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LymphomaPhase 1NCT00598169

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

A Phase 1 study testing rituximab, bortezomib and carboplatin in people with Lymphoma, run by AIDS Malignancy Consortium at 17 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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… Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Lymphoma
What is being tested?
rituximab, bortezomib and carboplatin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
17 sitesUnited States
Study dates
Nov 2007to Nov 2014
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 12Show fewer
  • 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

Who cannot join

  • 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
Show all 31Show fewer
  • 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 locations and contacts

17 sites in 1 country.

17 sites in 1 country

United States17 sites

  • Emory Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231-2410

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Northwestern Cancer Center

    Chicago, Illinois, 60611

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

    Columbus, Ohio, 43210-1240

  • Cancer Research Center of Hawaii

    Honolulu, Hawaii, 96813

  • Thomas Street Health Center

    Houston, Texas, 77009

  • Baylor College of Medicine

    Houston, Texas, 77030-2707

  • Rebecca and John Moores UCSD Cancer Center

    La Jolla, California, 92093-0658

  • USC/Norris Comprehensive Cancer Center and Hospital

    Los Angeles, California, 90089-9181

  • UCLA Clinical AIDS Research and Education (CARE) Center

    Los Angeles, California, 90095-1793

  • University of Miami Sylvester Comprehensive Cancer Center - Miami

    Miami, Florida, 33136

  • Memorial Sloan-Kettering Cancer Center

    New York, New York, 10065

  • Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia

    Philadelphia, Pennsylvania, 19106

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

    Sacramento, California, 95814

  • Virginia Mason Medical Center

    Seattle, Washington, 98101

  • Montefiore Medical Center

    The Bronx, New York, 10467-2490

Other trials in United States

About this study

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

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.

Read the 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.

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
Medical subject headings
Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rituximabBiological

    375mg/m2 on Day 1

  • bortezomibDrug

    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.

  • carboplatinDrug

    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.

  • dexamethasoneDrug

    Part A: 20 mg IV on Days 8-10. Part B: 20 mg IV on Days 1-3 and on Day 8.

  • etoposideDrug

    Part A: 100 mg/m2 IV Days 8-10. Part B: 100 mg/m2 IV daily on Days 1 to 3.

  • ifosfamideDrug

    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.

  • polymerase chain reactionGenetic

    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 blottingGenetic

    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.

Study groups in NCT00598169
Study groupRoleWhat they receive
CD20+ Non-Hodgkin LymphomaExperimentalPart 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.
Receives: Biological: rituximab; Drug: bortezomib; Drug: carboplatin; Drug: dexamethasone; Drug: etoposide; Drug: ifosfamide; Genetic: polymerase chain reaction; Genetic: western blotting
CD20- Non-Hodgkin LymphomaExperimentalPart 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.
Receives: Drug: bortezomib; Drug: carboplatin; Drug: dexamethasone; Drug: etoposide; Drug: ifosfamide; Genetic: polymerase chain reaction; Genetic: western blotting

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose of bortezomib

    Measured: Assessed at end of cycle 1 for each group of 3 subjects

  2. Overall lymphoma response rate

    Measured: End of treatment

  3. Safety as assessed using the CTCAE

    Measured: Every cycle of treatment and all post-treatment visits

Secondary outcomes (6)

  1. Median overall survival at 1 year

    Measured: 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

    Measured: 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

    Measured: 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

    Measured: Every cycle of treatment and all post-treatment visits

  5. Correlation of EBV/HHV-8 viral load changes with lymphoma response

    Measured: 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

    Measured: Upon availability of both studies' results

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2008 (estimated)
  2. Study startNov 2007
  3. Primary completionOct 2014
  4. Study completionNov 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00598169
Sponsor's protocol ID
AMC-053
Other IDs
U01CA121947, CDR0000581078
Status last verified
Aug 2020
First submitted
9 Jan 2008
Last updated
10 Aug 2020
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 30573564

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing rituximab, bortezomib and carboplatin in people with Lymphoma, run by AIDS Malignancy Consortium at 17 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose of bortezomib (time frame: Assessed at end of cycle 1 for each group of 3 subjects). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00598169, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2020.

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