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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

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ClinicalTrials.gov Identifier: NCT00931918
Recruitment Status : Completed
First Posted : July 2, 2009
Results First Posted : January 11, 2017
Last Update Posted : January 11, 2017
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-Germinal B-Cell-like (GCB) Diffuse Large B-cell Lymphoma (DLBCL) Drug: Bortezomib Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone Phase 2

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  (Clinical Trial)
Actual Enrollment : 206 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2009
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Bortezomib

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: Rituximab
Rituximab IV

Drug: Cyclophosphamide
Cyclophosphamide IV

Drug: Doxorubicin
Doxorubicin IV solution

Drug: Vincristine
Vincristine IV

Drug: Prednisone
Prednisone tablet

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: Bortezomib
Bortezomib IV
Other Name: VELCADE®

Drug: Rituximab
Rituximab IV

Drug: Cyclophosphamide
Cyclophosphamide IV

Drug: Doxorubicin
Doxorubicin IV solution

Drug: Vincristine
Vincristine IV

Drug: Prednisone
Prednisone tablet




Primary Outcome Measures :
  1. Progression-Free Survival (PFS) in Patients With Non-germinal Center B-cell-like (Non-GCB) Diffuse Large B-cell Lymphoma (DLBCL) [ Time Frame: Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm ]
    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.

  2. Progression-Free Survival Rate [ Time Frame: 2 Years (Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm) ]
    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.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm ]
    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.

  2. Overall Response Rate (ORR) [ Time Frame: End of Cycle 2, End of Treatment (Cycle 6) [Median of 16 weeks on treatment] ]
    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.

  3. Complete Response Rate [ Time Frame: End of Cycle 2, End of Treatment (Cycle 6) [Median of 16 weeks on treatment] ]
    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.

  4. Duration of Response [ Time Frame: Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm ]
    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.

  5. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Negative Rate [ Time Frame: End of Cycle 2 and End of Treatment (Cycle 6) [Median of 16 weeks on treatment] ]
    FDG-PET negative rate is defined as the percentage of participants FDG-PET negative at the given time-point.

  6. Time to Progression (TTP) [ Time Frame: Median Follow-up of 34.3 months for RCHOP arm and 34.4 months for Vc-RCHOP arm ]
    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.

  7. Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) by Category [ Time Frame: First dose of study drug through 30 days after the last dose of study drug (Up to 26 Weeks) ]
    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.

  8. Percentage of Participants With Chemistry and Hematology Laboratory Values Grade 3 or Higher [ Time Frame: Days 1, 4 and 10 of each cycle and end of treatment visit (Median of 16 weeks on treatment) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00931918


  Show 70 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00931918     History of Changes
Other Study ID Numbers: C05013
U1111-1183-0186 ( Registry Identifier: WHO )
First Posted: July 2, 2009    Key Record Dates
Results First Posted: January 11, 2017
Last Update Posted: January 11, 2017
Last Verified: November 2016

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Non-Hodgkin
Bortezomib
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Rituximab
Liposomal doxorubicin
Doxorubicin
Prednisone
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors