Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Mantle Cell Lymphoma

A Randomized, Open-Label, Multicenter Phase 3 Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone (VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell Lymphoma Who Are Not Eligible for a Bone Marrow Transplant

This is a randomized, open-label, multicenter, prospective study to compare the efficacy and safety of the combination of VcR-CAP to that of R-CHOP in participants who have newly diagnosed mantle cell lymphoma grade II, III or IV and who are ineligible to undergo bone marrow transplantation.

Study Overview

• Status: Completed
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: Rituximab 375 mg/m^2; Drug: Cyclophosphamide 750 mg/m^2; Drug: Doxorubicin 50 mg/m^2; Drug: Prednisone 100 mg/m^2; Drug: Vincristine 1.4 mg/m^2; Drug: VELCADE 1.3 mg/m^2

Detailed Description

The drug being tested in this study were combination of VcR-CAP and R-CHOP. Combination of VcR-CAP and R-CHOP is being tested to treat people who had mantle cell lymphoma (MCL).

The study enrolled 487 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in a 1:1 ratio:

Treatment Group A (VcR-CAP) Treatment Group B (R-CHOP)

The study included a screening phase, a treatment phase, a short-term follow-up phase, and a long-term follow-up phase. The screening phase was up to 28 days (56 days for bone marrow evaluation) prior to randomization.

This multi-center trial was conducted worldwide. The total study duration from randomization of the first patient until the last progression-free survival (PFS) event required for the final analysis was expected to be approximately 42 months (24 months for enrollment and 18 months for follow-up) and survival follow-up every 12 weeks until death.

• Study Type: Interventional
• Enrollment (Actual): 487
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria
    • St.Johanns Spital/Landeskrankenhaus Salzburg
  • Wien, Austria
    • Allgemeines Krankenhaus der Stadt Wien
• Belgium
  • Antwerpen, Belgium
    • AZ Stuivenberg Oncologie/ Hematologie
  • Brugge, Belgium
    • AZ St Jan AV
  • Brussels, Belgium
    • UZ Brussel Department Medical Oncology
  • Edegem, Belgium
    • UZA Hematologie, 1e verdiep
  • Gent, Belgium
    • Universitair Ziekenhuis Gent - UZ GENT, Hematologie, 9K12IE 9de verdiep- polikliniek Hematologie
  • Leuven, Belgium
    • UZ Leuven Gasthuisberg Hematologie
  • Liege, Belgium
    • Centre Hospitalier Universitaire
  • Liege, Belgium
    • C.H.R. Citadelle
  • Yvoir, Belgium
    • Ucl de Mont-Godinne
• Brazil
  • Campinas, Brazil
    • Centro de Hematologia E Hemoterapia - Unicamp
  • Jau, Brazil
    • Fundacao Hospital Amaral Carvalho
  • Porto Alegre, Brazil
    • Hospital Nossa Senhora da Conceicao
  • Porto Alegre, Brazil
    • Hospital São Lucas PUC-RS
  • Rio de Janeiro, Brazil
    • INCA - Instituto Nacional Do Cancer
  • Sao Paulo, Brazil
    • Hospital Alemao Oswaldo Cruz
  • Sao Paulo, Brazil
    • Hospital Das Clinicas Da Faculdade De Medicina Da USP
  • Sao Paulo, Brazil
    • Centro de Estudos de Hematologia E Oncologia Da Fmabc
  • Sao Paulo, Brazil
    • Fundacao Pio Xii - Hospital De Cancer De Barretos
  • Sao Paulo, Brazil
    • Hospital AC Camargo
  • Sao Paulo, Brazil
    • Santa Casa de Misericórida de São Paulo
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Cross Cancer Institute
  • Ontario
    • Toronto, Ontario, Canada
      • University Health Network, Princess Margaret Hospital
• Chile
  • Santiago, Chile
    • Instituto Nacional del Cancer
  • Santiago, Chile
    • Hospital del Salvador
  • Santiago, Chile
    • Hospital Clínico Universidad Católica de Chile
• China
  • Beijing, China
    • Peking University Third Hospital
  • Beijing, China
    • Beijing Cancer Hospital
  • Beijing, China
    • Cancer Institute & Cancer Hospital, CAMS&PUMC
  • Shanghai, China
    • Ruijin Hospital
  • Shanghai, China
    • Cancer Hospital, FuDan University
  • Tianjin, China
    • Tianjin medical university cancer hospital and institute
  • Guangdong
    • Guangzhou, Guangdong, China
      • Sun Yat-sen University Cancer Center
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital, Sichuan University
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Zhejiang University First Hospital
• Colombia
  • Bogota, Colombia
    • Clínica Reina Sofia
  • Medellin, Colombia
    • Hospital Pablo Tobon Uribe
  • Medellin, Colombia
    • Hospital Universitario San Vicente de Paúl
• Czechia
  • Brno, Czechia
    • Interni hematoonkoligicka klinika
  • Hradec Kralove, Czechia
    • Interni klinika - Oddeleni klin. hematologie Fakultni nemocnice Hradec Kralove
  • Praha, Czechia
    • Oddeleni klinicke hematologie, Fakultni nemocnice Kralovske Vinohrady
• Germany
  • Berlin, Germany
    • Vivantes Klinikum Neukölln Klinik für Innere Medizin Hämatologie und Onkologie
  • Berlin, Germany
    • Vivantes Klinikum Spandau Klinik für Innere Medizin - Hämatologie, Onkologie und Gastroenterologie
  • Frankfurt, Germany
    • Städt. Kliniken Frankfurt-Hoechst Med. Klinik II - Hämatologie und Onkologie
  • Freiburg, Germany
    • Tumorklinik SANAFONTIS Alpine GmbH
  • Goch, Germany
    • Wilhelm-Anton-Hospital Goch gGmbH Klinik für Hämatologie und internistische Onkologie
  • Lemgo, Germany
    • Klinikum Lippe-Lemgo Med. Klinik II - Hämatologie und Onkologie
  • Mainz, Germany
    • Johannes-Gutenberg-Universität Mainz III. Med. Klinik
  • Trier, Germany
    • Mutterhaus der Borromäerinnen Med. Klinik I
  • Villingen, Germany
    • Schwarzwald-Baar-Kliniken Innere Med. II
• Hungary
  • Debrecen, Hungary
    • Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum, III. sz. Belgyogyaszati Klinika
  • Győr, Hungary
    • Petz Aladár Kórház, II. Belgyógyászat
  • Kaposvar, Hungary
    • Kaposi Mor Megyei Korhaz, Belgyogyaszat
• India
  • Andhra Pradesh
    • Hyderabad 500033, Andhra Pradesh, India
      • Apollo Hospital and Research Foundation, Apollo Hospitals
  • Delhi
    • New Delhi- 110060, Delhi, India
      • Sir Ganga Ram Hospital
  • Karnataka
    • Bangalore 560 029, Karnataka, India
      • Kidwai Memorial Institute of Oncology
  • Kerala-695011
    • Thiruvananthapuram, Kerala-695011, India
      • Regional Cancer Centre, Medical Oncology
  • Maharashtra
    • Pune-411002, Maharashtra, India
      • Jehangir Hospital
  • Tamil Nadu
    • Chennai-600035, Tamil Nadu, India
      • Apollo Speciality Hospital, Chennai
  • West Bengal
    • Kolkata- 700016, West Bengal, India
      • Netaji Subash Chanda Bose Cancer Research Institute
• Israel
  • Haifa, Israel
    • Rambam Medical Center-Hematology department
  • Jerusalem, Israel
    • Hadassah Medical Center - Hematology department
  • Petach Tiqva, Israel
    • Rabin Medical Center, Beilinson campus
  • Ramat-Gan, Israel
    • Sheba Medical Center
  • Rechovot, Israel
    • Kaplan Medical Center - Hematology Institute
• Italy
  • Bologna, Italy
    • Azienda Ospedaliera Universitaria di Bologna Policlinico S.Orsola-Malpighi Dipartimento di Ematologia e Scienze Oncologiche "L. e A. Seragnoli"
  • Brescia, Italy
    • Spedali Civili di Brescia
  • Modena, Italy
    • Dipartimento di Oncologia ed Ematologia Università di Modena e Reggio Emilia
  • Roma, Italy
    • AZIENDA OSPEDALIERA UNIVERSITARIA POLICLINICO TOR VERGATA DIPARTIMENTO DI MEDICINA U.O.C. Ematologia
  • Torino, Italy
    • Azienda Ospedaliera San Giovanni Battista "Molinette" Struttura Complessa Ematologia 2
• Malaysia
  • Kuala Lumpur, Malaysia
    • University Malaya Medical Centre
  • Pulau Pinang, Malaysia
    • Gleneagles Medical Centre
• Morocco
  • Casablanca, Morocco
    • Hopital Du 20 Aout 1953
  • Rabat, Morocco
    • Institut National D'Oncologie
  • Rabat, Morocco
    • Centre D'oncologie Al Azhar
• Philippines
  • Quezon City, Philippines
    • National Kidney and Transplant Institute
  • Quezon City, Philippines
    • St Lukes Medical Center
• Poland
  • Gdynia, Poland
    • Szpital Morski im. PCK w Gdyni Gdynskie Centrum Onkologii Oddzial Chemioterapii
  • Lodz, Poland
    • Klinika Hematologii Uniwersytetu Medycznego w Lodzi
  • Poznan, Poland
    • "Katedra i Klinika Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego
  • Wroclaw, Poland
    • Klinika Hematologii Nowotworow Krwi i Transplantacji Szpiku Akademii Medycznej we Wroclawiu
• Portugal
  • Braga, Portugal
    • Hospital São Marcos
  • Coimbra, Portugal
    • Hospitais da universidade de Coimbra
  • Lisboa, Portugal
    • Hospital De Santa Maria
  • Porto, Portugal
    • Instituto Portugues de Oncologia
• Romania
  • Baia Mare, Romania
    • Spitalul Judetean de Urgenta "Dr. Constantin Opris", Hematologie
  • Bucuresti, Romania
    • Institutul Clinic Fundeni, Hematologie
  • Bucuresti, Romania
    • Spitalul Clinic Coltea, Clinica Hematologie
  • Bucuresti, Romania
    • Spitalul Clinic Universitar de Urgenta Bucuresti, Hematologie
  • Iasi, Romania
    • Spitalul Clinic Judetean de Urgenta "Sf. Spiridon" Iasi, Oncologie Medicala
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Arkhangelsk Regional Clinical Hospital
  • Belgorod, Russian Federation
    • Belgorod Regional Oncology Center
  • Chelyabinsk, Russian Federation
    • Chelyabinsk Regional Oncology Center
  • Ekaterinburg, Russian Federation
    • Sverdlovsk Regional Oncology Dispensary
  • Izhevsk, Russian Federation
    • 1st Republican Clinical Hospital of Udmurtia
  • Moscow, Russian Federation
    • Cancer Research Center RAMS - N.N. Blokhin - Academy of Medical Science
  • Moscow, Russian Federation
    • Hematology Scientific Center
  • Moscow, Russian Federation
    • Moscow Regional Clinical Research Institute
  • Moscow, Russian Federation
    • S.P. Botkin Moscow City Clinical Hospital
  • Nizhniy Novgorod, Russian Federation
    • Nizhniy Novgorod Region Clinical Hospital
  • Obninsk, Russian Federation
    • Medical Scientific Radiology - Center
  • Omsk, Russian Federation
    • Omsk Regional Oncology Dispensary
  • Perm, Russian Federation
    • Medical Sanitary Unit # 1
  • Petrozavodsk, Russian Federation
    • Republikan Hospital named after V.A/ Baranov
  • Rostov-on-Don, Russian Federation
    • Rostov Research Institute of Oncology
  • St Petersburg, Russian Federation
    • City Clinical Oncology Dispensary
  • St-Petersburg, Russian Federation
    • Central Res. Inst. of Roentgen-Radiology
  • St-Petersburg, Russian Federation
    • Pavlov State Medical Univercity
  • St. Petersburg, Russian Federation
    • Leningrad region clinical hospital
  • St. Petersburg, Russian Federation
    • St.-Petersburg Clinical Research Institute of Hematology and Transfusiology
• Singapore
  • Singapore, Singapore
    • National Cancer Centre
  • Singapore, Singapore
    • Singapore General Hospital - Hematology
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa
      • Chris Hani Baragwanath Hospital
    • Johannesburg, Gauteng, South Africa
      • Medical Oncology Center of Rosebank
    • Johannesburg, Gauteng, South Africa
      • University of the Witwatersrand Oncology
    • Pretoria, Gauteng, South Africa
      • Pretoria Academic Hospital-Dr. Savage Road, 3rd Floor Radiotherapy Building, Prinshof
  • Kwazulu Natal
    • Durban, Kwazulu Natal, South Africa
      • Dr AI Pirjol & Dr WM Szpak Inc.
• Spain
  • Barcelona, Spain
    • Hospital Clinic i Provincial de Barcelona
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital De La Princesa
  • Salamanca, Spain
    • Hospital Clinico Universitario Salamanca
  • Barcelona
    • Badalona, Barcelona, Spain
      • Hospital Universitario Germans Trias i Pujol
• Taiwan
  • Tao-Yuan, Taiwan
    • Chang Gung Memorial Hospital, Linkou
• Thailand
  • Bangkok, Thailand
    • Ramathibodi Hospital
  • Bangkok, Thailand
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand
    • Siriraj Hospital-Hematology Unit
  • Chiang Mai, Thailand
    • Maharaj Nakorn Chiang Mai hospital - Faculty of Medicine
• Tunisia
  • Sousse, Tunisia
    • Hôpital Farhat Hached
  • Tunis, Tunisia
    • Hôpital Aziza Othmana
  • Tunis, Tunisia
    • Centre National de Greffe de Moelle Osseuse
  • Tunis, Tunisia
    • Institut Salah Azaiz
• Turkey
  • Ankara, Turkey
    • Hacettepe University Medical Faculty
  • Izmir, Turkey
    • Dokuz Eylul University Med. Fac.
• Ukraine
  • Cherkassy, Ukraine
    • Cherkassy Regional Oncology Center, Dept. of Hematology
  • Dnepropetrovsk, Ukraine
    • Dnepropetrovsk City Clinical Hospital #4, Regional Hematology Center
  • Donetsk, Ukraine
    • Institute of Urgent and Recovery Surgery named after V.K.Gusaka of AMS of Ukraine, Haematology Dept.
  • Khmelnitsky, Ukraine
    • Khmelnitskiy Regional Hospital, Hematology Department
  • Kiev, Ukraine
    • National Cancer Institute, Department of chemotherapy of hemoblastosis
  • Lviv, Ukraine
    • Institute of Blood Pathology and Transfusion Medicine, Lviv Clinical Hospital #5, Hematology Dept.
  • Simferopol, Ukraine
    • Crimean Republic Clinical Oncology Dispensary, Haematology Department
• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06105
      • St. Francis Hosptial and Medical Center
  • Indiana
    • Goshen, Indiana, United States, 46526
      • Center for Cancer Care at Goshen Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Capitol Comp. Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Cancer Specialists
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Hematology-Oncology Associates of Northern NJ
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Legacy Pharma Research
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Division of Hematology and Oncology Vanderbilt University
  • Virginia
    • Abingdon, Virginia, United States, 24211
      • Cancer Outreach Associates, Pc

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female patients 18 years or older (the patient must be at least the legal age limit to be able to give informed consent within the jurisdiction the study is taking place)

• Diagnosis of mantle cell lymphoma MCL (Stage II, III or IV) as evidenced by lymph node histology and either expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) translocation, such as by cytogenetics, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR). Patients with a diagnosis of Stage I MCL will not be permitted to enter study.

  - Paraffin embedded biopsy tissue block (preferably of lymph node origin) must be sent to the central laboratory for confirmation of MCL diagnosis prior to randomization. In China, a paraffin embedded lymph node biopsy tissue block must be sent for central confirmation of sample adequacy, prior to randomization

• At least 1 measurable site of disease
• No prior therapies for MCL
• Not eligible for bone marrow transplantation as assessed by the treating physician (e.g., age or the presence of co-morbid conditions that may have a negative impact on the tolerability to transplantation).
• Eastern Cooperative Oncology Group ECOG status ≤2
• Absolute neutrophil count (ANC) ≥1500 cells/µL,
• Platelets ≥100,000 cells/µL or ≥75,000 cells/µL if thrombocytopenia is considered by the investigator to be secondary to MCL (e.g., due to bone marrow infiltration or sequestration from splenomegaly).
• Alanine transaminase ≤3 x upper limit of normal (ULN)
• Aspartate transaminase ≤3 x ULN
• Total bilirubin ≤1.5 x ULN,
• Calculated creatinine clearance ≥20 mL/min.
• Female patients must be post menopausal for at least 1 year (must not have had a natural menses for at least 12 months), surgically sterile, or practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) and have a negative serum βHCG or urine pregnancy test at screening. They must also be prepared to continue birth control measures for at least 6 months after terminating treatment.
• Male patients must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study.
• All patients (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
• In order to participate in the pharmacogenomics component of this study, patients (or their legally acceptable representative) must have signed the informed consent form for pharmacogenomics research indicating willingness to participate in the pharmacogenomics component of the study. Acquisition of tumor sample collections is required for all patients (where available); all other sample collections are optional

Exclusion Criteria:

• Prior treatment with VELCADE

• Prior antineoplastic (including unconjugated therapeutic antibodies), experimental or radiation therapy, radioimmunoconjugates or toxin immunoconjugates for the treatment of MCL. In the event that a patient has received doxorubicin for the treatment of any condition, other than MCL, the maximum dose and exposure received prior to entry into this study should not exceed 150 mg/m2.

  - short course (maximum of 10 days, not exceeding 100 mg/day) prednisone or equivalent steroids are allowed to treat symptoms in patients with advanced disease who enter the screening phase and are waiting to be randomized.

• Major surgery (at the discretion of the treating physician and in consultation with the sponsor's medical monitor) within 2 weeks before randomization
• Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the investigators assessment)
• Diagnosed or treated for a malignancy other than MCL within 1 year of randomization, or who were previously diagnosed with a malignancy other than MCL and have any radiographic or biochemical marker evidence of malignancy. Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded.
• Active systemic infection requiring treatment and patients with known diagnosis of human immunodeficiency virus HIV or active hepatitis B (carriers of hepatitis B are permitted to enter study)
• History of allergic reaction attributable to compounds containing boron, mannitol, or hydroxybenzoates
• Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab including polysorbate 80 and sodium citrate dihydrate
• Female or male patients of child-bearing potential who will not use adequate contraception during the course of the study.
• Serious medical (e.g., pericardial disease, cardiac failure [New York Heart Association; NYHA Class III or IV, Attachment 12 or left ventricular ejection fraction; LVEF <50%], active peptic ulceration, uncontrolled diabetes mellitus, or acute diffuse infiltrative pulmonary disease), or psychiatric illness likely to interfere with participation in this clinical study
• Concurrent treatment with another investigational agent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: R-CHOP; Rituximab 375 mg/m^2, Cyclophosphamide 750 mg/m^2, Doxorubicin 50 mg/m^2, Vincristine 1.4 mg/m^2, and Prednisone 100 mg/m^2	Drug: Rituximab 375 mg/m^2; Intravenous rituximab 375 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles.; Drug: Cyclophosphamide 750 mg/m^2; Intravenous cyclophosphamide 750 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Drug: Doxorubicin 50 mg/m^2; Intravenous doxorubicin 50 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Drug: Prednisone 100 mg/m^2; Oral prednisone 100 mg/m^2 on Day 1 to Day 5 of a 21-day (3 week) cycle for 6 cycles; Drug: Vincristine 1.4 mg/m^2; Intravenous vincristine 1.4 mg/m^2 on Day 1of a 21-day (3 week) cycle for 6 cycles. Maximum of 2 mg. Participants could receive 8 cycles if a response was initially documented at the Cycle 6 assessment.
EXPERIMENTAL: VcR-CAP; Rituximab 375 mg/m^2, Cyclophosphamide 750 mg/m^2, Doxorubicin 50 mg/m^2, VELCADE 1.3 mg/m^2, and Prednisone 100 mg/m^2	Drug: Rituximab 375 mg/m^2; Intravenous rituximab 375 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles.; Drug: Cyclophosphamide 750 mg/m^2; Intravenous cyclophosphamide 750 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Drug: Doxorubicin 50 mg/m^2; Intravenous doxorubicin 50 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles; Drug: Prednisone 100 mg/m^2; Oral prednisone 100 mg/m^2 on Day 1 to Day 5 of a 21-day (3 week) cycle for 6 cycles; Drug: VELCADE 1.3 mg/m^2; Intravenous VELCADE 1.3 mg/m^2 on Days 1,4,8, and 11of a 21-day (3 week) cycle for 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS was defined as the interval between the date of randomization and the date of progressive disease (PD) or death, whichever occurred first. PD was based on the assessment of an Independent Review Committee.	Median duration of follow-up of 40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Progression (TTP)	Time to progression was defined as the duration from the date of randomization until the date of first documented evidence of progressive disease (PD) or date of relapse for subjects who experienced complete response (CR) or complete response, unconfirmed (CRu). PD and response were based on the assessment of an Independent Review Committee.	Median duration of follow-up of 40 months
Duration of Response	The duration of treatment response was defined as the time from the date of the first response to the date of PD or death due to PD for those participants with a best response of CR, CRu, or PR as determined by the Independent Review Committee. The duration of response for complete responders was defined as the time from the date of the first response to the date of PD or death due to PD for those participants with a best response of CR or CRu verified by bone marrow and lactate dehydrogenase (LDH).	Median duration of follow-up of 40 months
Time to Next Anti-lymphoma Treatment (TTNT)	The time to next anti-lymphomatreatment was measured from the date of initiation of study treatment as per protocol to the start date of new anti-lymphoma treatment. Death due to disease progression prior to subsequent therapy was considered as an event. Otherwise, time to next anti lymphoma treatment was censored at the date of death or the last date known to be alive.	: Median duration of follow-up of 40 months
Treatment-free Interval (TFI)	The TFI was defined as the duration from the date of last dose plus 1 day to the start date of the new treatment. Death due to disease progression prior to subsequent therapy was considered as an event. Otherwise, treatment-free interval was censored at the date of death or the last date known to be alive.	Median duration of follow-up of 40 months
Overall Response Rate (ORR)	ORR was defined as complete response (CR) + complete response, unconfirmed (CRu) + partial response (PR) as determined by the Independent Review Committee. Response assessment was carried out every 6 weeks for 18 weeks; thereafter, every 8 weeks until PD/initiation of alternate therapy/withdrawal from study/death.	Median duration of follow-up of 40 months
Overall Complete Response (CR + CRu)	Overall complete response was defined as the number of participants with complete response (CR) and those with unconfirmed complete response (CRu). Response assessment was carried out every 6 weeks for 18 weeks; thereafter, every 8 weeks until PD/initiation of alternate therapy/withdrawal from study/death.	Median duration of follow-up of 40 months
Overall Survival (OS)	OS was measured from the date of randomization to the date of the participant's death. If the participant was alive or the vital status was unknown, OS was censored at the date that the subject was last known to be alive.	Median duration of follow-up of 40 months
18-Month Survival	18-month survival was defined as the estimated probability of survival at 18 months (Kaplan-Meier estimate).	Up to month 18 from the time of randomization
Overall Survival (OS) in Long Term Follow-up Period	OS was measured from the date of randomization to the date of the participant's death. If the participant was alive or the vital status was unknown, OS was censored at the date that the subject was last known to be alive.	Up to 107.4 months
Number of Participants Experiencing an Adverse Event (AE)	An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. AEs were collected from the first dose of study drug through 30 days after the last dose of study drug. Treatment was administered for up to 8 cycles (24 weeks) and AEs were collected for up to 30 days following the last dose of study drug.	Up to 107.4 months

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Collaborators: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Publications and helpful links

General Publications

• Robak T, Jin J, Pylypenko H, Verhoef G, Siritanaratkul N, Drach J, Raderer M, Mayer J, Pereira J, Tumyan G, Okamoto R, Nakahara S, Hu P, Appiani C, Nemat S, Cavalli F; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-1458. doi: 10.1016/S1470-2045(18)30685-5. Epub 2018 Oct 19.
• Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Pereira J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F. Association between bortezomib dose intensity and overall survival in mantle cell lymphoma patients on frontline VR-CAP in the phase 3 LYM-3002 study. Leuk Lymphoma. 2019 Jan;60(1):172-179. doi: 10.1080/10428194.2017.1321750. Epub 2017 Jun 5.
• Verhoef G, Robak T, Huang H, Pylypenko H, Siritanaratkul N, Pereira J, Drach J, Mayer J, Okamoto R, Pei L, Rooney B, Cakana A, van de Velde H, Cavalli F. Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP versus R-CHOP in the phase 3 LYM-3002 study. Haematologica. 2017 May;102(5):895-902. doi: 10.3324/haematol.2016.152496. Epub 2017 Feb 9.
• Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F; LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-53. doi: 10.1056/NEJMoa1412096.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2008
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): June 17, 2017

Study Registration Dates

• First Submitted: July 23, 2008
• First Submitted That Met QC Criteria: July 23, 2008
• First Posted (ESTIMATE): July 25, 2008

Study Record Updates

• Last Update Posted (ACTUAL): July 12, 2018
• Last Update Submitted That Met QC Criteria: June 14, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Prednisone; Bortezomib; Doxorubicin; Vincristine
• Other Study ID Numbers: 26866138-LYM-3002; 26866138-LYM-3002CTIL (OTHER: Israel); 2007-005669-37 (EUDRACT_NUMBER); 0970313683 (REGISTRY: TCTIN); U1111-1195-3827 (OTHER: WHO)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No