BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC)

Lung Cancer Clinical Trial

— BELIEF  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01562028
• Other study ID #: ETOP 2-11 / MO27911
• Secondary ID: 2011-004481-15MO
• Status: Completed
• Phase: Phase 2
• Start date: June 2012
• Est. completion date: October 31, 2018

Study information

• Verified date: August 2022
• Source: ETOP IBCSG Partners Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: October 31, 2018
• Est. primary completion date: October 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lung Cancer
• Lung Neoplasms

Intervention

Drug:
• Erlotinib
Patients will be treated with erlotinib, 150 mg p.o., daily
• Bevacizumab
Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days)

Locations

Country	Name	City	State
France	Centre Francois Baclesse	Caen
France	Hôpital de Marseille	Marseille
Germany	Hospital Grosshansdorf	Grosshansdorf
Germany	Thoraxklinik Heidelberg GmbH	Heidelberg
Germany	Lungenklinik Hemer	Hemer
Germany	Universitätsklinikum Ulm	Ulm
Greece	University General Hospital of Heraklion	Heraklion
Greece	Papageorgias Hospital	Thessaloniki
Ireland	St Vincent's University Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	University Hospital Galway	Galway
Ireland	Mid-Western Regional Hospital	Limerick
Ireland	AMCCH	Tallaght
Italy	Ospedale San Gerardo	Monza
Italy	Istituto Oncologico Veneto IRCCS	Padova
Italy	Casa di Cura Maddalena	Palermo
Italy	Policlinico Tor Vergata Roma	Roma
Italy	Policlinico Umberto	Roma
Italy	San Camillo Hospital	Roma
Spain	Hospital General Universitario Alicante	Alicante
Spain	ICO - Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital Clínic Barcelona	Barcelona
Spain	Hospital De La Santa Creu I Sant Pau	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	ICO - Girona	Girona
Spain	ICO - Hospital Duran i Reynals	L'Hospitalet de Llobregat
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Clinico Universitario San Carlos	Madrid
Spain	Hospital General de Valencia	Valencia
Spain	Hospital La Fe	Valencia
Switzerland	University Hospital Basel	Basel
Switzerland	Istituto Oncologica della Svizzera Italiana	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Geneva University Hospital	Geneva
Switzerland	Fondation du centre Pluridisciplinaire d'Oncologie (CePO)	Lausanne
Switzerland	Kantonsspital Luzern	Luzern
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	Onkologiezentrum Berner Oberland	Thun
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	University Hospital Zurich	Zurich
United Kingdom	Queen's Hospital	Burton-upon-Trent
United Kingdom	Mid Essex Hospital Services NHS Trust	Chelmsford	Essex
United Kingdom	University Hospitals of Leicester	Leicester
United Kingdom	Royal Marsden Hospital	London
United Kingdom	Kent Oncology Centre	Maidstone
United Kingdom	Christie Hospital Manchester	Manchester
United Kingdom	Wythenshawe Hospital Manchester	Manchester
United Kingdom	Wrexham Maelor Hospital	Wrexham

Sponsors (2)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	Spanish Lung Cancer Group

Countries where clinical trial is conducted

France,  Germany,  Greece,  Ireland,  Italy,  Spain,  Switzerland,  United Kingdom, 

References & Publications (4)

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).

Kobayashi S, Boggon TJ, Dayaram T, Jänne 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. — View Citation

Paez JG, Jänne 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. Epub 2004 Apr 29. — View 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, Muñoz-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 Français de Pneumo-Cancérologie 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival	Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first.; Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.	From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.
Secondary	Overall Survival	Time from the date of enrollment until death from any cause.	From the date of enrollment until death, assessed up to 48 months.
Secondary	Time to Treatment Failure	Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.	From the date of enrollment until discontinuation of treatment, assessed up to 48 months.
Secondary	Objective Response	Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.; Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.	Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
Secondary	Disease Control	Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.	Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
Secondary	Duration of Response	Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.; Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.	Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).
Secondary	Adverse Events	Adverse events graded according to NCI CTCAE V4.	Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).