Clinical trial NCT02633189: Study Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer
Official title: A Randomized Open-label Phase 3 Trial Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Non-squamous Non-small Cell Lung Cancer
Keywords: stage IV
stage IIIB
EGFR mutation
non-squamous
liquid biopsy
erlotinib
bevacizumab
Lead sponsor: National Cancer Institute, Naples
Sponsor class: OTHER
First posted: 2015-12-17
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.

Detailed description: The co-primary objectives are to assess investigator-assess, and blinded independent centrally-reviewed progression-free survival .

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years
2. Histological documentation of primary non squamous lung carcinoma
3. Stage IV or IIIB disease with supraclavicular metastatic nodes (according to TNM 7th edition)
4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q, exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). EGFR mutation testing must be performed at participating centres in a certified lab (AIOM-SIAPEC program or other European Quality Assurance \[EQA\] schemes)
5. Clinical or radiologic evidence of disease (at least one target or non target lesion according to RECIST 1.1)
6. ECOG performance status 0 to 2
7. Life expectancy \> 3 months
8. Use of an acceptable mean of contraception for men and women of childbearing potential
9. Written informed consent.

Exclusion Criteria:

1. EGFR T790M mutation alone or exon 20 insertions as unique mutation
2. Tumors with a squamous component
3. Prior chemotherapy or any other medical treatment for advanced NSCLC (previous neoadjuvant or adjuvant chemotherapy is allowed if \> 6 months before randomisation)
4. Radiotherapy to any site for any reason within 28 days prior to randomization (palliative radiotherapy to bone lesions is allowed if ≥ 14 days before randomization)
5. Full-dose anticoagulation with warfarin
6. Current or recent (within 10 days of enrolment) use of aspirin (\>325 mg/day) or chronic use of other full-dose nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-platelet activity
7. Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450 3A4 (CYP3A4) are prohibited =\< 7 days prior to registration
8. Receiving any medications or substances that are inducers of CYP3A4 use of inducers are prohibited =\< 7 days prior to registration
9. Inadequate coagulation parameters:

   * activated partial thromboplastin time (APTT) \>1.5 x the upper limit of normal (ULN) or
   * INR \>1.5
10. Inadequate liver function, defined as:

    * serum (total) bilirubin \>1.5 x ULN
    * AST/SGOT or ALT/SGPT \>2.5 x ULN
11. Inadequate renal function, defined as:

    * serum creatinine \>2.0 mg/dl or \>177 micromol/l
    * urine dipstick for proteinuria \>2+. Patients with \> o = 1+ proteinuria at baseline dipstick analysis must undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection.
12. Pregnancy or breast-feeding
13. Inadequately controlled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \>100 mmHg on antihypertensive medications)
14. History of gross hemoptysis within 3 months prior to randomization unless definitively treated with surgery or radiation
15. History of any of the following within 6 months prior to randomisation: serious systemic disease, unstable angina, New York Heart Association (NYHA) Grade 2 or greater Congestive Heart Failure (CHF), unstable symptomatic arrhythmia requiring medication, clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
16. Serious, non-healing wound, ulcer, or bone fracture
17. Evidence of bleeding diathesis or coagulopathy or other serious or acute internal bleeding within 6 months prior to randomization
18. Central Nervous System (CNS) bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months
19. In-patient surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
20. Minor surgical procedure, fine needle aspirations or core biopsy within 7 days prior to randomization
21. Anticipation of need for a major surgical procedure during the course of the study
22. Inability to take oral medication or requirement for intravenous (IV) alimentation or total parenteral nutrition with lipids, or prior surgical procedures affecting absorption
23. Evidence of confusion or disorientation, or history of major psychiatric illness that may impair the patient's understanding of the Informed Consent Form or his/her ability to comply with study requirements
24. Any other invasive malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA)
25. Brain metastasis
26. Patients who have had radiotherapy ≥ 4 weeks prior to the first dose of study treatment, but who are still experiencing acute toxic effects of radiotherapy
27. Known HIV positive patients (patients with both acute or chronic infection are excluded)
28. Active HBV or HCV infection (patients with chronic non-active infection are eligible)
29. Any already known inflammatory changes of the surface of the eye at baseline
30. Any other concomitant pathologies or laboratory alterations that prevent or contraindicate the use of erlotinib or bevacizumab.

Primary outcomes:
measure: progression free survival
timeFrame: up to 2 years
measure: progression free survival
timeFrame: up to 2 years
Secondary outcomes:
measure: overall survival
timeFrame: 1 year
measure: changes in quality of life scores from baseline
timeFrame: up to 2 years
measure: number of patients with complete and partial responses , investigator assessed
timeFrame: 6 months
measure: number of patients with complete and partial responses , centrally reviewed
timeFrame: 6 months
measure: worst grade toxicity per patient
timeFrame: up to one year
measure: progression free survival according to type of EGFR mutation (exon 19del, exon 21L858R, other)
timeFrame: 2 years
Other outcomes:
measure: number and type of EGFR mutations in plasma samples
timeFrame: up to 2 years
Locations:
city: Carpi
country: Italy
facility: Ospedale Ramazzini, Day Hospital Oncologico
state: MO
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena S.p.A., Dipartimento Oncologico
state: PA
city: Prato
country: Italy
facility: Ospedale di Prato
state: PO
city: Trento
country: Italy
facility: Ospedale S. Chiara
state: TN
city: Vicenza
country: Italy
facility: Ospedale S. Bortolo ULSS 6, U.O. di Oncologia Medica
state: VI
city: Alessandria
country: Italy
facility: A.S.O. SS Antonio e Biagio e Cesare Arrigo
city: Avellino
country: Italy
facility: A.O. S. Giuseppe Moscati
city: Aviano
country: Italy
facility: Centro Riferimento Oncologico
city: Benevento
country: Italy
facility: AO G. Rummo
city: Brindisi
country: Italy
facility: Ospedale Senatore Antonio Perrino
city: Campobasso
country: Italy
facility: Ospedale A. cardarelli
city: Camposampiero
country: Italy
facility: U.L.S.S. 15 Veneto
city: Catania
country: Italy
facility: A.O. Garibaldi Nesima
city: Catania
country: Italy
facility: Centro Clinico Diagnostico G.B. Morgagni
city: Catania
country: Italy
facility: Policlinico vittorio Emanuele
city: Faenza
country: Italy
facility: Ospedale Civile per gli Infermi
city: Fano
country: Italy
facility: Ospedale S. Croce
city: Ferrara
country: Italy
facility: A.O.U. Arcispedale Sant'Anna
city: Genova
country: Italy
facility: Ospedale Villa Scassi
city: Guastalla
country: Italy
facility: Ospedale di Guastalla
city: Lecce
country: Italy
facility: A.O. Vito Fazzi
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Milano
country: Italy
facility: Ospedale San Paolo
city: Mirano
country: Italy
facility: A.O. U.L.S.S. 13
city: Modena
country: Italy
facility: A.O.U. Policlinico Modena
city: Napoli
country: Italy
facility: Azienda Ospedaliera Cardarelli
city: Napoli
country: Italy
facility: A.O.U. Seconda Università di Napoli
city: Napoli
country: Italy
facility: AORN Ospedale dei Colli - Osp Monaldi
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
city: Negrar
country: Italy
facility: Istituto Sacro Cuore Don Calabria
city: Novara
country: Italy
facility: A.O.U. Maggiore della Carità
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
city: Palermo
country: Italy
facility: Policlinico Giaccone
city: Pavia
country: Italy
facility: Fondazione Salvatore Maugeri
city: Perugia
country: Italy
facility: Osp. S. Maria della Misericordia
city: Pesaro
country: Italy
facility: A.O. Ospedali Riuniti Marche Nord
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto
city: Potenza
country: Italy
facility: A.O. San Carlo
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci - AUSL
city: Ravenna
country: Italy
facility: Ospedale Umberto I
city: Rimini
country: Italy
facility: Ospedale degli Infermi Rimini - Ospedale Cervesi Cattolica
city: Rionero in Vulture
country: Italy
facility: IRCCS Centro di Riferimento Oncologico Basilicata
city: Roma
country: Italy
facility: Istituto Regina Elena
city: Roma
country: Italy
facility: Ospedale Camillo Forlanini
city: Roma
country: Italy
facility: Ospedale S. Giovanni Calibita Fatebenefratelli
city: Roma
country: Italy
facility: Policlinico Universitario Campus Bio Medico
city: Sondrio
country: Italy
facility: Ospedale di Sondrio
city: Sora
country: Italy
facility: Ospedale Fabrizio Spaziani di Frosinone
city: Trieste
country: Italy
facility: Ospedale Maggiore
city: Udine
country: Italy
facility: Azienda Ospedaliero-Universitaria S.M. della Misericordia di Udine
city: Vercelli
country: Italy
facility: Ospedale S. Andrea
city: Verona
country: Italy
facility: A.O.U. Integrata
city: Viterbo
country: Italy
facility: ASL Viterbo - Ospedale Belcolle
Study officials:
affiliation: S.G.Moscati Hospital
name: Cesare Gridelli, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Piccirillo MC, Bonanno L, Garassino MC, Esposito G, Dazzi C, Cavanna L, Burgio MA, Rosetti F, Rizzato S, Morgillo F, Cinieri S, Veccia A, Papi M, Tonini G, Gebbia V, Ricciardi S, Pozzessere D, Ferro A, Proto C, Costanzo R, D'Arcangelo M, Proietto M, Gargiulo P, Di Liello R, Arenare L, De Marinis F, Crino L, Ciardiello F, Normanno N, Gallo C, Perrone F, Gridelli C, Morabito A. Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial. J Thorac Oncol. 2022 Sep;17(9):1086-1097. doi: 10.1016/j.jtho.2022.05.008. Epub 2022 Jun 1.
citation: Deng Z, Qin Y, Liu Y, Zhang Y, Lu Y. Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis. Clin Lung Cancer. 2021 Jan;22(1):e70-e83. doi: 10.1016/j.cllc.2020.08.005. Epub 2020 Sep 18.