Clinical trial NCT02268045: Study of RTXM83 Plus CHOP Chemotherapy Versus a Rituximab Plus CHOP Therapy in Patients With Non Hodgkin's Lymphoma
Official title: A Randomized, Double-blind, Phase III Study Comparing Biosimilar Rituximab (RTXM83) Plus CHOP Chemotherapy Versus a Reference Rituximab Plus CHOP (R-CHOP) in Patients With Diffuse Large B-cell Lymphoma (DLBCL) Given as First Line
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Non-Hodgkin Lymphoma
DLBCL
Diffuse large b-cell lymphoma
Lead sponsor: mAbxience Research S.L.
Sponsor class: INDUSTRY
Collaborators: name: Pisa® Farmacéutica
name: Laboratorios de Productos Éticos C.E.I.S.A.
name: Laboratorio Elea Phoenix S.A.
name: Tecnoquimicas S.A
name: Innogene Kalbiotech Pte. Ltd
name: Libbs Farmacêutica LTDA
name: Key Oncologics (Pty) Ltd
name: Nanolek LLC
name: Actoverco
First posted: 2014-10-20
Enrollment: 272
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, double-blind, randomized study comparing the efficacy, pharmacokinetics (PK)/pharmacodynamics (PD), safety and immunogenicity profile of RTXM83 (rituximab biosimilar) vs reference rituximab (MabThera®), both with CHOP, as first-line treatment of Diffuse-Large-B-Cell-Lymphoma (DLBCL).

Rituximab biosimilar and MabThera® were both administered intravenously on Day 1 of each 3-week cycle with CHOP chemotherapy for six cycles. Two additional cycles of treatment were permitted at the Investigator's discretion. Patients were followed up for 9 months after last study dose.

Detailed description: The primary endpoint of the investigation is to determine if the response rate obtained with RTXM83 combined with CHOP is non inferior to the response rate obtained with reference rituximab combined with CHOP.

The present study is a non inferiority trial and the study hypothesis is the following: H0: pc ≥ pe + δ vs. H1: pc \< pe + δ where, pe: proportion of successes in the experimental group (RTXM83+CHOP) pc: proportion of successes in the control group (Reference Rituximab+CHOP) Type I error: the difference pc-pe is less than δ when in fact the difference is greater than or equal to δ ie, the investigators choose the experimental treatment when the control treatment is actually substantially better.

Type II error: the difference -pe is greater than or equal to δ when it is actually lest than δ ie, the investigators choose the control treatment when the experimental treatment is essentially just as good.

Eligibility criteria: Inclusion Criteria:

1. Patients with measurable disease defined as existence of a unidimensional or bidimensional lesion greater than 2 cm in its longest diameter or malignant lymphocytosis greater than 5x109/L. Any other procedure for measurable disease in particular cases, may be allowed upon Sponsor approval
2. Newly diagnosed patients with a confirmed pathologic diagnosis of Diffuse large B cell-non-Hodgkin's lymphoma (DLBCL) with untreated CD20+ receptor (CD20+). Defined by the local Haematopathologist at the local laboratory according to World Health Organization (WHO) criteria
3. Stage II-III or IV or stage I with bulk defined by the referring physician on the basis of the Cotswolds modification of the Ann Arbor classification 2
4. Age-adjusted International Prognostic Index (IPI) score 0 or 1
5. Age ≥18 to ≤65 years of age
6. Performance status according to Eastern Cooperative Oncology Group (ECOG) of ≤2
7. Written informed consent obtained before starting any study-specific procedure
8. Females of child-bearing potential must test negative on standard serum pregnancy test and must be willing to practice appropriate contraceptive methods for the duration of the study (e.g. oral contraceptive, double barrier method, intra-uterine device, intra-muscular contraceptive)
9. All male patients must take adequate contraceptive precautions during the course of the study

Exclusion Criteria:

1. Life expectancy of less than three months
2. Any other lymphoma other than CD20+ DLBCL
3. Indolent lymphoma, Primary central nervous system (CNS) Lymphoma or gastro-intestinal Mucosa Associated Lymphoid Tissue (MALT) Lymphoma
4. Known hypersensitivity to active ingredients, excipients and murine and foreign proteins
5. Concurrent disease or general status that would exclude giving the treatment as outlined in the protocol
6. Active uncontrolled infection requiring systemic treatment with antibiotics or antiviral agents at Screening or history of documented recurrent clinically significant infection (e.g. 2 or more viral, bacterial or fungal infections requiring inpatient treatment)
7. Cardiac contra-indication to Doxorubicin therapy: non-compensated heart failure, dilated cardiomyopathy, coronary heart disease with ST segment depression on electrocardiogram (ECG), myocardial infarction in the last 6 months
8. Neurologic contra-indication to Vincristine as it is indicated in the Summary of Product Characteristics (SmPC): (e.g. peripheral neuropathy)
9. Chronic lung disease with hypoxemia measured by pulse oximetry (gasometry is not mandatory)
10. Severe uncontrolled hypertension, despite optimal medical treatment
11. Severe uncontrolled diabetes mellitus, despite optimal medical treatment
12. Renal insufficiency (Serum Creatinine \>2 x Upper Normal Limit \[UNL\])
13. Hepatic insufficiency: aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)\>3 x UNL or \>5 x UNL with involvement of the liver, total bilirubin \>34.2 µmol/L, or both) not related to lymphoma
14. Clinical signs of cerebral dysfunction
15. Severe psychiatric disease
16. Known human immunodeficiency virus (HIV) infection or active chronic hepatitis B or C
17. Abnormal bone marrow function (platelets \<100x109/L, neutrophils \<1.5x109/L and Haemoglobin \<9g/dL)
18. Post-transplantation lymphoproliferative disease
19. Pregnant or lactating women or women that intend to get pregnant during study or within 12 months following the last infusion
20. Treatment with any investigational product in the 30 days period before inclusion in the study
21. Prior radiotherapy to treat the DLBCL Non-Hodgkin's Lymphoma (NHL)
22. Limitation of the patient's ability to comply with the treatment or follow-up protocol

Primary outcomes:
measure: Response Rate (RR) Achieved After Cycle 6 With RTXM83 Plus CHOP Compared to the RR Obtained With Mabthera® Plus CHOP (R-CHOP) in Patients With DLBCL
timeFrame: Tumor response assessed after Cycle 6 or at the end of treatment
Secondary outcomes:
measure: AUC 0-∞ (h μg/mL) at Cycle 1 of RTXM83 and Mabthera®
timeFrame: Cycle 1 (first dose): Day 1 (pre-dose, mid-infusion), Day 8 and Day 15
measure: AUC 0-∞ (h μg/mL) at Cycle 6 of RTXM83 and Mabthera®
timeFrame: Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
measure: Cmax (μg/mL) at Cycle 1 of RTXM83 and Mabthera®
timeFrame: Cycle 1 (first dose): Day 1 (pre-dose, mid-infusion), Day 8 and Day 15
measure: Cmax (μg/mL) at Cycle 6 of RTXM83 and Mabthera®
timeFrame: Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
measure: Percentage Change From Baseline in Pharmacodynamic (PD) Markers (CD19+ and CD20+ Cells) Blood Counts of RTXM83 and Mabthera®
timeFrame: Up to follow-up 3 (FU3); 9 months after last dose of treatment
measure: Comparable Safety Profile in Both Treatment Arms
timeFrame: Up to FU3; 9 months after last dose of treatment
measure: Comparable Immunogenicity Profile Between RTXM83 and Mabthera®
timeFrame: Up to FU3; 9 months after last dose of treatment
measure: Event Free Survival (EFS) in RTXM83 Arm and Mabthera® Arm
timeFrame: Up to FU3; 9 months after last dose of treatment
Other outcomes:
Locations:
city: Ciudadela
country: Argentina
facility: Hosp. Interzonal "R" Carrillo
state: Bariloche
city: Cipolletti
country: Argentina
facility: Clinica Radiologica del Sur
state: Río Negro
city: Viedma
country: Argentina
facility: Clinica Viedma
state: Río Negro
city: Buenos Aires
country: Argentina
facility: Hospital Britanico
city: Buenos Aires
country: Argentina
facility: Hospital Gral. de Agudos Donación Francisco Santojanni
city: Buenos Aires
country: Argentina
facility: Instituto Roffo
city: Cordoba
country: Argentina
facility: Centro Oncologico Riojano Integral (CORI)
city: Cordoba
country: Argentina
facility: Hospital Nacional de Clinicas
city: Cordoba
country: Argentina
facility: Hospital Privado de Cordoba
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: Rosario
country: Argentina
facility: Ctr. Oncologico de Rosario
city: Rosario
country: Argentina
facility: Inst. Cardiovascular Rosario
city: Rosario
country: Argentina
facility: Instituto de Hematología y Medicina Clínica Dr. Rubén Dávoli
city: Rosario
country: Argentina
facility: Sanatorio Parque
city: San Salvador de Jujuy
country: Argentina
facility: Fundación ARS Médica
city: Santa Fe
country: Argentina
facility: Hospital J. B. Iturraspe
city: Tucumán
country: Argentina
facility: Hospital Angel Padilla
city: Pôrto Alegre
country: Brazil
facility: Hospital Clinicas Porto Alegre
state: Rio Grande Do Sul
city: Ijuí
country: Brazil
facility: Hospital de Caridade de Ijuí
state: RS
city: Passo Fundo
country: Brazil
facility: Hospital da Cidade de Passo Fundo
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas da PUCRS
state: RS
city: Itaquera
country: Brazil
facility: Hospital Santa Marcelina
state: Sao Paulo
city: Jaú
country: Brazil
facility: Hospital Amaral Carvalho Jaú
state: SP
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo-HCFMRP
state: SP
city: Santo André
country: Brazil
facility: CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia / Faculdade de Medicina do ABC
state: SP
city: Sao Paulo
country: Brazil
facility: Fundação Antônio Prudente - AC Camargo Câncer Center
state: SP
city: Belo Horizonte
country: Brazil
facility: Hospital das Clinicas-UFMG
city: Campinas
country: Brazil
facility: UNICAMP-Univ Zeferino Vaz
city: Cascavel
country: Brazil
facility: Hospital Uniao Oeste Paranaense de Estudos e Comabte ao Cancer (UOPECCAN)
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner CEPEP
city: Goiânia
country: Brazil
facility: Hospital das Clínicas da Universidade Federal de Goiás
city: Porto Alegre
country: Brazil
facility: Santa Casa de Porto Alegre
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitário Clemente Fraga Filho - UFRJ
city: Rio de Janeiro
country: Brazil
facility: Instituto COI de Educação e Pesquisa
city: Rio de Janeiro
country: Brazil
facility: Instituto Est. de Hematologia Arthur de Siqueira Cavalcanti
city: Salvador
country: Brazil
facility: Monte Tabor - Hospital São Rafael
city: Sao Paulo
country: Brazil
facility: Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC
city: Sao Paulo
country: Brazil
facility: Hospital Clinica Faculdade Medicina USP
city: São José do Rio Prêto
country: Brazil
facility: Hospital de Base de São José
city: Bogotá
country: Colombia
facility: Inst. Nacional de Cancerologia
city: Cali
country: Colombia
facility: Fundación Valle de Lili
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe
city: Bangalore
country: India
facility: Srinivasam Cancer Care Hospital
city: Chennai
country: India
facility: Cancer Institute
city: Delhi
country: India
facility: Rajiv Gandhi Cancer Institute and Research Centre
city: Hyderabad
country: India
facility: Bibi General Hospital&Canc Ct
city: Jaipur
country: India
facility: Birla Cancer Center - SMS Hospital
city: Kolkata
country: India
facility: Health Point Multi-specialty Hospital
city: Kolkata
country: India
facility: Institute of Hematology and Transfusion Medicine
city: Kolkata
country: India
facility: Netaji Subhash Chandra Bose Cancer Research Institute
city: Madurai
country: India
facility: Acharya Tulsi Regional Cancer Treatment and Research Institute
city: Madurai
country: India
facility: Guru Hospital
city: Madurai
country: India
facility: Meenakshi Mission Hospital
city: Vadodara
country: India
facility: Kailash Cancer Hospital and Research Centre
city: Bandung
country: Indonesia
facility: Dr. Hasan Sadikin Hospital
city: Jakarta
country: Indonesia
facility: Dharmais N. C. Center
city: Tehrān
country: Iran, Islamic Republic of
facility: Imam Khomeini Complex Hospital - Cancer Institute
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre - UMMC
city: Pulau Pinang
country: Malaysia
facility: Mount Miriam Cancer Hospital
city: Pulau Pinang
country: Malaysia
facility: Hospital Pulau Pinang
city: Mexico City
country: Mexico
facility: Insituto Nacional de Cancerología
city: Asunción
country: Paraguay
facility: Instituto Privado de Hematologia e Investigaciona Clinica
city: Cebu
country: Philippines
facility: Cebu Doctors University Hospital
city: Cebu
country: Philippines
facility: Perpetual Succour Hospital
city: Davao
country: Philippines
facility: Davao Doctors Hospital
city: Quezon City
country: Philippines
facility: National Kidney and Transplant Institute
city: Quezon City
country: Philippines
facility: Veterans Memorial Medical Center
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk Clinical Oncology Dispensary
city: Kursk
country: Russian Federation
facility: Kursk regional clinical oncology dispensary
city: Moscow
country: Russian Federation
facility: N.N. Blokhin Russian Cancer Research Cente
city: Moscow
country: Russian Federation
facility: National Medical Surgical Center n.a. N.I. Pirogov
city: Murmansk
country: Russian Federation
facility: Murmansk regional oncology dispensary
city: Pyatigorsk
country: Russian Federation
facility: State Budgetary Healthcare Institution of Stavropol region "Pyatigorsk oncology center"
city: Rostov-na-Donu
country: Russian Federation
facility: Rostov Scientific Research Oncology Institute
city: Saint-Petersburg
country: Russian Federation
facility: Russian Research Center for Radiology and Surgical Technologies
city: Saint-Petersburg
country: Russian Federation
facility: Saint-Petersburg State Budgetary Institution "City Clinical Oncology Dispensary"
city: Saint-Petersburg
country: Russian Federation
facility: Scientific Research Institute of Oncology n.a. N.N. Petrov
city: Sochi
country: Russian Federation
facility: Oncology Center # 2
city: Syktyvkar
country: Russian Federation
facility: Komi Republican Oncology Dispensary
city: Tula
country: Russian Federation
facility: State Healthcare Institution of Tula region "Tula regional clinical hospital"
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Dispensary
city: Volgograd
country: Russian Federation
facility: Volgograd Regional Clinical Oncology Center
city: Amanzimtoti
country: South Africa
facility: Rainbow Oncology Centre
city: Cape Town
country: South Africa
facility: Tygerberg Academic Hosp
city: Port Elizabeth
country: South Africa
facility: GVI Oncology
city: Soweto
country: South Africa
facility: Chris Hani Baragwanath Hospital
Study officials:
affiliation: mAbxience Research S.L.
name: Susana Millán, Phd
role: STUDY_DIRECTOR
References: