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Gene Therapy in Treating Patients With Human Immunodeficiency Virus-Related Lymphoma Receiving Stem Cell Transplant

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by AIDS Malignancy Consortium
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
AIDS Malignancy Consortium
ClinicalTrials.gov Identifier:
NCT02797470
First received: June 8, 2016
Last updated: December 15, 2016
Last verified: December 2016
  Purpose
This phase I/II trial studies the side effects and best dose of gene therapy in treating patients with human immunodeficiency virus (HIV)-related lymphoma that did not respond to therapy or came back after an original response receiving stem cell transplant. In gene therapy, small stretches of deoxyribonucleic acid (DNA) called "anti-HIV genes" are introduced into the stem cells in the laboratory to make the gene therapy product used in this study. The type of anti-HIV genes and therapy in this study may make the patient's immune cells more resistant to HIV-1 and prevent new immune cells from getting infected with HIV-1.

Condition Intervention Phase
HIV Infection
Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Plasmablastic Lymphoma
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Non-Hodgkin Lymphoma
Recurrent Burkitt Lymphoma
Recurrent Follicular Lymphoma
Stage III Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage IV Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Drug: Carmustine
Drug: Cytarabine
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Biological: Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor Cells
Drug: Melphalan
Procedure: Peripheral Blood Stem Cell Transplantation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Stem Cell Gene Therapy for HIV Mediated by Lentivector Transduced, Pre-selected CD34+ Cells

Resource links provided by NLM:


Further study details as provided by AIDS Malignancy Consortium:

Primary Outcome Measures:
  • Efficacy of the candidate product defined as establishment of > 5% mononuclear blood cells expressing anti-HIV genes in the peripheral blood [ Time Frame: 3 months post-transplant ]
    Efficacy rates will be summarized by the proportion of participants who meet the criteria for efficacy, with 95% exact binomial CIs.

  • Incidence of adverse events, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: 1 month post-transplant ]
    Defined as timely engraftment (collective establishment of a persistent absolute neutrophil count of at least 500 cells/mm^3 and platelet count of 20,000 cells/mm^3 without transfusion for 3 consecutive days) in the absence of any study candidate-specific grade 3 and 4 non-hematopoietic organ toxicity or any clonal expansion. Toxicity will be summarized as the proportion experiencing a given toxicity or group of toxicities, at or above a specified level of severity, with exact 95% confidence intervals (CIs).


Secondary Outcome Measures:
  • CD4 recovery [ Time Frame: Up to 24 months post-treatment ]
  • Complete response rate [ Time Frame: Up to 15 years ]
    Summarized descriptively. For dichotomous endpoints, the frequency, proportion, and exact 95% confidence interval for proportion will be calculated.

  • Duration of complete response (CR) [ Time Frame: Time from the first documentation of CR until first date that relapsed or progressive disease is objectively documented, assessed up to 15 years ]
    Time-to-event data will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval.

  • Duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells [ Time Frame: Up to 24 months post-transplant ]
    Summarized descriptively. Continuous measures will be summarized by mean (SD) and median (range), with log transformation if necessary for skewed measures, as would be typical for cell counts.

  • Hematologic function, defined as ANC > 1500, Hb > 10 g/dl without transfusion, and platelets > 100,000 [ Time Frame: Day 100 ]
  • HIV-1 viral load over time [ Time Frame: Up to 24 months post-transplant ]
  • Incidence of toxicities, infections, transfusions, and infusion-related reactions, using the NCI CTCAE version 4.0 [ Time Frame: Up to 15 years ]
  • Integration sites of vector sequences in circulating cells [ Time Frame: Up to 24 months post-transplant ]
  • Overall survival [ Time Frame: Time from start of study treatment to death, assessed up to 15 years ]
    Time-to-event data will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval.

  • Partial response rate [ Time Frame: Up to 15 years ]
  • Persistence of vector-transduced cells over time [ Time Frame: Up to 15 years ]
  • Presence of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells [ Time Frame: Up to 24 months post-transplant ]
    Summarized descriptively. For dichotomous endpoints, the frequency, proportion, and exact 95% confidence interval for proportion will be calculated.

  • Progression-free survival [ Time Frame: Time from start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed up to 15 years ]
    Time-to-event data will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval.

  • Quantity of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells [ Time Frame: Up to 24 months post-transplant ]
    Summarized descriptively. Continuous measures will be summarized by mean (standard deviation [SD]) and median (range), with log transformation if necessary for skewed measures, as would be typical for cell counts.

  • Time to neutrophil engraftment, defined as the first of 3 consecutive days of ANC > 500 cells/mm^3 [ Time Frame: Up to 15 years ]
  • Time to platelet engraftment, defined as the first of 3 consecutive days of platelets > 20,000 cells/mm^3 without platelet transfusions 7 days prior [ Time Frame: Up to 15 years ]

Other Outcome Measures:
  • Presence and the magnitude of expansion of HIV-1 resistant immune cells in the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding ART [ Time Frame: Up to 24 months post-transplant ]

Estimated Enrollment: 18
Study Start Date: May 2016
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (anti-HIV gene transduced CD34+ cells)
Patients receive BEAM regimen administered as standard of care comprising carmustine on day -6, cytarabine BID on days -5 to -2, etoposide BID on days -5 to -2, and melphalan on day -1. Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour.
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Other Name: Autologous Stem Cell Transplantation
Drug: Carmustine
Other Names:
  • BCNU
  • Becenum
  • Becenun
  • BiCNU
  • Bis(chloroethyl) Nitrosourea
  • Bis-Chloronitrosourea
  • Carmubris
  • Carmustin
  • Carmustinum
  • FDA 0345
  • Gliadel
  • N,N'-Bis(2-chloroethyl)-N-nitrosourea
  • Nitrourean
  • Nitrumon
  • SK 27702
  • SRI 1720
  • WR-139021
Drug: Cytarabine
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453
Drug: Etoposide
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor Cells
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Other Name: Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive HPCs
Drug: Melphalan
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-Sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine Nitrogen Mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation

Detailed Description:

PRIMARY OBJECTIVES:

I. Safety, defined as timely engraftment (the collective establishment of a persistent absolute neutrophil count of at least 500 cells/mm^3 and platelet count of 20,000 cells/mm^3 without transfusion for 3 consecutive days) at one month post transplant, in the absence of any study candidate specific grade 3 and 4 non-hematopoietic organ toxicity or any clonal expansion.

II. Efficacy of the candidate product, defined as establishment of > 5% mononuclear blood cells expressing anti-HIV genes in the peripheral blood at 3 months post-transplant.

SECONDARY OBJECTIVES:

I. To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells.

II. To study the integration sites of vector sequences in circulating cells. III. To study progression-free survival. IV. To study overall survival. V. To study complete response rate and duration. VI. To study partial response rate and duration. VII. To study time to neutrophil engraftment (first of 3 consecutive days of absolute neutrophil count [ANC] > 500 cells/mm^3).

VIII. To study time to platelet engraftment (first of 3 consecutive days of platelets > 20,000 cells/mm^3 without platelet transfusions 7 days prior).

IX. To study hematologic function at day 100 (ANC > 1500, hemoglobin [Hb] > 10 g/dl without transfusion and platelets > 100,000) X. To study cluster of differentiation (CD)4 recovery at the conclusion of the trial.

XI. To study safety in terms of toxicities, infections, transfusions, and infusion-related reactions.

XII. To study HIV-1 viral load over time. XIII. To study persistence of vector-transduced cells over time.

TERTIARY OBJECTIVES:

I. To evaluate the presence and the magnitude of expansion of HIV-1 resistant immune cells in the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding anti-retroviral therapy (ART).

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive BEAM regimen administered as standard of care comprising carmustine on day -6, cytarabine twice daily (BID) on days -5 to -2, etoposide BID on days -5 to -2, and melphalan on day -1. Patients undergo infusion of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells over 1 hour.

After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 42, 60, 90, 120, 180, 240, 300, 360, 420, 480, 520, 600, 660, and 720, and then yearly for at least 15 years.

  Eligibility

Ages Eligible for Study:   19 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Inclusion criteria associated with type and status of lymphoma
  • Biopsy-proven intermediate or high-grade non-Hodgkin's lymphoma, meeting one of the following criteria (timeline 4 months prior to start of trial):

    • In partial remission
    • Relapsed after initial complete remission
    • Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive disease)
    • In complete remission with high-risk features as specified by the International Prognostic Index
  • Biopsy-proven advanced stage follicular lymphoma, that have failed at least two lines of therapy multi-agent chemotherapy, but responds to salvage therapy (i.e., chemosensitive disease) (timeline 4 months prior to start of trial)
  • Biopsy-proven advanced stage mantle cell lymphoma with proliferation-related Ki-67 antigen (Ki-67) > 10% in first complete remission (timeline 4 months prior to start of trial)
  • Biopsy-proven Hodgkin's lymphoma, meeting one of the following criteria (timeline 4 months prior to start of trial)

    • In first, or greater relapse after initial complete remission
    • In partial remission
    • Failed induction therapy, but responds to salvage therapy (i.e., chemosensitive disease)
  • Biopsy-proven Burkitt's lymphoma, meeting one of the following criteria (timeline 4 months prior to start of trial):

    • In second complete remission after relapse following initial complete remission,
    • Failed induction therapy, but responds (very good partial remission, complete remission, or near complete remission) to salvage therapy (i.e., chemosensitive disease)
  • Biopsy proven plasmablastic lymphomas, or peripheral T cell lymphoma (with the exception of anaplastic lymphoma kinase positive [ALK+] type in first or second complete remission) (timeline 4 months prior to start of trial)
  • INCLUSION CRITERIA ASSOCIATED WITH HIV-1 STATUS
  • HIV-1 infection, as documented by any federally approved, licensed HIV rapid test performed in conjunction with screening (or enzyme linked immunosorbent assay [ELISA], test kit, and confirmed by western blot or other approved test); alternatively, this documentation may include a record demonstrating that another physician has documented the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the referring physician's written record that HIV infection was documented, with supporting information on the participant's relevant medical history and/or current management of HIV infection
  • Must be on a multi-drug anti-HIV regimen (excluding zidovudine [AZT, ZDV, Retrovir®, or agents containing zidovudine (e.g., Combivir® and Trizivir®)], and efavirenz [Sustiva®, or agents containing efavirenz (e.g., Atripla®)]), and have an HIV-1 viral load < 50 copies/mL by reverse transcriptase-polymerase chain reaction (RT-PCR) at the time of study enrollment; participants on zidovudine [AZT, ZDV, Retrovir®; including Combivir® and Trizivir®] and efavirenz [Sustiva®; including Atripla®] must switch to an alternative regimen without anticipated drug-drug interactions or myelosuppressive properties based on known viral resistance patterns and/or ART history, such as raltegravir and Truvada (emtricitabine and tenofovir) at least two weeks prior to the transplant
  • Participants with CD4 counts > 50/microL are eligible for this study if their viral load is < 50 copies/mL by reverse transcription polymerase chain reaction (RT-PCR) since majority of the participants have received aggressive chemotherapy that can potentially decrease the CD4 counts despite the ART therapy; timeline: within 3 weeks prior to start of trial
  • GENERAL INCLUSION CRITERIA (TIMELINE: 8 WEEKS PRIOR TO START OF TRIAL, UNLESS OTHERWISE SPECIFIED)
  • Karnofsky performance status of 70-100%; Eastern Cooperative Oncology Group (ECOG) performance status =< [2]
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) >= 2.5 times upper limit of normal (ULN)
  • Serum bilirubin =< 2.5 times ULN except for participants who are on atazanavir or indinavir, provided that the participant's direct bilirubin is within normal institutional limits
  • Participants who are hepatitis C virus antibody positive, or hepatitis B virus surface antigen positive must be free of clinical evidence of cirrhosis as determined by the principal investigator in consultation with the gastroenterology service; timeline: within 3 weeks prior to start of trial
  • Participants with hepatitis B should be on appropriate anti-viral therapy at the time of the transplant, and their viral load should be under control; timeline: within 3 weeks prior to start of trial
  • Serum creatinine =< 2 times ULN; timeline: within 3 weeks prior to start of trial
  • Creatinine clearance >= 60 mL/min; timeline: within 3 weeks prior to start of trial
  • Prothrombin time (PT)/partial thromboplastin time (PTT) =< 2 times normal; timeline: within 3 weeks prior to start of trial
  • Forced expiratory volume in 1 second (FEV-1) or diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% predicted; timeline: within 4 weeks prior to start of trial
  • Left ventricular ejection fraction (LVEF) >= 50% by 20-dimensional (20D) echocardiogram (ECHO) or multigated acquisition (MUGA) scan; timeline: within 4 weeks prior to start of trial
  • Not pregnant or nursing, with negative pregnancy test; timeline: within 3 weeks prior to start of trial
  • Life expectancy of greater than 3 months
  • Ability to understand and the willingness to sign a written informed consent document
  • Receipt of a stable ART regimen for at least 3 weeks prior to start of trial

Exclusion Criteria:

  • Participants with > 5% involvement of bone marrow by malignant cells (either by manual count or flow cytometry) prior to stem cell collection
  • Participants with any abnormal cytogenetics in the bone marrow not related to the lymphoma, and not deemed to be constitutional
  • Participants with unexplained anemia, and/or thrombocytopenia
  • Participants with clear evidence of myeloproliferative disorders, or myelodysplastic disorders in the marrow
  • Presence of any active central nervous system (CNS) disease at the time of evaluation (parenchymal or leptomeningeal)
  • Any history of HIV-1 associated encephalopathy
  • History of other acquired immune deficiency syndrome (AIDS)-related syndromes that are perceived to cause excessive risk for morbidity post-transplantation, as determined by the principal investigator
  • Symptomatic/active bacterial, or fungal, or any other opportunistic infection
  • Active cytomegalovirus (CMV) retinitis, or other active CMV-related organ dysfunction
  • Relapse of pneumocystis carinii pneumonia within the past year
  • Intractable, severe diarrhea, defined as > 1.500 cc diarrheal fluid per day, or diarrhea causing persistent severe electrolyte abnormalities, or hypoalbuminemia
  • History of active myocardial ischemia, cardiomyopathy, uncontrolled dysrhythmia, or congestive heart failure within the last 6 months before the evaluation
  • Dementia of any kind
  • Seizures within the past 12 months
  • History of grade III hemorrhagic cystitis due to prior cyclophosphamide chemotherapy
  • History of other prior malignancy, except squamous cell carcinoma of the cervix or anus, superficial basal cell or squamous cell skin cancer, or other malignancy curatively treated more than 5 years ago
  • Active psychosocial condition that would hinder study compliance and follow-up
  • Any perceived inability to directly (and without the means of a legal guardian) provide informed consent
  • Any medical or physical contraindication, or other inability to undergo hematopoietic progenitor cell (HPC) collection
  • Participants who are receiving any other investigational agents
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued; these potential risks may also apply to other agents used in this study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02797470

Locations
United States, California
UC San Diego Moores Cancer Center Not yet recruiting
La Jolla, California, United States, 92093
Contact: Mehrdad Abedi    916-734-3772    Mehrdad.abedi@ucdmc.ucdavis.edu   
Principal Investigator: Mehrdad Abedi         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Mehrdad Abedi    916-734-3772    Mehrdad.abedi@ucdmc.ucdavis.edu   
Principal Investigator: Mehrdad Abedi         
UCSF Medical Center-Mount Zion Not yet recruiting
San Francisco, California, United States, 94115
Contact: Mehrdad Abedi    916-734-3772    Mehrdad.abedi@ucdmc.ucdavis.edu   
Principal Investigator: Mehrdad Abedi         
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Ariela Noy    212-639-7423    noya@mskcc.org   
Principal Investigator: Ariela Noy         
Sponsors and Collaborators
AIDS Malignancy Consortium
National Cancer Institute (NCI)
Investigators
Principal Investigator: Mehrdad Abedi AIDS Malignancy Consortium
  More Information

Responsible Party: AIDS Malignancy Consortium
ClinicalTrials.gov Identifier: NCT02797470     History of Changes
Other Study ID Numbers: AMC-097
NCI-2015-01745 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9933 ( Other Identifier: CTRP (Clinical Trial Reporting Program) )
AMC 097 ( Other Identifier: AIDS Malignancy Consortium )
097 ( Other Identifier: AIDS Malignancy Consortium )
AMC-097 ( Other Identifier: CTEP )
U01CA121947 ( US NIH Grant/Contract Award Number )
Study First Received: June 8, 2016
Last Updated: December 15, 2016
Individual Participant Data  
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
HIV Infections
Lymphoma, Non-Hodgkin
Burkitt Lymphoma
Hodgkin Disease
Lymphoma, Mantle-Cell
Lymphoma, T-Cell, Peripheral
Lymphoma, T-Cell
Plasmablastic Lymphoma
Lymphoma, Large-Cell, Immunoblastic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse

ClinicalTrials.gov processed this record on March 29, 2017