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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-Germinal B-Cell-like (GCB) Diffuse Large B-cell Lymphoma (DLBCL)
• Intervention / Treatment: Drug: Prednisone; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Bortezomib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Tower Cancer Research Foundation
    • Fountain Valley, California, United States, 92708
      • Fountain Valley Regional Hospital
    • Fullerton, California, United States, 92835
      • St. Jude Heritage Healthcare
    • La Jolla, California, United States, 92093
      • Moores Cancer Center- UCSD
    • Lancaster, California, United States, 93534
      • Antelope Valley Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Center
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90095
      • Jonsson Comprehensive Cancer Center
    • Los Angeles, California, United States
      • TORI- Central Pharmacy
    • Los Angeles, California, United States
      • TORI- Central Regulatory
    • Montebello, California, United States, 90640
      • Oncology Care Medical Associates
    • Pleasant Hill, California, United States, 94523
      • Bay Area Cancer Research Group
    • Rancho Cucamonga, California, United States, 91730
      • Wilshire Oncology Medical Group
    • San Diego, California, United States, 32123
      • Sharp Healthcare
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corporation
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center
  • Florida
    • Fort Myers, Florida, United States, 33619
      • Florida Cancer Specialists
    • Gainsville, Florida, United States, 32605
      • Florida Cancer Specialists & Research Institute
    • Hollywood, Florida, United States, 33019
      • Alves/ Domenech Oncology-Hematology Clinic
    • New Port Richey, Florida, United States, 34655
      • Florida Cancer Institute ATI
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center of Orlando
    • Ormond Beach, Florida, United States, 32174
      • Coastal Oncology, PL
  • Georgia
    • Atlanta, Georgia, United States, 30341
      • Georgia Cancer Specialists
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute at Emory University
    • Dublin, Georgia, United States, 31021
      • Dublin Hematology and Oncology
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Fishers, Indiana, United States, 46227
      • Central Indiana Cancer Centers
    • New Albany, Indiana, United States, 47150
      • Cancer Care Center Inc. P.C.
  • Iowa
    • Cedar Rapids, Iowa, United States, 52401
      • Iowa Blood and Cancer Care
    • Des Moines, Iowa, United States, 50309
      • Iowa Oncology Research Association
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology and Oncology Associates LLP
  • Kansas
    • Overland Park, Kansas, United States, 66210
      • Kansas City Cancer Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital of Baltimore
    • Silver Spring, Maryland, United States, 20910
      • Holy Cross Hospital
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
    • Pittsfield, Massachusetts, United States, 01201
      • Berkshie Hematology Oncology
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
    • Lansing, Michigan, United States, 48912
      • Mid Michigan Physicians
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • St. Luke's Hospital Cancer Care Center
    • Duluth, Minnesota, United States, 55805
      • Duluth Clinic
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Missouri Cancer Associates
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Morristown, New Jersey, United States, 07962
      • Hematology/Oncology Associates of Northern New Jersey, P.A.
    • Mount Holly, New Jersey, United States, 08060
      • Hematology Oncology Associates of South Jersey
  • New York
    • New York, New York, United States, 10019
      • St. Luke's- Roosevelt Medical Center
    • New York, New York, United States
      • Cornell
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Hematology Oncology Associates P.C.
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Health System
    • Cincinnati, Ohio, United States, 45267
      • Oncology Hematology Care
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Group Health
  • Pennsylvania
    • Dunmore, Pennsylvania, United States, 18512
      • Hematology and Oncology Associates of NEPA
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Center
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Clinic
    • W Reading, Pennsylvania, United States, 19611
      • Berks Hematology Oncology Associates
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • South Carolina Oncology Associates, PA
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology and Hematology Associates, PC
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Oncology Cancer Center
    • Fort Worth, Texas, United States, 76177
      • US Oncology- Central Drug
    • Fort Worth, Texas, United States, 76177
      • US Oncology- Central Laboratory
    • Houston, Texas, United States, 77030
      • Oncology Consultants
    • Houston, Texas, United States, 77024
      • Oncology Consultants P.A.
    • The Woodlands, Texas, United States, 77380
      • US Oncology- Central Regulatory
    • Tyler, Texas, United States, 75702
      • Tyler Cancer Center
    • Wichita Falls, Texas, United States, 76310
      • Texoma Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23230
      • Virginia Cancer Institute
  • Washington
    • Edmonds, Washington, United States, 98026
      • Puget Sound Cancer Centers
    • Vancover, Washington, United States, 98686
      • Northwest Cancer Specialists 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

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.

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
Active Comparator: RCHOP; 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: Prednisone; Prednisone tablet; Drug: Rituximab; Rituximab IV; Drug: Cyclophosphamide; Cyclophosphamide IV; Drug: Doxorubicin; Doxorubicin IV solution; Drug: Vincristine; Vincristine IV
Experimental: Vc-RCHOP; 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: Prednisone; Prednisone tablet; Drug: Rituximab; Rituximab IV; Drug: Cyclophosphamide; Cyclophosphamide IV; Drug: Doxorubicin; Doxorubicin IV solution; Drug: Vincristine; Vincristine IV; Drug: Bortezomib; Bortezomib IV; Other Names: VELCADE®

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: July 1, 2009
• First Submitted That Met QC Criteria: July 1, 2009
• First Posted (Estimate): July 2, 2009

Study Record Updates

• Last Update Posted (Estimate): January 11, 2017
• Last Update Submitted That Met QC Criteria: November 14, 2016
• Last Verified: November 1, 2016

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: C05013; U1111-1183-0186 (Registry Identifier: WHO)