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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00598169
• Other study ID #: AMC-053
• Secondary ID: U01CA121947CDR00
• Status: Completed
• Phase: Phase 1
• Start date: November 2007
• Est. completion date: November 2014

Study information

• Verified date: August 2020
• Source: AIDS Malignancy Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: November 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

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

Locations

Country	Name	City	State
United States	Emory Winship Cancer Institute	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Northwestern Cancer Center	Chicago	Illinois
United States	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Thomas Street Health Center	Houston	Texas
United States	Rebecca and John Moores UCSD Cancer Center	La Jolla	California
United States	UCLA Clinical AIDS Research and Education (CARE) Center	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia	Philadelphia	Pennsylvania
United States	University of California at Davis Center for Aids Research and Education Services	Sacramento	California
United States	Virginia Mason Medical Center	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
AIDS Malignancy Consortium	National Cancer Institute (NCI), The Emmes Company, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of bortezomib		Assessed at end of cycle 1 for each group of 3 subjects
Primary	Overall lymphoma response rate		End of treatment
Primary	Safety as assessed using the CTCAE		Every cycle of treatment and all post-treatment visits
Secondary	Median overall survival at 1 year		1 year post-treatment
Secondary	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
Secondary	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
Secondary	Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas		Every cycle of treatment and all post-treatment visits
Secondary	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
Secondary	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		Upon availability of both studies' results