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

Phase 1

Active, not recruiting

Conditions: Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
HIV Infection
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

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

Registration Number: NCT02797470

Lead Sponsor: AIDS Malignancy Consortium

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 OBJECTIVE:

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 measurements of laboratory values obtained on different days) by one month post-transplant, in the absence of any grade 3 and 4 non-hematopoietic organ toxicity that can be attributed (possibly, probably, or definitely) to lentiviral transduced stem cell transplant, excluding alopecia, or any clonal expansion and excluding expected toxicities that are associated with the pre-transplant conditioning regimen.

SECONDARY OBJECTIVES:

I. To determine 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.

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

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

IX. To study time to platelet engraftment (first measurement of 3 consecutive measurements laboratory values obtained on different days) of platelets \>= 20,000 cells/mm\^3 without platelet transfusions 7 days prior).

X. To study hematologic function at day 100 (ANC \> 1500, hemoglobin \[Hb\] \> 10 g/dl without transfusion and platelets \> 100,000) XI. To study CD4 recovery at the conclusion of the trial. XII. To study safety in terms of toxicities, infections, transfusions, and infusion-related reactions.

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

EXPLORATORY OBJECTIVE:

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 dose-escalation study of lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced autologous CD34-positive hematopoietic progenitor cells.

Patients receive BEAM or BEAM-R 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 with B-cell lymphoma also receive rituximab on day -6 before chemotherapy and on days 21 and 28 post-transplant as standard of care. Patients undergo intravenous (IV) 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 11

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (anti-HIV gene transduced CD34+ cells)	Laboratory Biomarker Analysis	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Lentivirus Vector CCR5 shRNA/TRIM5alpha/TAR Decoy-transduced Autologous CD34-positive Hematopoietic Progenitor 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.
Treatment (anti-HIV gene transduced CD34+ cells)	Autologous Hematopoietic Stem Cell Transplantation	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Peripheral Blood Stem Cell Transplantation	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Carmustine	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Cytarabine	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Etoposide	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.
Treatment (anti-HIV gene transduced CD34+ cells)	Melphalan	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Achieve a Timely Engraftment	1 month post-transplant	Timely engraftment is defined as a persistent an absolute neutrophil count (ANC) of at least 500 cells/mm3 and a platelet count of at least 20,000 cells/mm3 for at least 3 days

Secondary Outcome Measures

Name	Time	Method
Proportion of Study Participants Who Achieve Greater Than 5% Mononuclear Blood Cells Expressing Anti-HIV Genes in Peripheral Blood	3 months post-transplant	To determine efficacy of the candidate product, defined as establishment of \> 5% mononuclear blood cells expressing anti-HIV genes
Proportion of Study Participants With Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells	Up to 24 months post-transplant	To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells
Quantity of Gene Modified HIV-1 Resistant Peripheral Blood Cells and Gut Mucosal Immune Cells	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.
Integration Sites of Vector Sequences in Circulating Cells	Up to 24 months post-transplant	Single genome sequencing of HIV gp120 and HIV pol will be performed to understand sequence evolution following transplantation and detection of minority resistance variants.
Progression-free Survival	Time from start of study treatment to relapse, progression, or death from any cause	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.
Number of Days From the First Documentation of a Complete Response Until the First Day of Relapse	Time from the first documentation of CR until first date that relapsed or progressive disease is objectively documented, assessed up to 15 years	Complete response is defined as the absence of any disease on imaging or by exam; progressive disease is defined as new lesions or new evidence of disease
Partial Response Rate and Duration	Up to 15 years	Will be assessed following the Lugano Classification. In the absence of evident disease progression, response will be assessed formally at 3, 6, 12 and 24 months post transplant per study calendar.
CD4 Count Recovery	Up to 24 months post-treatment	At six months post-transplant, or later, ART will be voluntarily withheld for a 12 week period only for participants who have a CD4 count of 300 or higher with no detectable viral load. for participants in which the CD4 T-cell count has not risen to ≥ 300 cells/mm3 at the time of the planned ART interruption, ART will continue until the T-cell count has risen to ≥ 300 cells/mm3.
Overall Survival	Up to 15 years	The length of time from the start of treatment until death
Time to Neutrophil Engraftment	Up to 15 years	First measurement of 3 consecutive laboratory values obtained on different days) of ANC \> 500 cells/mm3 .
Time to Platelet Engraftment	Up to 15 years	First measurement of 3 consecutive laboratory values obtained on different days) of platelets \> 20,000 cells/mm3 without platelet transfusions 7 days prior
Number of Participants With an Absolute Neutrophil Count of at Least 1500 Cells/mm3, Hemoglobin of at Least 10 g/dL, and Platelets Greater Than 100,000.	100 days	To study hematologic function at Day 100
Number of Participants With Adverse Events as Assessed by the CTCAE	Up to 15 years	To study safety in terms of the frequency of toxicities, infections, transfusions, and infusion-related reactions
HIV-1 Viral Load	At week 4, months 3, 6, 8, 10, 12, 14, 16, 20, and 24 post-transplant.	To study HIV-1 viral load over time
Persistence of Vector-transduced Cells Over Time	Up to 15 years	Vector stability analysis will be performed via qPRC sequencing.
Number of Participants With a Complete Response	24 months	A complete response is the complete disappearance of any disease, as determined by imaging

Trial Locations

Locations (4): UC San Diego Moores Cancer Center
🇺🇸
La Jolla, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States