Study to Assess the Effectiveness of RCHOP With or Without VELCADE in Previously Untreated Non-Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma Patients

Study Overview
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Brief Summary
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This is a randomized, open-label, multi-center, phase 2 study of RCHOP with or without VELCADE in adult patients with previously untreated non-(Germinal B-Cell-like) GCB Diffuse Large B-cell Lymphoma (DLBCL). The study will determine whether the addition of VELCADE to RCHOP improves progression-free survival (PFS) in patients with non-GCB DLBCL.

Detailed Description
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The drug tested in this study is called bortezomib (VELCADE®). VELCADE® was tested in people who have Non-Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma. This study looked at the efficacy of RCHOP [rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone] with or without VELCADE®. The study enrolled 206 patients. Participants were enrolled in one of the two open label treatment groups: RCHOP Vc-RCHOP [bortezomib (VELCADE®), rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone] Participants received treatment for up to six, 21-day cycles. This multi-center trial was conducted in the United States. The overall time to participate in this study was up to 48 months. Participants made multiple visits to the clinic, and were followed for progression free survival and overall survival until patient withdrawal, death, or 2 years after the last participant was enrolled.

Official Title
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An Open-Label, Randomized, Phase 2 Study to Assess the Effectiveness of RCHOP With or Without VELCADE in Previously Untreated Non-Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma Patients

Conditions
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Non-Germinal B-Cell-like (GCB) Diffuse Large B-cell Lymphoma (DLBCL)

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


Participation Criteria
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Eligibility Criteria
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Each patient must meet all of the following inclusion criteria to be enrolled in the study: Inclusion Criteria: Patients with previously untreated DLBCL that has been sub classified as the non-GCB subtype. At least 1 measurable tumor mass. Availability of paraffin block with sufficient tumor tissue. No evidence of central nervous system lymphoma. Eastern Cooperative Oncology Group (ECOG) performance status of < or equal to 2. Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse. Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse. Patients meeting any of the following exclusion criteria are not to be enrolled in the study: Exclusion Criteria: Diagnosed or treated for a malignancy other than DLBCL within 2 years of first dose or evidence of active malignancy other than DLBCL. Peripheral neuropathy of Grade 2 or greater. Known history of human immunodeficiency virus (HIV) infection, unless receiving highly active antiretroviral therapy (HAART). Active infection requiring systemic therapy. Major surgery within 2 weeks before first dose. Patients with a left ventricular ejection fraction (LVEF) or less than 45%. Myocardial infarction with 6 months of enrollment or evidence of current uncontrolled cardiovascular conditions as described in the protocol. History of allergic reaction/ hypersensitivity attributable to boron, mannitol, polysorbate 80 or sodium citrate dehydrate, or anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab.

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 |
| --- | --- |
| Active Comparator: RCHOP<br>RCHOP [rituximab, cyclophosphamide, doxorubicin, prednisone] administered as follows: rituximab 375 mg/m^2 intravenous (IV) infusion, cyclophosphamide 750 mg/m^2 IV infusion, doxorubicin 50 mg/m^2 IV injection and vincristine 1.4 mg/m^2 (maximum total dose 2 mg) IV injection on Day 1 with prednisone orally on Days 1 through 5 of a 21-day (3-week) cycle for 6 cycles. | Drug: Rituximab<br>* Rituximab IV<br>Drug: Cyclophosphamide<br>* Cyclophosphamide IV<br>Drug: Doxorubicin<br>* Doxorubicin IV solution<br>Drug: Vincristine<br>* Vincristine IV<br>Drug: Prednisone<br>* Prednisone tablet<br>|
| Experimental: Vc-RCHOP<br>Vc-RCHOP [bortezomib (VELCADE®), rituximab, cyclophosphamide, doxorubicin, prednisone] administered as follows: bortezomib (VELCADE ®) 1.3 mg/m^2 administered intravenous (IV) push on Days 1 and 4 of each cycle with RCHOP administered as follows: rituximab 375 mg/m^2 intravenous (IV) infusion, cyclophosphamide 750 mg/m^2 IV infusion, doxorubicin 50 mg/m^2 IV injection and vincristine 1.4 mg/m^2 (maximum total dose 2 mg) IV injection on Day 1 with prednisone orally on Days 1 through 5 of a 21-day (3-week) cycle for 6 cycles. | Drug: Bortezomib<br>* Bortezomib IV<br>* Other names: VELCADE®;Drug: Rituximab<br>* Rituximab IV<br>Drug: Cyclophosphamide<br>* Cyclophosphamide IV<br>Drug: Doxorubicin<br>* Doxorubicin IV solution<br>Drug: Vincristine<br>* Vincristine IV<br>Drug: Prednisone<br>* Prednisone tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) in Patients With Non-germinal Center B-cell-like (Non-GCB) Diffuse Large B-cell Lymphoma (DLBCL) | PFS is defined as the time in months from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause. The date of progression is the earliest date of a computed tomography/positron emission tomography (CT/PET) scan that shows evidence of PD. For a participant that has not progressed and is alive at the end of his/her study follow-up or at the time of start of an alternate therapy (whichever is first), PFS is censored at the last overall response assessment that is stable disease or better, and which is prior to the start of the alternate therapy, if any. Disease response was assessed using International Working Group (IWG)-revised response criteria for malignant lymphoma. PD= any new lesion or increase by > 50% of previously involved sites from nadir. | Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm | 
| Progression-Free Survival Rate | PFS is defined as the time in months from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause. The date of progression is the earliest date of a computed tomography/positron emission tomography (CT/PET) scan that shows evidence of PD. For a participant that has not progressed and is alive at the end of his/her study follow-up or at the time of start of an alternate therapy (whichever is first), PFS is censored at the last overall response assessment that is stable disease or better, and which is prior to the start of the alternate therapy, if any. Disease response was assessed using International Working Group (IWG)-revised response criteria for malignant lymphoma. PD= any new lesion or increase by > 50% of previously involved sites from nadir. The progression-free survival rate is defined as the Kaplan-Meier (KM) estimate of progression-free survival at 2 years. | 2 Years (Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from the date of randomization to the date of death from any cause. A participant who is alive at the end of his/her study follow-up is censored at the date of last contact. | Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with the best overall response complete response (CR) + partial response (PR). Disease response was assessed using International Working Group (IWG)-revised response criteria for malignant lymphoma. CR=disappearance of all evidence of disease and PR=regression of measurable disease and no new sites. | End of Cycle 2, End of Treatment (Cycle 6) [Median of 16 weeks on treatment] | 
| Complete Response Rate | Complete Response Rate is defined as the percentage of participants with the best response of Complete Response (CR). Disease response was assessed using International Working Group (IWG)-revised response criteria for malignant lymphoma. CR=Disappearance of all evidence of disease. | End of Cycle 2, End of Treatment (Cycle 6) [Median of 16 weeks on treatment] | 
| Duration of Response | Duration of response is defined as the time (in months) from the date of first documentation of confirmed complete response (CR) or partial response (PR) to the date of first documentation of progressive disease (PD), relapse from CR or death related to disease. For a participant who has not progressed and is not known to have died due to disease under study at the end of his/her study follow-up or at the time of start of an alternate therapy (whichever is first), duration of response is censored at the last overall response assessment that is stable disease or better, and which is prior to the start of the alternate therapy, if any. Disease response was assessed using IWG-revised response criteria for malignant lymphoma. CR=Disappearance of all evidence of disease and PR=Regression of measurable disease and no new sites and PD= any new lesion or increase by > 50% of previously involved sites from nadir. | Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm | 
| Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Negative Rate | FDG-PET negative rate is defined as the percentage of participants FDG-PET negative at the given time-point. | End of Cycle 2 and End of Treatment (Cycle 6) [Median of 16 weeks on treatment] | 
| Time to Progression (TTP) | TTP is defined as the time from the date of randomization to the date of first documentation of progressive disease, relapse from CR, or death related to disease under study if participant did not have any documentation of disease progression prior to death caused by lymphoma or complications thereof. For a participant who has not progressed and is not known to have died due to disease under study at the end of his/her study follow-up or at the time of start of an alternate therapy (whichever is first), TTP is censored at the last overall response assessment that is stable disease or better, and which is prior to the start of the alternate therapy, if any. Disease response was assessed using International Working Group (IWG)-revised response criteria for malignant lymphoma. PD= any new lesion or increase by > 50% of previously involved sites from nadir. | Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm | 
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) by Category | Percentage of participants in the following categories: • At least 1 TEAE • Drug-related, TEAEs • Grade 3 or higher TEAEs. Grade 3 are AEs of Severe Intensity • Grade 3 or higher drug-related, TEAEs • TEAEs resulting in study drug discontinuation • Serious TEAEs An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. | First dose of study drug through 30 days after the last dose of study drug (Up to 26 Weeks) | 
| Percentage of Participants With Chemistry and Hematology Laboratory Values Grade 3 or Higher | Percentage of participants who shifted from a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 0, 1, or 2 at Baseline to a Grade 3 or higher on study (worst post-baseline grade). Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=Life-threatening consequences and 5=Death related to AE. | Days 1, 4 and 10 of each cycle and end of treatment visit (Median of 16 weeks on treatment) |