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

Mantle Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00722137
• Other study ID #: 26866138-LYM-3002
• Secondary ID: 26866138-LYM-300
• Status: Completed
• Phase: Phase 3
• Start date: May 1, 2008
• Est. completion date: June 17, 2017

Study information

• Verified date: June 2018
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 487
• Est. completion date: June 17, 2017
• Est. primary completion date: January 1, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ßHCG 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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

Intervention

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.
• Cyclophosphamide 750 mg/m^2
Intravenous cyclophosphamide 750 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles
• Doxorubicin 50 mg/m^2
Intravenous doxorubicin 50 mg/m^2 on Day 1 of a 21-day (3 week) cycle for 6 cycles
• 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
• 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
• 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.

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Brazil,  Canada,  Chile,  China,  Colombia,  Czechia,  Germany,  Hungary,  India,  Israel,  Italy,  Malaysia,  Morocco,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Singapore,  South Africa,  Spain,  Taiwan,  Thailand,  Tunisia,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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