Bortezomib, Ifosfamide, Carboplatin, and Etoposide, With or Without Rituximab, in Treating Patients With Relapsed or Refractory AIDS-Related Non-Hodgkin Lymphoma

This study is currently recruiting participants.
Verified March 2014 by AIDS Malignancy Clinical Trials Consortium
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier:
NCT00598169
First received: January 9, 2008
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving bortezomib together with combination chemotherapy is more effective with or without rituximab in treating AIDS-related non-Hodgkin lymphoma.

PURPOSE: This clinical trial is studying giving bortezomib together with dexamethasone, ifosfamide, carboplatin, and etoposide to see how well it works with or without rituximab in treating patients with relapsed or refractory AIDS-related non-Hodgkin lymphoma.


Condition Intervention Phase
Lymphoma
Biological: rituximab
Drug: bortezomib
Drug: carboplatin
Drug: dexamethasone
Drug: etoposide
Drug: ifosfamide
Genetic: polymerase chain reaction
Genetic: western blotting
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety and Efficacy Pilot Trial of the Anti-Viral and Anti-Tumor Activity of Velcade Combined With (R)ICE in Subjects With EBV and/or HHV-8 Positive Relapsed/Refractory AIDS-Associated Non-Hodgkin's Lymphoma

Resource links provided by NLM:


Further study details as provided by AIDS Malignancy Clinical Trials Consortium:

Primary Outcome Measures:
  • Maximum tolerated dose of bortezomib [ Time Frame: Assessed at end of cycle 1 for each group of 3 subjects ] [ Designated as safety issue: Yes ]
  • Overall lymphoma response rate [ Time Frame: End of treatment ] [ Designated as safety issue: No ]
  • Safety as assessed using the CTCAE [ Time Frame: Every cycle of treatment and all post-treatment visits ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Median overall survival at 1 year [ Time Frame: 1 year post-treatment ] [ Designated as safety issue: No ]
  • Impact of bortezomib alone and in combination with rituximab, ifosfamide, carboplatin, and etoposide ([R]ICE) on serum HIV viral loads and APOBEC3G levels [ Time Frame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment ] [ Designated as safety issue: No ]
  • Impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8 lytic activation using serum viral loads [ Time Frame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment ] [ Designated as safety issue: No ]
  • Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas [ Time Frame: Every cycle of treatment and all post-treatment visits ] [ Designated as safety issue: Yes ]
  • Correlation of EBV/HHV-8 viral load changes with lymphoma response [ Time Frame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment ] [ Designated as safety issue: No ]
  • Comparison of above outcomes to a parallel protocol employing ICE +/- rituximab in patients with EBV/HHV-8-negative AIDS-NHL to assess whether bortezomib has additional effects beyond (R)ICE alone [ Time Frame: Upon availability of both studies' results ] [ Designated as safety issue: No ]

Estimated Enrollment: 26
Study Start Date: November 2007
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CD20+ Non-Hodgkin Lymphoma

Part A: Velcade Day 1 and Day 8, with inter-subject dose escalation over four dose levels: 0.7 mg/m2, 1 mg/m2, 1.3 mg/m2 and 1.5 mg/m2. Dexamethasone 20 mg IV and etoposide 100 mg/m2 IV Days 8-10, carboplatin dosed to AUC=5 (maximum 750 mg) IV and ifosfamide 5000 mg/m2 mixed with an equal amount of Mesna on Day 9 of a 28-day cycle.

Part B: Velcade on Days 1 and 8, dexamethasone 20 mg IV Days 1-3 and Day 8; etoposide 100 mg/m2 IV on Days 1-3; carboplatin dosed to AUC=5 (maximum 750 mg) IV on Day 2; ifosfamide 5000 mg/m2 mixed with an equal amount of Mesna and administered as a continuous IV infusion over 24 hours on Day 2, rituximab 375mg/m2 on Day 1 of a 21-day cycle.

Biological: rituximab
375mg/m2 on Day 1
Drug: bortezomib
Part A: Velcade Day 1 and Day 8 of a 28-day cycle, with inter-subject dose escalation over four dose levels: 0.7 mg/m2, 1 mg/m2, 1.3 mg/m2 and 1.5 mg/m2 Part B: Velcade on Days 1 and 8 of a 21-day cycle.
Drug: carboplatin

Carboplatin will be dosed to an AUC=5, calculated using the Calvert formula (5 x [creatinine clearance + 25]; the maximum dose of carboplatin is 750 mg.

Part A: AUC=5 (maximum 750 mg) IV administered on Day 9. Part B: AUC=5 (maximum 750 mg) IV administered on Day 2.

Drug: dexamethasone
Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.
Drug: etoposide
Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.
Drug: ifosfamide

Part A: 5000 mg/m2 mixed with an equal amount of Mesna as a 24 hour continuous IV infusion on Day 9.

Part B: 5000 mg/m2 mixed with an equal dose of Mesna administered via continuous infusion for 24 hours beginning on Day 2.

Genetic: polymerase chain reaction
Correlate EBV/HHV-8 viral load changes with lymphoma response. HIV and EBV/HHV-8 viral loads will be assessed on baseline, day 2, 4, and 8 of week 1 of Part A.
Genetic: western blotting
Peripheral blood mononuclear cells will be collected at Day 1 prior to chemotherapy, Day 2, 4 and 8 (prior to chemotherapy) then weekly during Part A, just prior to each additional cycle of Part B and at treatment completion. Western blot using antibody specific for APOBEC3G and antibody against actin for internal control will be used to quantify APOBEC3G levels. Changes at will be compared with baseline using a paired t-test.
Experimental: CD20- Non-Hodgkin Lymphoma

Part A: Velcade Day 1 and Day 8, with inter-subject dose escalation over four dose levels: 0.7 mg/m2, 1 mg/m2, 1.3 mg/m2 and 1.5 mg/m2. Dexamethasone 20 mg IV and etoposide 100 mg/m2 IV Days 8-10, carboplatin dosed to AUC=5 (maximum 750 mg) IV and ifosfamide 5000 mg/m2 mixed with an equal amount of Mesna on Day 9 of a 28-day cycle.

Part B: Velcade on Days 1 and 8, dexamethasone 20 mg IV Days 1-3 and Day 8; etoposide 100 mg/m2 IV on Days 1-3; carboplatin dosed to AUC=5 (maximum 750 mg) IV on Day 2; ifosfamide 5000 mg/m2 mixed with an equal amount of Mesna and administered as a continuous IV infusion over 24 hours on Day 2, 21-day cycle.

Drug: bortezomib
Part A: Velcade Day 1 and Day 8 of a 28-day cycle, with inter-subject dose escalation over four dose levels: 0.7 mg/m2, 1 mg/m2, 1.3 mg/m2 and 1.5 mg/m2 Part B: Velcade on Days 1 and 8 of a 21-day cycle.
Drug: carboplatin

Carboplatin will be dosed to an AUC=5, calculated using the Calvert formula (5 x [creatinine clearance + 25]; the maximum dose of carboplatin is 750 mg.

Part A: AUC=5 (maximum 750 mg) IV administered on Day 9. Part B: AUC=5 (maximum 750 mg) IV administered on Day 2.

Drug: dexamethasone
Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.
Drug: etoposide
Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.
Drug: ifosfamide

Part A: 5000 mg/m2 mixed with an equal amount of Mesna as a 24 hour continuous IV infusion on Day 9.

Part B: 5000 mg/m2 mixed with an equal dose of Mesna administered via continuous infusion for 24 hours beginning on Day 2.

Genetic: polymerase chain reaction
Correlate EBV/HHV-8 viral load changes with lymphoma response. HIV and EBV/HHV-8 viral loads will be assessed on baseline, day 2, 4, and 8 of week 1 of Part A.
Genetic: western blotting
Peripheral blood mononuclear cells will be collected at Day 1 prior to chemotherapy, Day 2, 4 and 8 (prior to chemotherapy) then weekly during Part A, just prior to each additional cycle of Part B and at treatment completion. Western blot using antibody specific for APOBEC3G and antibody against actin for internal control will be used to quantify APOBEC3G levels. Changes at will be compared with baseline using a paired t-test.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed relapsed or refractory HIV-associated non-Hodgkin lymphoma (NHL)

    • Must have histologic or cytologic documentation of prior AIDS-associated NHL (i.e., at time of diagnosis) for clinically relapsed and/or refractory disease for which biopsy is not feasible
    • Must have documented HIV seropositivity
    • Must have documentation of Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive infection within the lymphoma (i.e., LMP-1, LANA expression, or positive Epstein-Barr-encoded RNAs [EBERs])

PATIENT CHARACTERISTICS:

Inclusion criteria:

  • ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%
  • Life expectancy > 2 months
  • ANC ≥ 1,000/mm³* (growth factor support allowed)
  • Hemoglobin ≥ 8.0 g/dL* (growth factor support allowed)
  • Platelet count ≥ 100,000/mm³
  • Total bilirubin ≤ 1.5 mg/dL
  • AST/ALT ≤ 2.5 times institutional upper limit of normal (ULN)
  • Serum creatinine ≤ ULN
  • Creatinine clearance ≥ 50 mL/min
  • Negative pregnancy test
  • Not pregnant or nursing
  • Fertile patients must use effective contraception NOTE: *Patients with lymphomatous involvement of the bone unable to meet hematologic criteria are allowed

Exclusion criteria:

  • Peripheral neuropathy ≥ grade 2
  • Uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection

      • Opportunistic infections controlled by antimicrobial or suppressive therapy allowed, unless the investigator judges the infection likely to become life-threatening in the setting of multi-agent chemotherapy
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • NYHA class III or IV heat failure
    • Myocardial infarction within the past 6 months
    • Uncontrolled angina
    • Severe uncontrolled ventricular or other cardiac arrhythmias
    • Acute ischemia or active conduction system abnormalities by ECG
    • Serious psychiatric or medical illness, that would interfere with study compliance
  • Social situations that would interfere with study compliance
  • Acute active HIV-associated opportunistic infection requiring antibiotic treatment

    • Mycobacterium avium or candidiasis allowed unless concurrent therapy with moderate-to-strong CYP3A4 inducers or inhibitors is required
    • Chronic myelosuppressive agent therapy allowed provided hematologic criteria are met
  • Hypersensitivity to compounds of similar chemical or biological composition to bortezomib, boron, mannitol, ifosfamide, carboplatin, or etoposide
  • Concurrent malignancy except carcinoma in situ of the cervix, in situ anal cancer, nonmetastatic nonmelanoma skin cancer, or Kaposi's sarcoma not requiring systemic chemotherapy
  • Active hepatitis B infection (hepatitis B surface antigen-positive), unless 1 of the following criteria are met:

    • Able to start dual anti-hepatitis B adefovir and telbivudine therapy prior to study
    • Receiving dual anti-hepatitis B therapy for at least 12 weeks prior to study with either agent active against HIV (i.e., entecavir, tenofovir, lamivudine, or emtricitabine)
  • Concurrent grapefruit juice/fruit or green tea

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from prior adverse effects due to agents administered more than 3 weeks earlier
  • Glucocorticoid therapy within the past 3 weeks allowed
  • More than 3 weeks since prior chemotherapy
  • More than 2 weeks since prior radiotherapy
  • More than 14 days since prior and no other concurrent investigational agents (other than bortezomib)
  • No concurrent moderate-to-strong CYP3A4 inducers or inhibitors other than protease inhibitors
  • Concurrent stable (at least 12 weeks) antiretroviral regimen allowed
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00598169

Contacts
Contact: Erin G Reid, MD 858-822-5354

Locations
United States, California
Rebecca and John Moores UCSD Cancer Center Recruiting
La Jolla, California, United States, 92093-0658
Contact: Clinical Trials Office - Rebecca and John Moores UCSD Cancer    858-822-5354    cancercto@ucsd.edu   
USC/Norris Comprehensive Cancer Center and Hospital Withdrawn
Los Angeles, California, United States, 90089-9181
UCLA Clinical AIDS Research and Education (CARE) Center Recruiting
Los Angeles, California, United States, 90095-1793
Contact: Ronald Mitsuyasu, MD    310-557-9680      
Principal Investigator: Ronald Mitsuyasu, MD         
University of California at Davis Center for Aids Research and Education Services Recruiting
Sacramento, California, United States, 95814
Contact: Richard Pollard, MD    916-734-3711      
Principal Investigator: Richard Pollard, MD         
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center - Miami Recruiting
Miami, Florida, United States, 33136
Contact: Juan Carlos Ramos, MD    305-243-6611      
Principal Investigator: Juan Carlos Ramos, MD         
United States, Georgia
Emory Winship Cancer Institute Withdrawn
Atlanta, Georgia, United States, 30322
United States, Hawaii
Cancer Research Center of Hawaii Withdrawn
Honolulu, Hawaii, United States, 96813
United States, Illinois
Northwestern Cancer Center Terminated
Chicago, Illinois, United States, 60611
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231-2410
Contact: Yvette Kasamon, MD    410-955-8839      
Principal Investigator: Yvette Kasamon, MD         
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467-2490
Contact: Stephan Barta, MD       sbarta@montefiore.org   
Principal Investigator: Stephan Barta, MD         
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ariela Noy, MD    212-639-7423      
Principal Investigator: Ariela Noy, MD         
United States, Ohio
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210-1240
Contact: Robert Baiocchi, MD    614-292-1551      
Principal Investigator: Robert Baiocchi, MD         
United States, Pennsylvania
Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19106
Contact: David H. Henry, MD    215-829-6088      
United States, Texas
Thomas Street Health Center Recruiting
Houston, Texas, United States, 77009
Contact: Martha Mimms, MD    713-873-4000      
Principal Investigator: Martha Mimms, MD         
Baylor University Medical Center - Houston Recruiting
Houston, Texas, United States, 77030-2707
Contact: Martha Mims, MD       mmims@bcm.edu   
Principal Investigator: Martha Mims, MD         
United States, Washington
Virginia Mason Medical Center Recruiting
Seattle, Washington, United States, 98101
Contact: David M. Aboulafia, MD    206-223-6193      
Principal Investigator: David Aboulafia, MD         
Sponsors and Collaborators
AIDS Malignancy Clinical Trials Consortium
Investigators
Study Chair: Erin G. Reid, MD University of California, San Diego
Principal Investigator: William Wachsman, MD University of California, San Diego
  More Information

Additional Information:
No publications provided

Responsible Party: AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier: NCT00598169     History of Changes
Other Study ID Numbers: CDR0000581078, U01CA121947, AMC-053
Study First Received: January 9, 2008
Last Updated: March 18, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government

Keywords provided by AIDS Malignancy Clinical Trials Consortium:
AIDS-related diffuse large cell lymphoma
AIDS-related diffuse mixed cell lymphoma
AIDS-related diffuse small cleaved cell lymphoma
AIDS-related immunoblastic large cell lymphoma
AIDS-related lymphoblastic lymphoma
AIDS-related peripheral/systemic lymphoma
AIDS-related primary CNS lymphoma
AIDS-related small noncleaved cell lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Etoposide phosphate
Isophosphamide mustard
Rituximab
Bortezomib
Etoposide
Ifosfamide
Carboplatin
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones

ClinicalTrials.gov processed this record on April 23, 2014