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

Diffuse Large B-cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02268045
• Other study ID #: RTXM83-AC-01-11
• Status: Completed
• Phase: Phase 3
• Start date: May 2013
• Est. completion date: July 2017

Study information

• Verified date: August 2019
• Source: mAbxience S.A
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 272
• Est. completion date: July 2017
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

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.
• 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.

Locations

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

Sponsors (10)

Lead Sponsor	Collaborator
mAbxience S.A	Actoverco, Innogene Kalbiotech Pte. Ltd, Key Oncologics (Pty) Ltd, Laboratorio Elea S.A.C.I.F. y A., Laboratorios de Productos Éticos C.E.I.S.A., Libbs Farmacêutica LTDA, Nanolek LLC, Pisa® Farmacéutica, Tecnoquimicas S.A

Countries where clinical trial is conducted

Argentina,  Brazil,  Colombia,  India,  Indonesia,  Iran, Islamic Republic of,  Malaysia,  Mexico,  Paraguay,  Philippines,  Russian Federation,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	AUC 0-8 (h µg/mL) at Cycle 1 of RTXM83 and Mabthera®	Compare the pharmacokinetic (PK) parameter (AUC 0-8) 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 0-8 ) falls completely within the range 80%-125%.	Cycle 1 (first dose): Day 1 (pre-dose, mid-infusion), Day 8 and Day 15
Secondary	AUC 0-8 (h µg/mL) at Cycle 6 of RTXM83 and Mabthera®	Compare the PK parameter (AUC 0-8) 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 0-8 ) falls completely within the range 80%-125%.	Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
Secondary	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
Secondary	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 0-8 ) falls completely within the range 80%-125%.	Cycle 6 (last dose): Day 1, Day 8, Day 15 and Day 21
Secondary	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
Secondary	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
Secondary	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
Secondary	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