: Le Coudray
country: France
facility: Chartres - CH
city: Le Mans
country: France
facility: Centre Hospitalier - Pneumologie
city: Longjumeau
country: France
facility: CH
city: Marseille
country: France
facility: APHM - Hôpital Sainte Marguerite
city: Marseille
country: France
facility: Marseille - CRLCC
city: Maubeuge
country: France
facility: Maubeuge - Polyclinique du Parc
city: Meaux
country: France
facility: Meaux - CH
city: Metz
country: France
facility: Metz - CHR
city: Mont de Marsan
country: France
facility: Mont de Marsan - CH
city: Montpellier
country: France
facility: Montpellier - CHRU
city: Mulhouse
country: France
facility: Mulhouse - CH
city: Neuilly
country: France
facility: Neuilly - Hôpital Américain de Paris
city: Nevers
country: France
facility: Nevers - CH
city: Nice
country: France
facility: Nice - CAC
city: Orléans
country: France
facility: Orléans - CH
city: Paris
country: France
facility: APHP - Saint-Antoine - pneumologie
city: Paris
country: France
facility: APHP - Hopital Tenon - Pneumologie
city: Pau
country: France
facility: Pau - CH
city: Pierre Bénite
country: France
facility: HCL - Lyon Sud (Pneumologie)
city: Reims
country: France
facility: Reims - CHU
city: Reims
country: France
facility: Reims - CRLCC
city: Rouen
country: France
facility: Rouen - CHU
city: Saint Brieuc
country: France
facility: Saint Brieuc - CHG
city: Saint Nazaire
country: France
facility: Saint Nazaire - Centre Etienne Dolet
city: Saint Priest en Jarez
country: France
facility: Saint Priest en Jarez - ICL
city: Saint Quentin
country: France
facility: Saint Quentin - CH
city: Saverne
country: France
facility: Saverne - CH
city: Senlis
country: France
facility: Senlis - CH
city: Strasbourg
country: France
facility: Nouvel Hopital Civil - Pneumologie
city: Suresnes
country: France
facility: Suresnes - Hopital Foch
city: Thonon les bains
country: France
facility: Thonon les bains
city: Toulon
country: France
facility: Toulon - HIA
city: Toulouse
country: France
facility: CHU Toulouse - Pneumologie
city: Toulouse
country: France
facility: Toulouse - Clinique Pasteur
city: Tours
country: France
facility: Tours - CHU
city: Vandoeuvre lès Nancy
country: France
facility: Nancy - CHU
city: Verdun
country: France
facility: Verdun - CHG
city: Vesoul
country: France
facility: Vesoul - CHI
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: CHRU Montpellier
name: Jean-Louis PUJOL, Pr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pujol JL, Breton JL, Gervais R, Tanguy ML, Quoix E, David P, Janicot H, Westeel V, Gameroff S, Geneve J, Maraninchi D. Phase III double-blind, placebo-controlled study of thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: an intergroup study FNCLCC cleo04 IFCT 00-01. J Clin Oncol. 2007 Sep 1;25(25):3945-51. doi: 10.1200/JCO.2007.11.8109.
citation: Pujol JL, Daures JP, Riviere A, Quoix E, Westeel V, Quantin X, Breton JL, Lemarie E, Poudenx M, Milleron B, Moro D, Debieuvre D, Le Chevalier T. Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst. 2001 Feb 21;93(4):300-8. doi: 10.1093/jnci/93.4.300.
citation: Horn L, Dahlberg SE, Sandler AB, Dowlati A, Moore DF, Murren JR, Schiller JH. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol. 2009 Dec 10;27(35):6006-11. doi: 10.1200/JCO.2009.23.7545. Epub 2009 Oct 13.
citation: Pujol JL, Lavole A, Quoix E, Molinier O, Souquet PJ, Barlesi F, Le Caer H, Moro-Sibilot D, Fournel P, Oster JP, Chatellain P, Barre P, Jeannin G, Mourlanette P, Derollez M, Herman D, Renault A, Dayen C, Lamy PJ, Langlais A, Morin F, Zalcman G; French Cooperative Thoracic Intergroup (IFCT). Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trialdagger. Ann Oncol. 2015 May;26(5):908-914. doi: 10.1093/annonc/mdv065. Epub 2015 Feb 16.
citation: Negre E, Coffy A, Langlais A, Daures JP, Lavole A, Quoix E, Molinier O, Greillier L, Audigier-Valette C, Moro-Sibilot D, Westeel V, Morin F, Roch B, Pujol JL. Development and Validation of a Simplified Prognostic Score in SCLC. JTO Clin Res Rep. 2020 Feb 12;1(1):100016. doi: 10.1016/j.jtocrr.2020.100016. eCollection 2020 Mar.