Clinical trial NCT00598169: Bortezomib, Ifosfamide, Carboplatin, and Etoposide, With or Without Rituximab, in Treating Patients With Relapsed or Refractory AIDS-Related Non-Hodgkin Lymphoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: AIDS Malignancy Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: The Emmes Company, LLC
First posted: 2008-01-18
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Maximum tolerated dose of bortezomib
timeFrame: Assessed at end of cycle 1 for each group of 3 subjects
measure: Overall lymphoma response rate
timeFrame: End of treatment
measure: Safety as assessed using the CTCAE
timeFrame: Every cycle of treatment and all post-treatment visits
Secondary outcomes:
measure: Median overall survival at 1 year
timeFrame: 1 year post-treatment
measure: Impact of bortezomib alone and in combination with rituximab, ifosfamide, carboplatin, and etoposide ([R]ICE) on serum HIV viral loads and APOBEC3G levels
timeFrame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment
measure: Impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8 lytic activation using serum viral loads
timeFrame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment
measure: Safety of bortezomib alone in patients with relapsed or refractory AIDS-associated lymphomas
timeFrame: Every cycle of treatment and all post-treatment visits
measure: Correlation of EBV/HHV-8 viral load changes with lymphoma response
timeFrame: baseline, day 2, 4, and 8 of week 1 of Part A, end of treatment
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
timeFrame: Upon availability of both studies' results
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Los Angeles
country: United States
facility: UCLA Clinical AIDS Research and Education (CARE) Center
state: California
city: Sacramento
country: United States
facility: University of California at Davis Center for Aids Research and Education Services
state: California
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center - Miami
state: Florida
city: Atlanta
country: United States
facility: Emory Winship Cancer Institute
state: Georgia
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Thomas Street Health Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
Study officials:
affiliation: University of California, San Diego
name: Erin G. Reid, MD
role: STUDY_CHAIR
affiliation: University of California, San Diego
name: William Wachsman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.