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

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ClinicalTrials.gov Identifier: NCT02797470
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : June 11, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
AIDS Malignancy Consortium

Tracking Information
First Submitted Date  ICMJE June 8, 2016
First Posted Date  ICMJE June 13, 2016
Last Update Posted Date June 11, 2020
Study Start Date  ICMJE May 2016
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2016)
  • 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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2016)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 8, 2016)
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 ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Gene Therapy in Treating Patients With Human Immunodeficiency Virus-Related Lymphoma Receiving Stem Cell Transplant
Official Title  ICMJE Stem Cell Gene Therapy for HIV Mediated by Lentivector Transduced, Pre-selected CD34+ Cells
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 8, 2016)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2036
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02797470
Other Study ID Numbers  ICMJE 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 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AIDS Malignancy Consortium
Study Sponsor  ICMJE AIDS Malignancy Consortium
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • California Institute for Regenerative Medicine (CIRM)
Investigators  ICMJE
Principal Investigator: Mehrdad Abedi AIDS Malignancy Consortium
PRS Account AIDS Malignancy Consortium
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP