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

Sponsor:	AIDS Malignancy Clinical Trials Consortium
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier:	NCT00598169

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:

MedlinePlus related topics: Cancer Kaposi's Sarcoma Lymphoma

Drug Information available for: Dexamethasone Dexamethasone acetate Dexamethasone Sodium Phosphate Ifosfamide Mesna Etoposide Carboplatin Etoposide phosphate Rituximab Bortezomib

U.S. FDA Resources

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:	18
Study Start Date:	November 2007
Estimated Study Completion Date:	June 2014
Estimated Primary Completion Date:	June 2013 (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.

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	Recruiting
Los Angeles, California, United States, 90089-9181
Contact: Clinical Trials Office - USC/Norris Comprehensive Cancer Cente 323-865-0451
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, Hawaii
Cancer Research Center of Hawaii	Not yet recruiting
Honolulu, Hawaii, United States, 96813
Contact: Bruce Shiramizu, MD 808-586-3010
Principal Investigator: Bruce Shiramizu, MD
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: Samir S. Parekh, MD 718-920-4826 sparekh@montefiore.org
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
United States, Washington
Virginia Mason Medical Center	Recruiting
Seattle, Washington, United States, 98101
Contact: David M. Aboulafia, MD 206-223-6193

Sponsors and Collaborators

AIDS Malignancy Clinical Trials Consortium

National Cancer Institute (NCI)

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:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

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:	December 1, 2011
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 May 24, 2012