Clinical trial NCT01562028: BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC)
Official title: An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Cancer
Keywords: non small cell lung cancer
advanced
non-squamous
EGFR
mutations
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: Spanish Lung Cancer Group
First posted: 2012-03-23
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Rationale:

Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.

The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

Detailed description: Objectives:

1. To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. Primary endpoint: progression-free survival
2. To evaluate the efficacy and tolerability of the combination
3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival
4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally
5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab

Design:

This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. Patients will be stratified into two subgroups, with and without EGFR T790M mutation. The stratification will be done after the inclusion of patients.

Sample size: 102 patients

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* ECOG performance status 0-2
* Adequate haematological function, coagulation, liver function and renal function
* Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC)
* TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radiochemotherapy for stage III disease)
* Measurable or evaluable disease (according to RECIST 1.1 criteria).
* Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R)

Exclusion Criteria:

* Patients with increased risk of bleeding
* Patients with clinically significant cardiovascular diseases
* Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment
* Patients with gastrointestinal problems
* Patients with neurologic problems
* Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma.
* Patients with any known significant ophthalmologic anomaly of the ocular surface
* Patients who received prior chemotherapy for metastatic disease
* Patients who received previous treatment for lung cancer with drugs targeting EGFR or VEGF
* Pregnancy

Primary outcomes:
measure: Progression Free Survival
timeFrame: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.
Secondary outcomes:
measure: Overall Survival
timeFrame: From the date of enrollment until death, assessed up to 48 months.
measure: Time to Treatment Failure
timeFrame: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.
measure: Objective Response
timeFrame: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
measure: Disease Control
timeFrame: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
measure: Duration of Response
timeFrame: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).
measure: Adverse Events
timeFrame: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).
Other outcomes:
Locations:
city: Caen
country: France
facility: Centre Francois Baclesse
city: Marseille
country: France
facility: Hôpital de Marseille
city: Grosshansdorf
country: Germany
facility: Hospital Grosshansdorf
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg GmbH
city: Hemer
country: Germany
facility: Lungenklinik Hemer
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Heraklion
country: Greece
facility: University General Hospital of Heraklion
city: Thessaloniki
country: Greece
facility: Papageorgias Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Limerick
country: Ireland
facility: Mid-Western Regional Hospital
city: Tallaght
country: Ireland
facility: AMCCH
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
city: Palermo
country: Italy
facility: Casa di Cura Maddalena
city: Roma
country: Italy
facility: Policlinico Tor Vergata Roma
city: Roma
country: Italy
facility: San Camillo Hospital
city: Roma
country: Italy
facility: Policlinico Umberto
city: Alicante
country: Spain
facility: Hospital General Universitario Alicante
city: Badalona
country: Spain
facility: ICO - Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Girona
country: Spain
facility: ICO - Girona
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital Clinico Universitario San Carlos
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Valencia
country: Spain
facility: Hospital La Fe
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bellinzona
country: Switzerland
facility: Istituto Oncologica della Svizzera Italiana
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneva
country: Switzerland
facility: Geneva University Hospital
city: Lausanne
country: Switzerland
facility: Fondation du centre Pluridisciplinaire d'Oncologie (CePO)
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Thun
country: Switzerland
facility: Onkologiezentrum Berner Oberland
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: Chelmsford
country: United Kingdom
facility: Mid Essex Hospital Services NHS Trust
state: Essex
city: Burton-upon-Trent
country: United Kingdom
facility: Queen's Hospital
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Maidstone
country: United Kingdom
facility: Kent Oncology Centre
city: Manchester
country: United Kingdom
facility: Christie Hospital Manchester
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital Manchester
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
Study officials:
affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol
name: Rafael Rosell, MD
role: STUDY_CHAIR
affiliation: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zuerich
name: Stahel Rolf, MD
role: STUDY_CHAIR
affiliation: Medical Oncology Service-ICO, Hospital Germans Trias i Pujol
name: Miquel Taron
role: STUDY_CHAIR
References:
citation: Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004 Jun 4;304(5676):1497-500. doi: 10.1126/science.1099314. Epub 2004 Apr 29.
citation: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Francais de Pneumo-Cancerologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. doi: 10.1016/S1470-2045(11)70393-X. Epub 2012 Jan 26.
citation: Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.
citation: Kabbinavar F, Miller VA, Johnson BE, O'Connor P, Soh C-H, ATLAS Investigators. Overall survival in ATLAS, a Phase IIIb trial comparing bevacizumab therapy +/- erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28 (May suppl; abstr 7526).
citation: Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massuti B, Palmero R, Aix SP, Carcereny E, Fruh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gomez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA; BELIEF collaborative group. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017 May;5(5):435-444. doi: 10.1016/S2213-2600(17)30129-7. Epub 2017 Apr 10.