Study of the Combination of VELCADE, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

A Randomized, Open-Label, Multicenter Phase 2 Study of the Combination of VELCADE, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

This is a randomized, open-label, active-control, parallel-group, multicenter, multinational Phase 2 Study of the efficacy and safety of VELCADE, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Patients With Newly Diagnosed Non-Germinal Center B-Cell (non-GCB) Subtype of Diffuse Large B-Cell Lymphoma (DLBCL)

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: VELCADE; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone; Drug: Vincristine

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium
    • Universitair Ziekenhuis Gent - UZ GENT, Hematologie, 9K12IE 9de verdiep- polikliniek Hematologie

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.
• Newly Diagnosed non-GCB subtype of DLBCL (Stage II, III or IV).
• At least 1 measurable site of disease.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Female subjects must be postmenopausal (for at least 6 months), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control before entry and throughout the study; and have a negative pregnancy test at screening.
• Male subjects must agree to use a double barrier method of birth control

Exclusion Criteria:

• Prior treatment with VELCADE.
• Prior extended radiotherapy or chemotherapy for lymphoma
• More than 150 mg/m2 of prior doxorubicin
• Major surgery within 3 weeks of study.
• Peripheral neuropathy or neuralgia of Grade 2 or worse.
• Active CNS lymphoma
• Diagnosed or treated for a malignancy other than NHL, with some exceptions
• Pregnant or breast feeding
• Active systemic infection
• Documented of suspected human immunodeficiency virus (HIV)/AIDS
• Uncontrolled or severe cardiovascular disease
• Known allergies, hypersensitivity or intolerance to study drugs
• Serious medical condition that could interfere with study
• Concurrent treatment with another investigational agent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VR-CAP; VR-CAP arm received rituximab 375 mg/m2 IV on Day 1, cyclophosphamide 750 mg/m2 IV on Day 1, doxorubicin 50 mg/m2 IV on Day 1, VELCADE 1.3 mg/m2 IV on Days 1, 4, 8, and 11, and prednisone 100 mg/m2 orally on Days 1 through 5 of each 21-day (3-week) cycle for up to 6 cycles.	Drug: VELCADE; VELCADE intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles.; Drug: Rituximab; Rituximab intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Cyclophosphamide; Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Doxorubicin; Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Prednisone; Orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles
Active Comparator: R-CHOP; R-CHOP received rituximab 375 mg/m2IV on Day 1, cyclophosphamide 750 mg/m2 IV on Day 1, doxorubicin 50 mg/m2 IV on Day 1, vincristine 1.4 mg/m2 (maximum total of 2 mg) IV on Day 1, and prednisone 100 mg/m2 orally on Days 1 through 5 of each 21-day (3-week) cycle for up to 6 cycles.Prednisone	Drug: Rituximab; Rituximab intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Cyclophosphamide; Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Doxorubicin; Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Drug: Prednisone; Orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Drug: Vincristine; Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate	Complete response was evaluated by an Independent Radiology Review Committee using available computed tomography (CT) and positron emission tomography (PET) scans collected at Baseline, end of cycle 3, and end of cycle 6 (or end of treatment) based on the Revised Response Criteria for Malignant Lymphoma.; Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.; PET scan was negative.; The spleen and/or liver, if enlarged before therapy on the basis of physical examination or CT scan, was not palpable on physical examination and was considered normal size by imaging studies; all splenic and hepatic nodules related to lymphomas disappeared.; If bone marrow was involved before treatment, the infiltrate cleared on repeated bone marrow biopsy.; No new sites of disease were detected.	6 cycles

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall response = Complete Response (CR) + Partial Response (PR) Response was evaluated by an Independent Radiology Review Committee using available computed tomography (CT) and positron emission tomography (PET) scans collected at Baseline, end of cycle 3, and end of cycle 6 (or end of treatment) based on the Revised Response Criteria for Malignant Lymphoma. Complete Response: see primary endpoint Partial Response: At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses.	6 cycles
Rate of Durable Response	Proportion of subjects who achieved a CR or PR with duration of at least 6 months. Duration of response (CR or PR) was calculated from the date of initial documentation of a response to the date of first documented evidence of disease progression or death due to disease progression. Response was evaluated by an Independent Radiology Review Committee using available computed tomography (CT) and positron emission tomography (PET) scans collected at Baseline, end of cycle 3, end of cycle 6 (or end of treatment) based on the Revised Response Criteria for Malignant Lymphoma.	Median follow up approx. 12 months
Rate of Durable Complete Response	Proportion of subjects who achieved a CR with duration of at least 6 months	Median follow up approx 12 months
Subsequent Anti-lymphoma Therapy Rate at 1-year	Kaplan-meier estimate of subsequent anti-lymphoma therapy at 1-year. Time to subsequent anti-lymphoma therapy was measured from the date of randomization to the start date of new 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.	1 year
Progression-free Survival (PFS)Rate at 1-year	Kaplan-meier estimate of progression-free survival at 1-year. Progression-free survival was defined as the interval between the date of randomization and the date of first documented evidence of disease progression or death.	1 year
Overall Survival Rate at 1-year	Kaplan-meier estimate of overall survival at 1-year measured from date of randomization.	1 year
Change in Fatigue and Patient Utility Scores		18-24 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Offner F, Samoilova O, Osmanov E, Eom HS, Topp MS, Raposo J, Pavlov V, Ricci D, Chaturvedi S, Zhu E, van de Velde H, Enny C, Rizo A, Ferhanoglu B. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015 Oct 15;126(16):1893-901. doi: 10.1182/blood-2015-03-632430. Epub 2015 Jul 31.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: December 29, 2009
• First Submitted That Met QC Criteria: December 29, 2009
• First Posted (Estimate): December 30, 2009

Study Record Updates

• Last Update Posted (Estimate): January 13, 2014
• Last Update Submitted That Met QC Criteria: December 11, 2013
• Last Verified: December 1, 2013

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, B-Cell; Lymphoma, Large B-Cell, Diffuse; 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-2034

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No