Clinical trial NCT03296163: A Study Comparing MB02 and Avastin® in Subjects With Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Official title: A Randomized, Multicenter, Multinational, Double-Blind Study to Assess the Efficacy and Safety of MB02 (Bevacizumab Biosimilar Drug) Versus Avastin® in Combination With Carboplatin and Paclitaxel for the Treatment of Subjects With Stage IIIB/IV Non-squamous Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Lead sponsor: mAbxience Research S.L.
Sponsor class: INDUSTRY
First posted: 2017-09-28
Enrollment: 627
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, multinational, double-blind, 1:1 randomized, parallel-group, equivalence Phase 3 study to compare the efficacy and safety of MB02 plus chemotherapy (carboplatin and paclitaxel) versus Avastin® plus chemotherapy (carboplatin and paclitaxel) in subjects with Stage IIIB/IV non-squamous NSCLC

Detailed description: Efficacy parameters, safety profiles and immunogenicity will be compared between MB02 (Bevacizumab Biosimilar Drug) and European (EU)-approved Avastin®

Eligibility criteria: Inclusion Criteria:

1. Males and female subjects aged ≤ 18 years to ≤ 80 years.
2. Signed informed consent must be obtained before initiation of any study-specific procedures or treatment as confirmation of the subject's awareness and willingness to comply with the study requirements.
3. Subjects should have newly diagnosed or recurrent Stage IIIB/IV (defined by seventh edition of the Tumor, Node and Metastasis (TNM) classification for Lung Cancer, 2010) non-squamous NSCLC not amenable to curative intent surgery, and not have received any systemic therapy for advanced disease (exclusion criteria 3 and 4). For subjects with recurrent disease, at least 6 months must have elapsed before randomization from previous adjuvant treatment.
4. Previous radiation therapy if completed \>4 weeks before randomization. Palliative radiotherapy to bone lesions is allowed if completed \>2 weeks of randomization.
5. Subjects must have at least 1 unidimensional measurable lesion per RECIST version 1.1 (assessed locally).
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 at Screening.
7. Subjects must have adequate hepatic, renal and hematologic function defined as:

   * Hepatic function: bilirubin level \<1.5 the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels\<2.5×ULN.
   * Renal function: serum creatinine level \<1.5×ULN, calculated creatinine clearance (CrCl) \>50 mL/min (Cockcroft-Gault formula), urine protein to creatinine ratio \<1. Subjects with urine protein-to-creatinine ratio \>1 may be enrolled if they have \<1 g of protein in 24-hour urine collection.
   * Hematological function: Absolute neutrophil count \>1.5×109 /L; platelets \>100×109 /L, hemoglobin (Hb) \>9 g/dL.
   * Adequate coagulation parameters such as: INR ≤ 2.0 and aPTT ≤ 1.5 x ULN within 7 days prior to randomization for patients not receiving anticoagulation therapy.
8. Eligible subjects must have a systolic blood pressure of ≤ 140 mm Hg and a diastolic blood pressure of ≤90 mm Hg at screening.
9. Women of childbearing potential, and their partners, must agree to adhere to pregnancy prevention methods throughout the duration of the study (including the Follow-up visits, where applicable). Women of childbearing potential are defined as those who are not surgically sterile (did not underwent bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and not postmenopausal.

Subjects and their partners must agree to use a highly effective method of contraception, to avoid women becoming pregnant throughout the course of the study. Medically acceptable forms of birth control can include the following, with approval of the treating physician:

* Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence.

  10. Non fertile women can be included, that is, those who are physiologically incapable of becoming pregnant, because of:
* Hysterectomy.
* Bilateral oophorectomy (ovariectomy).
* Bilateral tubal ligation or,
* Postmenopausal women defined as:

Subjects not using hormone replacement therapy (HRT) and have experienced total cessation of menses for ≥ 1 year and be greater than 45 years of age, OR, in questionable cases, have a follicle stimulating hormone \>40 mIU/mL and an estradiol value \<40 pg/mL (\<140 pmol/L).

Subjects must discontinue HRT before study enrolment because of the potential for inhibition of cytochrome enzymes that metabolize estrogens and progestins. For most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of HRT and determination of menopausal status; the length of this interval depends on the type and dosage of HRT.

If a female subject is determined not to be postmenopausal, that subject must use adequate contraception, as defined immediately above (inclusion 8).

Exclusion Criteria:

1. Inability to comply with protocol procedures.
2. Participation in another clinical trial or treatment with another investigational agent within 4 weeks or 5 half-lives of investigational agent before randomization, whichever is longer.
3. Subjects previously treated with monoclonal antibodies or small molecule inhibitors against Vascular Endothelial Growth Factor (VEGF) or VEGF receptors, including Avastin®.
4. Subjects who have received previous chemotherapy, immunotherapy, targeted therapy, or biological therapy for their lung cancer. Note: Adjuvant and neo- adjuvant therapy are permitted (see: inclusion criterion 3).
5. Subjects who have known central nervous system disease, with the exception of subjects with treated brain metastases who have completed treatment (radiation, surgery or stereotactic surgery) and have not received steroids for at least 4 weeks before randomization. Subjects with central nervous system metastases treated by neurosurgical resection or brain biopsy performed within 8 weeks before randomization will be excluded. Subjects with known or history of brain metastases must undergo brain imaging during screening.
6. Current or recent (within 10 days of the first dose of study treatment) use of aspirin (at least 325 mg/day) or other nonsteroidal anti-inflammatory drugs with antiplatelet activity or treatment with dipyridamole (Persantine®), ticlopidine (Ticlid®), clopidogrel (Plavix®), or cilostazol (Pletal®).
7. Current or recent (within 5 days) use of therapeutic anticoagulation or use of thrombolytic agent. Prophylactic use of low molecular weight heparin is allowed.
8. Subjects with an INR \>2, unless receiving active anticoagulation treatment, will be excluded.
9. Subjects who have a diagnosis of small cell carcinoma of the lung or squamous cell carcinoma of the lung. Mixed tumors should be categorized according to the predominant histology. If small cell elements are present, the subject will be excluded.
10. Subjects with known tumors that harbor activating epidermal growth factor receptor and anaplastic lymphoma receptor tyrosine kinase (assessed locally).
11. Subjects who have a history of hypersensitivity to the active substance (bevacizumab, carboplatin, and/or paclitaxel) or any of the excipients (such as trehalose dehydrate, sodium phosphate, or polysorbate 20).
12. Subjects with known active viral infection, including but not limited to: hepatitis B, hepatitis C, or HIV.
13. Subjects who are pregnant or breastfeeding. Women of child-bearing potential must have a negative pregnancy test at Screening.
14. Subjects with previous major surgery, open biopsy, open pleurodesis, or significant traumatic injury within 4 weeks before randomization or those anticipated to require major surgery during the study.
15. Subjects who have had a core biopsy taken or have had another minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 1 week of randomization.
16. Subjects with a history of abdominal fistula, GI perforation, intra-abdominal abscess within 6 months of randomization.
17. Subjects with a nonhealing wound, active ulcer, or untreated bone fracture.
18. Subjects with previous history of hypertensive crisis or hypertensive encephalopathy.
19. Subjects with New York Heart Association Grade II or greater congestive heart failure, or angina, myocardial infarction within 6 months before randomization; symptomatic arrhythmia or serious cardiac arrhythmia requiring medication; abnormal left ventricular ejection fraction \< 50% assessed by ultrasound or multigated acquisition scan.
20. Subjects with a previous malignancy within 3 years of randomization (other than superficial basal cell and superficial squamous (skin) cell carcinoma, or carcinoma in situ of the uterine cervix, bladder, or prostate).
21. Subjects with history of a significant vascular event within 6 months before randomization (including, but not limited to myocardial infarction and stroke or transient ischemic attack).
22. Subjects with known bleeding diathesis or significant coagulopathy defined as a bleeding event grade ≥ 2 within 3 months before randomization.
23. Subjects with history of grade ≥2 hemoptysis within 6 months before randomization (≥0.5 teaspoons of bright red blood per event).
24. Subjects with a tumor(s) invading or compressing major blood vessels.

Primary outcomes:
measure: Objective Response Rate (ORR) at Week 18
timeFrame: 18 weeks from randomisation
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: At Week 52 from randomisation
measure: Overall Survival (OS)
timeFrame: At Week 52 from randomisation
measure: Incidence of Treatment-emergent Adverse Events (TEAEs)
timeFrame: Week 1 to week 52
measure: Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb])
timeFrame: At Weeks 1, 4, 10, 19, 34 and 52 from randomization and, at the End of Treatment Visit if, an ADA sample has not been collected within the previous 3 weeks
Other outcomes:
Locations:
city: Maceió
country: Brazil
facility: MedRadius
state: AL
city: Fortaleza
country: Brazil
facility: Instituto do Câncer do Ceará - ICC
state: CE
city: Goiânia
country: Brazil
facility: Centro Brasileiro de Radioterapia Oncologia e Mastologia
state: GO
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner - Paranaense de Combate ao Câncer
state: PR
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional de Cancer- INCA
state: RJ
city: Caxias do Sul
country: Brazil
facility: Centro de Pesquisa e Educação da Serra Gaúcha (CEPESG)
state: RS
city: Caxias do Sul
country: Brazil
facility: IPCEM Universidade de Caxias Do Sul
state: RS
city: Ijuí
country: Brazil
facility: Hospital de Caridade de Ijuí
state: RS
city: Passo Fundo
country: Brazil
facility: Instituto do Câncer - Hospital São Vicente de Paulo
state: RS
city: Pôrto Alegre
country: Brazil
facility: Hospital São Lucas da PUCRS
state: RS
city: Barretos
country: Brazil
facility: Hospital de Câncer de Barretos
state: SP
city: São José do Rio Prêto
country: Brazil
facility: Hospital de Base de São José do Rio Preto
state: SP
city: São Paulo
country: Brazil
facility: Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC
state: SP
city: São Paulo
country: Brazil
facility: Instituto de Ensino e Pesquisa São Lucas
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Plovdiv
country: Bulgaria
facility: Central Hospital Plovdiv
city: Sofia
country: Bulgaria
facility: Acıbadem City Clinic Cancer Center UMHAT
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Oncology Diseases Sofia District EOOD
city: Santiago
country: Chile
facility: Fundación Arturo López Pérez - Instituto Oncológico FALP
city: Santiago
country: Chile
facility: Health & Care Spa
city: Temuco
country: Chile
facility: Instituto Clinico Oncologico del Sur ICOS
city: Viña del Mar
country: Chile
facility: Oncocentro APYS
city: Batumi
country: Georgia
facility: Cancer Center of Adjara Autonomous Republic
city: Tbilisi
country: Georgia
facility: Acad. F . Todua medical center-research institute of clinical medicine
city: Tbilisi
country: Georgia
facility: Consilium Medulla
city: Tbilisi
country: Georgia
facility: Institute of Clinical Oncology
city: Tbilisi
country: Georgia
facility: LTD Aversi Clinic
city: Tbilisi
country: Georgia
facility: LTD Cancer Research Centre
city: Tbilisi
country: Georgia
facility: Tbilisi State Medical Universitys First university Clinic
city: Athens
country: Greece
facility: General Hospital of Athens "Ippokratio"
city: Athens
country: Greece
facility: Sotiria General Hospital for Chest Diseases
city: Lárisa
country: Greece
facility: University General Hospital of Larissa
city: Néa Kifisiá
country: Greece
facility: Agioi Anargyroi General Oncological Hospital of Kifissia
city: Thessaloníki
country: Greece
facility: General Hospital of Thessaloniki "George Papanikolaou"
city: Budapest
country: Hungary
facility: National Koranyi Institute of TB and Pulmonology
city: Budapest
country: Hungary
facility: Országos Korányi Pulmonológiai Intézet (OKPI)
city: Deszk
country: Hungary
facility: Csongrád Megyei Önkormányzat Mellkasi Betegségek Szakkórháza
city: Farkasgyepű
country: Hungary
facility: Veszprém Megyei Tüdőgyógyinzézet
city: Miskolc
country: Hungary
facility: Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház
city: Ahmedabad
country: India
facility: Zydus Hospital
city: Delhi
country: India
facility: Action Cancer Hospital
city: Hisar
country: India
facility: Aadhar Health Institute
city: Hyderabad
country: India
facility: NIMS - Nizam's Institute of Medical Sciences
city: Jaipur
country: India
facility: Ganadhipati Purushottam Shekhawati Hospital Research Centre
city: Kerola
country: India
facility: PVS Hospital Pvt Ltd
city: Kolkata
country: India
facility: Apollo Gleneagles Hospital
city: Kolkata
country: India
facility: Netaji Subhas Chandra Bose Cancer Research Institute
city: Nashik
country: India
facility: Shatabdi Super Speciality Hospital
city: Pune
country: India
facility: Deenanath Mangeshkar Hospital & Research Center
city: Surat
country: India
facility: Nirmal Hospital Pvt. Ltd.
city: Sūrat
country: India
facility: Kiran Super Multispeciality Hospital
city: Vadodara
country: India
facility: Shree Himalaya Cancer Hospital Research Institute
city: Visakhapatnam
country: India
facility: Queen's NRI Hospital Gurudwara Lane
city: Jbaïl
country: Lebanon
facility: Notre Dame de Secours
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
state: Pulau Pinang
city: Kepala Batas
country: Malaysia
facility: Institut Perubatan dan Pergigian Termaju Universiti Sains Malaysia
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur
city: Kuala Lumpur
country: Malaysia
facility: Pusat Perubatan Universiti Kebangsaan Malaysia
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
city: Putrajaya
country: Malaysia
facility: National Cancer Institute
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cancerologia
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio González
city: Muscat
country: Oman
facility: Sultan Qaboos University Hospital
city: Baguio
country: Philippines
facility: Baguio General Hospital & Medical Center
city: Cebu
country: Philippines
facility: Cebu Doctors University Hospital - CDUH
city: Cebu
country: Philippines
facility: Perpetual Succour Hospital - PSH
city: Dasmariñas
country: Philippines
facility: De La Salle University Medical Center - DLSUMC
city: Davao
country: Philippines
facility: Davao Doctors Hospital - DDH
city: Makati City
country: Philippines
facility: Makati Medical Center
city: Manila
country: Philippines
facility: Philippine General Hospital - PGH
city: Pasig
country: Philippines
facility: The Medical City
city: Taguig
country: Philippines
facility: St. Luke's Medical Center - Global City
city: Arkhangel'sk
country: Russian Federation
facility: SBHI Arkhangelsk Region - Arkhangelsk Clinical Oncological Dispensary
city: Belgorod
country: Russian Federation
facility: Regional state budgetary Healthcare Institution "Belgorod oncology dispensary"
city: Ivanovo
country: Russian Federation
facility: State Budget Healthcare Institution Ivanovo Regional Oncology Dispensary
city: Kaluga
country: Russian Federation
facility: Kaluga Regional Clinical Oncology center
city: Kazan'
country: Russian Federation
facility: Republic Clinical Oncology Dispensary
city: Kursk
country: Russian Federation
facility: Kursk Republican Clinical Oncology Dispensary
city: Moscow
country: Russian Federation
facility: "VitaMed" LLC
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital No 62
city: Moscow
country: Russian Federation
facility: N. N. Blokhin Russian Cancer Research Center
city: Moscow
country: Russian Federation
facility: University Headache Clinic LLC
city: Novgorod
country: Russian Federation
facility: Federal budget Healthcare Institution "Volga District Medical Centre" under Federal Medical and Biological Agency
city: Pyatigorsk
country: Russian Federation
facility: GBUZ of SK Pyatigorsk Oncology Dispensary
city: Ryazan'
country: Russian Federation
facility: Ryazan Regional Clinical Oncology Dispensary
city: Saint Petersburg
country: Russian Federation
facility: City Clinical Oncology Dispensary
city: Saint Petersburg
country: Russian Federation
facility: GUZ "Leningrad Regional Clinical Hospital"
city: Samara
country: Russian Federation
facility: State Budgetary healthcare Institution "Samara regional clinical oncology dispensary"
city: Belgrade
country: Serbia
facility: CHC Bezanijska Kosa
city: Belgrade
country: Serbia
facility: Institute of Oncology and Radiology of Serbia (IORS)
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Niš
country: Serbia
facility: Clinical center Nis (Clinic for pulmonary diseases)
city: Sremska Kamenica
country: Serbia
facility: Institute for Pulmonary Diseases of Vojvodina
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Bangkok
country: Thailand
facility: Bangkok International Hospital And Wattanosod Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University (CMU) - Maharaj Nakhon Chiang Mai Hospital Nakorn Chiang Mai Hospital
city: Chiang Rai
country: Thailand
facility: Chiang Rai Prachanukroh Hospital
city: Hat Yai
country: Thailand
facility: Songklanagarind Hospital
city: Phitsanulok
country: Thailand
facility: Buddhachinaraj Hospital
city: İstanbul
country: Turkey
facility: Istanbul Medeniyet University Medical Faculty
city: İzmir
country: Turkey
facility: Suat Seren Chest Diseases Hospital
city: Cherkasy
country: Ukraine
facility: Municipal Institution Cherkasy Regional Oncology Dispensary of Cherkasy Regional Council
city: Chernivtsi
country: Ukraine
facility: Public Higher Education Insititution of Ukraine "Bukovinian State Medical University"
city: Dnepropetrovsk
country: Ukraine
facility: Multifield Clinical Hospital No.4
city: Dnipro
country: Ukraine
facility: Clinical Oncology Dispensary
city: Kharkiv
country: Ukraine
facility: State Institution "Grigoriev Institute for Medical Radiology National Academy of Medical Science of Ukraine"
city: Kharkiv
country: Ukraine
facility: State Institution "V.T. Zaycev Institute of general and urgent surgery of National academy medical sciences of Ukraine"
city: Kropyvnytskyi
country: Ukraine
facility: Medical and Diagnostic Centre Private Enterprise of Private Manufacturing Company "ACINUS"
city: Kryvyi Rih
country: Ukraine
facility: Municipal Institution "Kryviy Rih Oncology Dispensary" of Dnipropetrovsk Regional Council
city: Kyiv
country: Ukraine
facility: National Cancer Institute
city: Kyiv
country: Ukraine
facility: National Institute of Cancer
city: L'viv
country: Ukraine
facility: Lviv State Oncology Regional Treatment and Diagnostic Center
city: Luts'k
country: Ukraine
facility: Healthcare facility "Volyn regional Oncological Dispensary"
city: Odessa
country: Ukraine
facility: Odessa Regional Clinical Oncology Dispensary
city: Uzhgorod
country: Ukraine
facility: Uzhgorod National University
city: Vinnytsya
country: Ukraine
facility: Vinnytsia Regional Clinical Oncology Dispensary
city: Zaporizhzhya
country: Ukraine
facility: Communal Institution "Zaporizhzhya Regional Clinical Oncological Dispensary" of Zaporizhzhya regional council
Study officials:
References:
citation: Trukhin D, Poddubskaya E, Andric Z, Makharadze T, Bellala RS, Charoentum C, Yanez Ruiz EP, Fulop A, Hyder Ali IA, Syrigos K, Katgi N, Lopez Chuken YA, Rumyana I, Reyes-Igama J, Costamilan RC, Del Campo Garcia A, Florez A, Paravisini A, Millan S; STELLA Investigators. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. doi: 10.1007/s40259-021-00483-w. Epub 2021 Apr 29.