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

Study Overview
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Brief Summary
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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)

Official Title
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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

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: VELCADE
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VR-CAP<br>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<br>* VELCADE intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles.<br>Drug: Rituximab<br>* Rituximab intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Cyclophosphamide<br>* Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Doxorubicin<br>* Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Prednisone<br>* Orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles<br>|
| Active Comparator: R-CHOP<br>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<br>* Rituximab intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Cyclophosphamide<br>* Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Doxorubicin<br>* Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Prednisone<br>* Orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles<br>Drug: Vincristine<br>* Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles<br>|

What is the study measuring?
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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 |