Clinical Trials /

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

NCT02797470

Description:

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.

Related Conditions:
  • Burkitt Leukemia
  • Follicular Lymphoma
  • Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Non-Hodgkin Lymphoma
  • Peripheral T-Cell Lymphoma
  • Plasmablastic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gene Therapy in Treating Patients With Human Immunodeficiency Virus-Related Lymphoma Receiving Stem Cell Transplant
  • Official Title: Stem Cell Gene Therapy for HIV Mediated by Lentivector Transduced, Pre-selected CD34+ Cells

Clinical Trial IDs

  • ORG STUDY ID: AMC-097
  • SECONDARY ID: NCI-2015-01745
  • SECONDARY ID: 9933
  • SECONDARY ID: AMC 097
  • SECONDARY ID: 097
  • SECONDARY ID: AMC-097
  • SECONDARY ID: U01CA121947
  • NCT ID: NCT02797470

Conditions

  • 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

Interventions

DrugSynonymsArms
CarmustineBCNU, 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-139021Treatment (anti-HIV gene transduced CD34+ cells)
Cytarabine.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-28453Treatment (anti-HIV gene transduced CD34+ cells)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (anti-HIV gene transduced CD34+ cells)
Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor CellsLentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive HPCsTreatment (anti-HIV gene transduced CD34+ cells)
MelphalanAlanine 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-19813Treatment (anti-HIV gene transduced CD34+ cells)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (anti-HIV gene transduced CD34+ cells)ExperimentalPatients 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.
  • Carmustine
  • Cytarabine
  • Etoposide
  • Melphalan

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Efficacy rates will be summarized by the proportion of participants who meet the criteria for efficacy, with 95% exact binomial CIs.

Secondary Outcome Measures

Measure:CD4 recovery
Time Frame:Up to 24 months post-treatment
Safety Issue:
Description:
Measure:Complete response rate
Time Frame:Up to 15 years
Safety Issue:
Description:Summarized descriptively. For dichotomous endpoints, the frequency, proportion, and exact 95% confidence interval for proportion will be calculated.
Measure: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
Safety Issue:
Description: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.
Measure:Duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells
Time Frame:Up to 24 months post-transplant
Safety Issue:
Description: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.
Measure:Hematologic function, defined as ANC > 1500, Hb > 10 g/dl without transfusion, and platelets > 100,000
Time Frame:Day 100
Safety Issue:
Description:
Measure:HIV-1 viral load over time
Time Frame:Up to 24 months post-transplant
Safety Issue:
Description:
Measure:Incidence of toxicities, infections, transfusions, and infusion-related reactions, using the NCI CTCAE version 4.0
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Integration sites of vector sequences in circulating cells
Time Frame:Up to 24 months post-transplant
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Time from start of study treatment to death, assessed up to 15 years
Safety Issue:
Description: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.
Measure:Partial response rate
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Persistence of vector-transduced cells over time
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Presence of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells
Time Frame:Up to 24 months post-transplant
Safety Issue:
Description:Summarized descriptively. For dichotomous endpoints, the frequency, proportion, and exact 95% confidence interval for proportion will be calculated.
Measure: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
Safety Issue:
Description: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.
Measure:Quantity of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells
Time Frame:Up to 24 months post-transplant
Safety Issue:
Description: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.
Measure:Time to neutrophil engraftment, defined as the first of 3 consecutive days of ANC > 500 cells/mm^3
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AIDS Malignancy Consortium

Last Updated

December 15, 2016