Study of RTXM83 Plus CHOP Chemotherapy Versus a Rituximab Plus CHOP Therapy in Patients With Non Hodgkin's Lymphoma

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

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.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Biological: RTXM83; Biological: Mabthera

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.

• Study Type: Interventional
• Enrollment (Actual): 272
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Británico
  • Buenos Aires, Argentina
    • Hospital Gral. de Agudos Donación Francisco Santojanni
  • Buenos Aires, Argentina
    • Instituto Roffo
  • Cordoba, Argentina
    • Sanatorio Allende
  • Cordoba, Argentina
    • Hospital Privado de Cordoba
  • Cordoba, Argentina
    • Centro Oncologico Riojano Integral (CORI)
  • Cordoba, Argentina
    • Hospital Nacional de Clínicas
  • Rosario, Argentina
    • Ctr. Oncologico de Rosario
  • Rosario, Argentina
    • Inst. Cardiovascular Rosario
  • Rosario, Argentina
    • Instituto de Hematología y Medicina Clínica Dr. Rubén Dávoli
  • Rosario, Argentina
    • Sanatorio Parque
  • San Salvador de Jujuy, Argentina
    • Fundacion Ars Medica
  • Santa Fe, Argentina
    • Hospital J. B. Iturraspe
  • Tucumán, Argentina
    • Hospital Angel Padilla
  • Bariloche
    • Ciudadela, Bariloche, Argentina
      • Hosp. Interzonal "R" Carrillo
  • Río Negro
    • Cipolletti, Río Negro, Argentina
      • Clinica Radiologica del Sur
    • Viedma, Río Negro, Argentina
      • Clínica Viedma
• Brazil
  • Belo Horizonte, Brazil
    • Hospital das Clinicas-UFMG
  • Campinas, Brazil
    • UNICAMP-Univ Zeferino Vaz
  • Cascavel, Brazil
    • Hospital Uniao Oeste Paranaense de Estudos e Comabte ao Cancer (UOPECCAN)
  • Curitiba, Brazil
    • Hospital Erasto Gaertner CEPEP
  • Goiânia, Brazil
    • Hospital das Clínicas da Universidade Federal de Goiás
  • Porto Alegre, Brazil
    • Santa Casa de Porto Alegre
  • Rio de Janeiro, Brazil
    • Hospital Universitário Clemente Fraga Filho - UFRJ
  • Rio de Janeiro, Brazil
    • Instituto COI de Educação e Pesquisa
  • Rio de Janeiro, Brazil
    • Instituto Est. de Hematologia Arthur de Siqueira Cavalcanti
  • Salvador, Brazil
    • Monte Tabor - Hospital Sao Rafael
  • Sao Paulo, Brazil
    • Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC
  • Sao Paulo, Brazil
    • Hospital Clinica Faculdade Medicina USP
  • São José do Rio Prêto, Brazil
    • Hospital de Base de Sáo José
  • RS
    • Ijuí, RS, Brazil
      • Hospital de Caridade de Ijui
    • Passo Fundo, RS, Brazil
      • Hospital da Cidade de Passo Fundo
    • Porto Alegre, RS, Brazil
      • Hospital São Lucas da PUCRS
  • Rio Grande Do Sul
    • Pôrto Alegre, Rio Grande Do Sul, Brazil
      • Hospital Clinicas Porto Alegre
  • SP
    • Jaú, SP, Brazil
      • Hospital Amaral Carvalho Jaú
    • Ribeirão Preto, SP, Brazil
      • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo-HCFMRP
    • Santo André, SP, Brazil
      • CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia / Faculdade de Medicina do ABC
    • Sao Paulo, SP, Brazil
      • Fundação Antônio Prudente - AC Camargo Câncer Center
  • Sao Paulo
    • Itaquera, Sao Paulo, Brazil
      • Hospital Santa Marcelina
• Colombia
  • Bogotá, Colombia
    • Inst. Nacional de Cancerologia
  • Cali, Colombia
    • Fundación Valle de Lili
  • Medellin, Colombia
    • Hospital Pablo Tobon Uribe
• India
  • Bangalore, India
    • Srinivasam Cancer Care Hospital
  • Chennai, India
    • Cancer Institute
  • Delhi, India
    • Rajiv Gandhi Cancer Institute And Research Centre
  • Hyderabad, India
    • Bibi General Hospital&Canc Ct
  • Jaipur, India
    • Birla Cancer Center - SMS Hospital
  • Kolkata, India
    • Health Point Multi-specialty Hospital
  • Kolkata, India
    • Institute of Hematology and Transfusion Medicine
  • Kolkata, India
    • Netaji Subhash Chandra Bose Cancer Research Institute
  • Madurai, India
    • Acharya Tulsi Regional Cancer Treatment and Research Institute
  • Madurai, India
    • Guru Hospital
  • Madurai, India
    • Meenakshi Mission Hospital
  • Vadodara, India
    • Kailash Cancer Hospital and Research Centre
• Indonesia
  • Bandung, Indonesia
    • Dr. Hasan Sadikin Hospital
  • Jakarta, Indonesia
    • Dharmais N. C. Center
• Iran, Islamic Republic of
  • Tehrān, Iran, Islamic Republic of
    • Imam Khomeini Complex Hospital - Cancer Institute
• Malaysia
  • Johor Bahru, Malaysia
    • Hospital Sultanah Aminah
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre - UMMC
  • Pulau Pinang, Malaysia
    • Hospital Pulau Pinang
  • Pulau Pinang, Malaysia, 11200
    • Mount Miriam Cancer Hospital
• Mexico
  • Mexico City, Mexico
    • Insituto Nacional de Cancerología
• Paraguay
  • Asunción, Paraguay
    • Instituto Privado de Hematologia e Investigaciona Clinica
• Philippines
  • Cebu, Philippines
    • Cebu Doctors University Hospital
  • Cebu, Philippines
    • Perpetual Succour Hospital
  • Davao, Philippines
    • Davao Doctors Hospital
  • Quezon City, Philippines
    • Veterans Memorial Medical Center
  • Quezon City, Philippines
    • National Kidney and Transplant Institute
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Arkhangelsk Clinical Oncology Dispensary
  • Kursk, Russian Federation
    • Kursk Regional Clinical Oncology Dispensary
  • Moscow, Russian Federation
    • N.N. Blokhin Russian Cancer Research Cente
  • Moscow, Russian Federation
    • National Medical Surgical Center n.a. N.I. Pirogov
  • Murmansk, Russian Federation
    • Murmansk Regional Oncology Dispensary
  • Pyatigorsk, Russian Federation
    • State Budgetary Healthcare Institution of Stavropol region "Pyatigorsk oncology center"
  • Rostov-na-Donu, Russian Federation
    • Rostov Scientific Research Oncology Institute
  • Saint-Petersburg, Russian Federation
    • Russian Research Center for Radiology and Surgical Technologies
  • Saint-Petersburg, Russian Federation
    • Saint-Petersburg State Budgetary Institution "City Clinical Oncology Dispensary"
  • Saint-Petersburg, Russian Federation
    • Scientific Research Institute of Oncology n.a. N.N. Petrov
  • Sochi, Russian Federation
    • Oncology Center # 2
  • Syktyvkar, Russian Federation
    • Komi Republican Oncology Dispensary
  • Tula, Russian Federation
    • State Healthcare Institution of Tula region "Tula Regional Clinical Hospital"
  • Ufa, Russian Federation
    • Republican Clinical Oncology Dispensary
  • Volgograd, Russian Federation
    • Volgograd Regional Clinical Oncology Center
• South Africa
  • Amanzimtoti, South Africa
    • Rainbow Oncology Centre
  • Cape Town, South Africa
    • Tygerberg Academic Hosp
  • Port Elizabeth, South Africa
    • GVI Oncology
  • Soweto, South Africa
    • Chris Hani Baragwanath Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RTXM83; Active Ingredient: Rituximab (Biosimilar)	Biological: RTXM83; Rituximab biosimilar (RTXM83) will be administered in combination with CHOP chemotherapy regimen (Cyclophosphamide 750 mg/m2, Doxorubicin 50 mg/m2 and Vincristine 1.4 mg/m2 up to a maximum of 2 mg on Day 1 plus Prednisone 40 mg/m2 or 100 mg per day from Day 1 to 5) at a dose of 375 mg/m2 on Day 1 of each 3 week cycle, for 6 cycles, although the administration of 2 additional cycles may be allowed.; Other Names: Rituximab Biosimilar
Active Comparator: MabThera; Active Ingredient: Rituximab	Biological: Mabthera; Mabthera will be administered in combination with CHOP chemotherapy regimen (Cyclophosphamide 750 mg/m2, Doxorubicin 50 mg/m2 and Vincristine 1.4 mg/m2 up to a maximum of 2 mg on Day 1 plus Prednisone 40 mg/m2 or 100 mg per day from Day 1 to 5) at a dose of 375 mg/m2 on Day 1 of each 3 week cycle, for 6 cycles, although the administration of 2 additional cycles may be allowed.; Other Names: Reference rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Per International Working Group (IWG) revised criteria for Malignant Lymphomas (Cheson et al. 2007) and assessed by positron-emission tomography scan, or by computed tomography scan and/or magnetic resonance imaging if Positron Emission Tomography (PET) scan was not feasible. Tumor response was classified according to the International Working Group criteria, as Complete Remission (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy; Partial Response (PR): At least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses; Stable disease (SD) or; Progressive disease. Response rate was the sum of CR and PR.	Tumor response assessed after Cycle 6 or at the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC 0-∞ (h μg/mL) at Cycle 1 of RTXM83 and Mabthera®	Compare the pharmacokinetic (PK) parameter (AUC 0-∞) calculated from start of the first infusion until start of the second infusion (i.e. at Cycle 1) in a population PK model. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio between the geometric means of the measure (AUC 0-∞ ) falls completely within the range 80%-125%.	Cycle 1 (first dose): Day 1 (pre-dose, mid-infusion), Day 8 and Day 15
AUC 0-∞ (h μg/mL) at Cycle 6 of RTXM83 and Mabthera®	Compare the PK parameter (AUC 0-∞) calculated from start of the first infusion until Day 21 of administration of Cycle 6 in a population PK model. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio between the geometric means of the measure (AUC 0-∞ ) falls completely within the range 80%-125%.	Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
Cmax (μg/mL) at Cycle 1 of RTXM83 and Mabthera®	Compare the PK parameter (Cmax) calculated from start of the first infusion until start of the second infusion (i.e. at Cycle 1) in a population PK model. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio between the geometric means of the measure (Cmax) falls completely within the range 80%-125%.	Cycle 1 (first dose): Day 1 (pre-dose, mid-infusion), Day 8 and Day 15
Cmax (μg/mL) at Cycle 6 of RTXM83 and Mabthera®	Compare the PK parameter (Cmax) calculated from start of the first infusion until Day 21 of administration of Cycle 6 in a population PK model. For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio between the geometric means of the measure (AUC 0-∞ ) falls completely within the range 80%-125%.	Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
Percentage Change From Baseline in Pharmacodynamic (PD) Markers (CD19+ and CD20+ Cells) Blood Counts of RTXM83 and Mabthera®	CD19 and CD20 are proteins found on the cell surface of B cells, and they can be detected in peripheral blood by flow cytometry. Flow cytometry of peripheral blood was performed for immediate analysis of cells with cluster of differentiation 19 (CD19+) and CD20+. To compare the percent Change From Baseline ((Cycle 1 pre-dose) in pharmacodynamic markers (CD19+ and CD20+ Cells) in Peripheral Blood achieved in RTXM83 and Mabthera® arms at Cycle 1 end of infusion (EOI), 6 months and 9 months after last dose of treatment.	Up to follow-up 3 (FU3); 9 months after last dose of treatment
Comparable Safety Profile in Both Treatment Arms	Compare the frequency and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) reported in each treatment arm.	Up to FU3; 9 months after last dose of treatment
Comparable Immunogenicity Profile Between RTXM83 and Mabthera®	Anti-Drug Antibody (ADA) developed de novo (seroconversion) after 6 cycles of treatment and 9 months of follow-up.	Up to FU3; 9 months after last dose of treatment
Event Free Survival (EFS) in RTXM83 Arm and Mabthera® Arm	Time from randomization to any of the following events: progressive disease, no achievement of CR, PR associated with treatment in excess of that per protocol, SD, relapse after achievement of CR, or death from any cause, whichever comes first.	Up to FU3; 9 months after last dose of treatment

Collaborators and Investigators

• Sponsor: mAbxience Research S.L.
• Collaborators: Laboratorio Elea Phoenix S.A.; Libbs Farmacêutica LTDA; Innogene Kalbiotech Pte. Ltd; Pisa® Farmacéutica; Laboratorios de Productos Éticos C.E.I.S.A.; Tecnoquimicas S.A; Key Oncologics (Pty) Ltd; Nanolek LLC; Actoverco
• Investigators: Study Director: Susana Millán, Phd, mAbxience Research S.L.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: September 19, 2014
• First Submitted That Met QC Criteria: October 15, 2014
• First Posted (Estimate): October 20, 2014

Study Record Updates

• Last Update Posted (Actual): September 26, 2019
• Last Update Submitted That Met QC Criteria: August 28, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: DLBCL; Non-Hodgkin Lymphoma; Diffuse large b-cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: RTXM83-AC-01-11