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

NCT00598169 | Completed Phase 1

• 3 other identifiers: AMC-053U01CA121947CDR0000581078
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 17

Brief Summary

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.

Conditions

Lymphoma

Keywords

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

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose of bortezomib

  Assessed at end of cycle 1 for each group of 3 subjects

• Overall lymphoma response rate

  End of treatment

• Safety as assessed using the CTCAE

  Every cycle of treatment and all post-treatment visits

Secondary Outcomes (6)

• Median overall survival at 1 year

  1 year post-treatment

• Impact of bortezomib alone and in combination with rituximab, ifosfamide, carboplatin, and etoposide ([R]ICE) on serum HIV viral loads and APOBEC3G levels

  baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment

• Impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8 lytic activation using serum viral loads

  baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment

• Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas

  Every cycle of treatment and all post-treatment visits

• Correlation of EBV/HHV-8 viral load changes with lymphoma response

  baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment

Study Arms (2)

CD20+ Non-Hodgkin Lymphoma

EXPERIMENTAL

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; Drug: bortezomib; Drug: carboplatin; Drug: dexamethasone; Drug: etoposide; Drug: ifosfamide; Genetic: polymerase chain reaction; Genetic: western blotting

CD20- Non-Hodgkin Lymphoma

EXPERIMENTAL

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; Drug: carboplatin; Drug: dexamethasone; Drug: etoposide; Drug: ifosfamide; Genetic: polymerase chain reaction; Genetic: western blotting

Interventions

rituximab BIOLOGICAL

375mg/m2 on Day 1

CD20+ Non-Hodgkin Lymphoma

bortezomib DRUG

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.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

carboplatin DRUG

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.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

dexamethasone DRUG

Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

etoposide DRUG

Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

ifosfamide DRUG

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.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

polymerase chain reaction GENETIC

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.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

western blotting GENETIC

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.

CD20+ Non-Hodgkin Lymphoma; CD20- Non-Hodgkin Lymphoma

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• AIDS Malignancy Consortium: lead
• National Cancer Institute (NCI): collaborator
• The Emmes Company, LLC: collaborator

Study Sites (17)

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, 92093-0658, United States

Location

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, 90089-9181, United States

Location

UCLA Clinical AIDS Research and Education (CARE) Center

Los Angeles, California, 90095-1793, United States

Location

University of California at Davis Center for Aids Research and Education Services

Sacramento, California, 95814, United States

Location

University of Miami Sylvester Comprehensive Cancer Center - Miami

Miami, Florida, 33136, United States

Location

Emory Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Cancer Research Center of Hawaii

Honolulu, Hawaii, 96813, United States

Location

Northwestern Cancer Center

Chicago, Illinois, 60611, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231-2410, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467-2490, United States

Location

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210-1240, United States

Location

Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia

Philadelphia, Pennsylvania, 19106, United States

Location

Thomas Street Health Center

Houston, Texas, 77009, United States

Location

Baylor College of Medicine

Houston, Texas, 77030-2707, United States

Location

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

Location

Related Publications (1)

• Reid EG, Looney D, Maldarelli F, Noy A, Henry D, Aboulafia D, Ramos JC, Sparano J, Ambinder RF, Lee J, Cesarman E, Yahyaei S, Mitsuyasu R, Wachsman W; AIDS Malignancy Consortium. Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas. Blood Adv. 2018 Dec 26;2(24):3618-3626. doi: 10.1182/bloodadvances.2018022095.

  PMID: 30573564 DERIVED

MeSH Terms

Conditions

Lymphoma

Interventions

Rituximab; Bortezomib; Carboplatin; Dexamethasone; Etoposide; Ifosfamide; Polymerase Chain Reaction; Blotting, Western

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Coordination Complexes; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Glucosides; Glycosides; Carbohydrates; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Oxazines; Nucleic Acid Amplification Techniques; Genetic Techniques; Investigative Techniques; Electrophoresis; Chemistry Techniques, Analytical; Electrochemical Techniques; Immunoblotting; Immunoassay; Immunologic Techniques; Molecular Probe Techniques

Study Officials

• Erin G. Reid, MD

  University of California, San Diego

  STUDY CHAIR

• William Wachsman, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2008
• First Posted: January 18, 2008
• Study Start: November 1, 2007
• Primary Completion: October 1, 2014
• Study Completion: November 1, 2014
• Last Updated: August 10, 2020

Record last verified: 2020-08

Locations

US (17)