Expired Study
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Los Angeles, California 90095


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.


Study summary:

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.


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


Study is Available At:


Original ID:

AMC-053


NCT ID:

NCT00598169


Secondary ID:

U01CA121947


Study Acronym:


Brief Title:

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


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


Overall Status:

Completed


Study Phase:

Phase 1


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

120 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

AIDS Malignancy Consortium


Oversight Authority:

  • United States: Food and Drug Administration
  • United States: Institutional Review Board
  • United States: Federal Government


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

23


Enrollment Type:

Actual


Overall Contact Information

Official Name:Erin G. Reid, MD
Study Chair
University of California, San Diego

Study Dates

Start Date:November 2007
Completion Date:November 2014
Completion Type:Actual
Primary Completion Date:October 2014
Primary Completion Type:Actual
Verification Date:February 2018
Last Changed Date:February 23, 2018
First Received Date:January 9, 2008

Study Outcomes

Outcome Type:Primary Outcome
Measure:Maximum tolerated dose of bortezomib
Time Frame:Assessed at end of cycle 1 for each group of 3 subjects
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Overall lymphoma response rate
Time Frame:End of treatment
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Safety as assessed using the CTCAE
Time Frame:Every cycle of treatment and all post-treatment visits
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Median overall survival at 1 year
Time Frame:1 year post-treatment
Safety Issues:False
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas
Time Frame:Every cycle of treatment and all post-treatment visits
Safety Issues:False
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False

Study Interventions

Intervention Type:Biological
Name:rituximab
Description:375mg/m2 on Day 1
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Drug
Name:bortezomib
Description: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.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Drug
Name:carboplatin
Description: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.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Drug
Name:dexamethasone
Description:Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Drug
Name:etoposide
Description:Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Drug
Name:ifosfamide
Description: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.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Genetic
Name:polymerase chain reaction
Description: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.
Arm Name:CD20+ Non-Hodgkin Lymphoma
Intervention Type:Genetic
Name:western blotting
Description: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.
Arm Name:CD20+ Non-Hodgkin Lymphoma

Study Arms

Study Arm Type:Experimental
Arm Name:CD20+ Non-Hodgkin Lymphoma
Description: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
Study Arm Type:Experimental
Arm Name:CD20- Non-Hodgkin Lymphoma
Description: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

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:AIDS Malignancy Consortium
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Cancer Institute (NCI)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: November 18, 2019

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