A Study Comparing MB02 and Avastin® in Subjects With Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Non-small Cell Lung Cancer Clinical Trial

— STELLA  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03296163
• Other study ID #: MB02-C-02-17
• Status: Completed
• Phase: Phase 3
• Start date: February 6, 2018
• Est. completion date: February 27, 2020

Study information

• Verified date: March 2021
• Source: mAbxience S.A
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 627
• Est. completion date: February 27, 2020
• Est. primary completion date: July 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• MB02 (Bevacizumab Biosimilar Drug)
15 mg/kg IV every 3 weeks on Day 1
• EU-approved Avastin®
15 mg/kg IV every 3 weeks on Day 1
• Carboplatin
Carboplatin Area under the curve (AUC) 6 IV every 3 weeks on Day 1 for 6 cycles
• Paclitaxel
Paclitaxel 200 mg/m2 IV every 3 weeks on Day 1 for 6 cycles

Locations

Country	Name	City	State
Brazil	Hospital de Câncer de Barretos	Barretos	SP
Brazil	Centro de Pesquisa e Educação da Serra Gaúcha (CEPESG)	Caxias do Sul	RS
Brazil	IPCEM Universidade de Caxias Do Sul	Caxias do Sul	RS
Brazil	Hospital Erasto Gaertner - Paranaense de Combate ao Câncer	Curitiba	PR
Brazil	Instituto do Câncer do Ceará - ICC	Fortaleza	CE
Brazil	Centro Brasileiro de Radioterapia Oncologia e Mastologia	Goiânia	GO
Brazil	Hospital de Caridade de Ijuí	Ijuí	RS
Brazil	MedRadius	Maceió	AL
Brazil	Instituto do Câncer - Hospital São Vicente de Paulo	Passo Fundo	RS
Brazil	Hospital São Lucas da PUCRS	Pôrto Alegre	RS
Brazil	Instituto Nacional de Cancer- INCA	Rio de Janeiro	RJ
Brazil	Hospital de Base de São José do Rio Preto	São José do Rio Prêto	SP
Brazil	Hospital Santa Marcelina	Sao Paulo
Brazil	Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC	São Paulo	SP
Brazil	Instituto de Ensino e Pesquisa São Lucas	São Paulo	SP
Bulgaria	Central Hospital Plovdiv	Plovdiv
Bulgaria	Acibadem City Clinic Cancer Center UMHAT	Sofia
Bulgaria	Specialized Hospital for Active Treatment of Oncology Diseases Sofia District EOOD	Sofia
Chile	Fundación Arturo López Pérez - Instituto Oncológico FALP	Santiago
Chile	Health & Care Spa	Santiago
Chile	Instituto Clinico Oncologico del Sur ICOS	Temuco
Chile	Oncocentro APYS	Viña del Mar
Georgia	Cancer Center of Adjara Autonomous Republic	Batumi
Georgia	Acad. F . Todua medical center-research institute of clinical medicine	Tbilisi
Georgia	Consilium Medulla	Tbilisi
Georgia	Institute of Clinical Oncology	Tbilisi
Georgia	LTD Aversi Clinic	Tbilisi
Georgia	LTD Cancer Research Centre	Tbilisi
Georgia	Tbilisi State Medical Universitys First university Clinic	Tbilisi
Greece	General Hospital of Athens "Ippokratio"	Athens
Greece	Sotiria General Hospital for Chest Diseases	Athens
Greece	University General Hospital of Larissa	Lárisa
Greece	Agioi Anargyroi General Oncological Hospital of Kifissia	Néa Kifisiá
Greece	General Hospital of Thessaloniki "George Papanikolaou"	Thessaloníki
Hungary	National Koranyi Institute of TB and Pulmonology	Budapest
Hungary	Országos Korányi Pulmonológiai Intézet (OKPI)	Budapest
Hungary	Csongrád Megyei Önkormányzat Mellkasi Betegségek Szakkórháza	Deszk
Hungary	Veszprém Megyei Tüdogyógyinzézet	Farkasgyepu
Hungary	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház	Miskolc
India	Zydus Hospital	Ahmedabad
India	Action Cancer Hospital	Delhi
India	Aadhar Health Institute	Hisar
India	NIMS - Nizam's Institute of Medical Sciences	Hyderabad
India	Ganadhipati Purushottam Shekhawati Hospital Research Centre	Jaipur
India	PVS Hospital Pvt Ltd	Kerola
India	Apollo Gleneagles Hospital	Kolkata
India	Netaji Subhas Chandra Bose Cancer Research Institute	Kolkata
India	Shatabdi Super Speciality Hospital	Nashik
India	Deenanath Mangeshkar Hospital & Research Center	Pune
India	Kiran Super Multispeciality Hospital	Surat
India	Nirmal Hospital Pvt. Ltd.	Surat
India	Shree Himalaya Cancer Hospital Research Institute	Vadodara
India	Queen's NRI Hospital Gurudwara Lane	Visakhapatnam
Lebanon	Notre Dame de Secours	Jbaïl
Malaysia	Hospital Pulau Pinang	George Town	Pulau Pinang
Malaysia	Institut Perubatan dan Pergigian Termaju Universiti Sains Malaysia	Kepala Batas
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	Pusat Perubatan Universiti Kebangsaan Malaysia	Kuala Lumpur
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Hospital Umum Sarawak	Kuching
Malaysia	National Cancer Institute	Putrajaya
Mexico	Instituto Nacional de Cancerologia	Mexico City
Mexico	Hospital Universitario Dr. Jose Eleuterio González	Monterrey
Oman	Sultan Qaboos University Hospital	Muscat
Philippines	Baguio General Hospital & Medical Center	Baguio
Philippines	Cebu Doctors University Hospital - CDUH	Cebu
Philippines	Perpetual Succour Hospital - PSH	Cebu
Philippines	De La Salle University Medical Center - DLSUMC	Dasmariñas
Philippines	Davao Doctors Hospital - DDH	Davao
Philippines	Makati Medical Center	Makati City
Philippines	Philippine General Hospital - PGH	Manila
Philippines	The Medical City	Pasig
Philippines	St. Luke's Medical Center - Global City	Taguig
Russian Federation	SBHI Arkhangelsk Region - Arkhangelsk Clinical Oncological Dispensary	Arkhangel'sk
Russian Federation	Regional state budgetary Healthcare Institution "Belgorod oncology dispensary"	Belgorod
Russian Federation	State Budget Healthcare Institution Ivanovo Regional Oncology Dispensary	Ivanovo
Russian Federation	Kaluga Regional Clinical Oncology center	Kaluga
Russian Federation	Republic Clinical Oncology Dispensary	Kazan'
Russian Federation	Kursk Republican Clinical Oncology Dispensary	Kursk
Russian Federation	"VitaMed" LLC	Moscow
Russian Federation	Moscow City Oncology Hospital No 62	Moscow
Russian Federation	N. N. Blokhin Russian Cancer Research Center	Moscow
Russian Federation	University Headache Clinic LLC	Moscow
Russian Federation	Federal budget Healthcare Institution "Volga District Medical Centre" under Federal Medical and Biological Agency	Novgorod
Russian Federation	GBUZ of SK Pyatigorsk Oncology Dispensary	Pyatigorsk
Russian Federation	Ryazan Regional Clinical Oncology Dispensary	Ryazan'
Russian Federation	City Clinical Oncology Dispensary	Saint Petersburg
Russian Federation	GUZ "Leningrad Regional Clinical Hospital"	Saint Petersburg
Russian Federation	State Budgetary healthcare Institution "Samara regional clinical oncology dispensary"	Samara
Serbia	CHC Bezanijska Kosa	Belgrade
Serbia	Institute of Oncology and Radiology of Serbia (IORS)	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinical center Nis (Clinic for pulmonary diseases)	Niš
Serbia	Institute for Pulmonary Diseases of Vojvodina	Sremska Kamenica
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Madrid
Thailand	Bangkok International Hospital And Wattanosod Hospital	Bangkok
Thailand	Chiang Mai University (CMU) - Maharaj Nakhon Chiang Mai Hospital Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Chiang Rai Prachanukroh Hospital	Chiang Rai
Thailand	Songklanagarind Hospital	Hat Yai
Thailand	Buddhachinaraj Hospital	Phitsanulok
Turkey	Istanbul Medeniyet University Medical Faculty	Istanbul
Turkey	Suat Seren Chest Diseases Hospital	Izmir
Ukraine	Municipal Institution Cherkasy Regional Oncology Dispensary of Cherkasy Regional Council	Cherkasy
Ukraine	Public Higher Education Insititution of Ukraine "Bukovinian State Medical University"	Chernivtsi
Ukraine	Multifield Clinical Hospital No.4	Dnepropetrovsk
Ukraine	Clinical Oncology Dispensary	Dnipro
Ukraine	State Institution "Grigoriev Institute for Medical Radiology National Academy of Medical Science of Ukraine"	Kharkiv
Ukraine	State Institution "V.T. Zaycev Institute of general and urgent surgery of National academy medical sciences of Ukraine"	Kharkiv
Ukraine	Medical and Diagnostic Centre Private Enterprise of Private Manufacturing Company "ACINUS"	Kropyvnytskyi
Ukraine	Municipal Institution "Kryviy Rih Oncology Dispensary" of Dnipropetrovsk Regional Council	Kryvyi Rih
Ukraine	National Cancer Institute	Kyiv
Ukraine	National Institute of Cancer	Kyiv
Ukraine	Lviv State Oncology Regional Treatment and Diagnostic Center	L'viv
Ukraine	Healthcare facility "Volyn regional Oncological Dispensary"	Luts'k
Ukraine	Odessa Regional Clinical Oncology Dispensary	Odessa
Ukraine	Uzhgorod National University	Uzhgorod
Ukraine	Vinnytsia Regional Clinical Oncology Dispensary	Vinnytsya
Ukraine	Communal Institution "Zaporizhzhya Regional Clinical Oncological Dispensary" of Zaporizhzhya regional council	Zaporizhzhya

Sponsors (1)

Lead Sponsor	Collaborator
mAbxience S.A

Countries where clinical trial is conducted

Brazil,  Bulgaria,  Chile,  Georgia,  Greece,  Hungary,  India,  Lebanon,  Malaysia,  Mexico,  Oman,  Philippines,  Russian Federation,  Serbia,  Spain,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) at Week 18	Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1 at Week 18, as assessed by independent radiological review committee (IRC).; Overall Response (OR) = CR + PR.	18 weeks from randomisation
Secondary	Progression-free Survival (PFS)	Progression-free survival was defined as the time from randomization to subsequent confirmed progression per RECIST version 1.1, or death (whichever occurred first), measured in weeks and months. For PFS assessment clinical progression (i.e., treatment discontinuation due to progression of disease) was also considered as an event.	At Week 52 from randomisation
Secondary	Overall Survival (OS)	Overall survival was defined as the time from randomization to subsequent death, measured in weeks and months.	At Week 52 from randomisation
Secondary	Incidence of Treatment-emergent Adverse Events (TEAEs)	Comparison of Safety profile. Safety was monitored by incidence of adverse events (AEs). AEs were coded as per MedDRA (version 20.1) and severity was graded according to NCI-CTCAE (version 4.03);	Week 1 to week 52
Secondary	Immunogenicity Assessments (Anti-drug Antibodies [ADA] and Neutralizing Antibodies [NAb])	Incidence of anti-drug antibodies (ADA) and neutralizing ADAs (NAb). Analyses of ADA incidence rate, antibody titer, and neutralizing antibodies (NAb) (following the recommended 3-tier approach) were performed.	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