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

AIDS Malignancy Consortium

Status and phase

Completed

Phase 1

Conditions

Lymphoma

Treatments

Drug: ifosfamide

Drug: carboplatin

Genetic: western blotting

Drug: bortezomib

Drug: dexamethasone

Drug: etoposide

Genetic: polymerase chain reaction

Biological: rituximab

Study type

Interventional

Funder types

NETWORK

Industry

NIH

Identifiers

NCT00598169

U01CA121947 (U.S. NIH Grant/Contract)

AMC-053

CDR0000581078 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

23 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

23 participants in 2 patient groups

CD20+ Non-Hodgkin Lymphoma

Experimental group

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 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.

Treatment: