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 introduce...

Detailed Description

PRIMARY OBJECTIVE:
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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2016-06-08
• Study First Submitted QC: 2016-06-08
• Study First Posted: 2016-06-13
• Study Start: 2016-06-23
• Primary Completion: 2021-05-13
• Results First Submitted: 2023-06-02
• Results First Submitted QC: 2023-07-18
• Results First Posted: 2023-07-20
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-29
• Last Update Posted: 2024-07-31
• Study Completion: 2025-06-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 11

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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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 rise...
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