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

• ClinicalTrials.gov Identifier: NCT00598169
• Recruitment Status: Completed
• First Posted: January 18, 2008
• Last Update Posted: August 10, 2020
• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC
• Information provided by (Responsible Party): AIDS Malignancy Consortium

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Lymphoma	Biological: rituximab; Drug: bortezomib; Drug: carboplatin; Drug: dexamethasone; Drug: etoposide; Drug: ifosfamide; Genetic: polymerase chain reaction; Genetic: western blotting	Phase 1

Detailed Description:

OBJECTIVES:

Primary

• Evaluate the safety and overall lymphoma response rate of bortezomib in combination with ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab in patients with Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive relapsed or refractory HIV-associated non-Hodgkin lymphoma (NHL).

Secondary

• Evaluate the impact of bortezomib alone and in combination with rituximab) and ICE ([R] ICE) on serum HIV viral loads and APOBEC3G levels.
• Estimate the impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8 lytic activation using serum viral loads.
• Estimate the median response duration and 1 year overall survival rate of patients treated with this regimen.
• Evaluate the safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas.
• Correlate EBV/HHV-8 viral load changes with lymphoma response.
• Compare the above outcomes to a parallel protocol employing ICE with or without rituximab in patients with EBV/HHV-8-negative AIDS-NHL to assess whether bortezomib has additional effects beyond (R)ICE alone.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are assigned to 1 of 2 treatment groups.

• CD20-negative patients

  • Part A: Patients receive bortezomib IV over 3-5 seconds on days 1 and 8, dexamethasone IV and etoposide IV over 2 hours on days 8-10, and ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 9. Treatment repeats every 28 days until the maximum tolerated dose (MTD) is determined. Patients who tolerate the MTD of bortezomib may move on to part B.
  • Part B: Patients receive bortezomib IV over 3-5 seconds at the MTD on days 1 and 8, dexamethasone IV on days 1-3 and 8, etoposide IV over 2 hours on days 1-3, and ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Some patients may undergo hematopoietic stem cell transplantation (HSCT).

• CD20-positive patients

  • Part A: Patients receive bortezomib, dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative patients part A group.
  • Part B: Patients receive rituximab IV on day 1. Patients also receive bortezomib, dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative patients part B group. Some patients may undergo HSCT.

Patients undergo blood sample collection periodically for correlative studies. Samples are analyzed for the effects of bortezomib on viral activation and replication via Taqman polymerase chain reaction (PCR), and for quantification of APOBEC3G levels via western blot. Similar studies are performed on the BCLB-1 EBV containing lines, as well as Daudi and other EBV-transformed B-lymphocyte lines via quantitative viral DNA PCR.

Patients complete the Functional Assessment of Cancer Therapy/GOG-Neurotoxicity Questionnaire, v4.0 at day 8 and week 4 of Part A and at least once per course of Part B for assessment of neuropathic pain and/or peripheral neuropathy.

After completion of study treatment, patients achieving complete response (CR) are followed at 2-4 weeks and then every 3 months for 1 year. Patients not achieving CR at completion of study treatment and declining further antineoplastic treatment are followed at 2-4 weeks and then every 3 months for 1 year.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: November 2007
• Actual Primary Completion Date: October 2014
• Actual Study Completion Date: November 2014

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose of bortezomib [ Time Frame: Assessed at end of cycle 1 for each group of 3 subjects ]
2. Overall lymphoma response rate [ Time Frame: End of treatment ]
3. Safety as assessed using the CTCAE [ Time Frame: Every cycle of treatment and all post-treatment visits ]

Secondary Outcome Measures :

1. Median overall survival at 1 year [ Time Frame: 1 year post-treatment ]
2. 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 ]
3. 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 ]
4. Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas [ Time Frame: Every cycle of treatment and all post-treatment visits ]
5. 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 ]
6. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, California

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, United States, 92093-0658

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, United States, 90089-9181

UCLA Clinical AIDS Research and Education (CARE) Center

Los Angeles, California, United States, 90095-1793

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

Sacramento, California, United States, 95814

United States, Florida

University of Miami Sylvester Comprehensive Cancer Center - Miami

Miami, Florida, United States, 33136

United States, Georgia

Emory Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Hawaii

Cancer Research Center of Hawaii

Honolulu, Hawaii, United States, 96813

United States, Illinois

Northwestern Cancer Center

Chicago, Illinois, United States, 60611

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21231-2410

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467-2490

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Ohio

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

Columbus, Ohio, United States, 43210-1240

United States, Pennsylvania

Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia

Philadelphia, Pennsylvania, United States, 19106

United States, Texas

Thomas Street Health Center

Houston, Texas, United States, 77009

Baylor College of Medicine

Houston, Texas, United States, 77030-2707

United States, Washington

Virginia Mason Medical Center

Seattle, Washington, United States, 98101

Sponsors and Collaborators

AIDS Malignancy Consortium

National Cancer Institute (NCI)

The Emmes Company, LLC

Investigators

• Study Chair: Erin G. Reid, MD; University of California, San Diego
• Principal Investigator: William Wachsman, MD; University of California, San Diego

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: AIDS Malignancy Consortium
• ClinicalTrials.gov Identifier: NCT00598169
• Other Study ID Numbers: AMC-053; U01CA121947 ( U.S. NIH Grant/Contract ); CDR0000581078 ( Other Identifier: NCI )
• First Posted: January 18, 2008
• Last Update Posted: August 10, 2020
• Last Verified: August 2020

Keywords provided by AIDS Malignancy 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; Rituximab; Carboplatin; Etoposide; Bortezomib; Ifosfamide; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors