Gene Therapy After Frontline Chemotherapy in Treating Patients With AIDS-Related Non-Hodgkin Lymphoma
This pilot clinical trial studies gene therapy after frontline chemotherapy in treating patients with acquired immune deficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). Placing genes for anti-human immunodeficiency virus (HIV) ribonucleic acid (RNA) into stem/progenitor cells may make the body build an immune response to AIDS. Giving the chemotherapy drug busulfan before gene therapy can help gene-modified cells engraft and work better.
AIDS-related Diffuse Large Cell Lymphoma
AIDS-related Diffuse Mixed Cell Lymphoma
AIDS-related Diffuse Small Cleaved Cell Lymphoma
AIDS-related Immunoblastic Large Cell Lymphoma
AIDS-related Lymphoblastic Lymphoma
AIDS-related Small Noncleaved Cell Lymphoma
Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Safety and Feasibility of Gene Transfer After Frontline Chemotherapy for Non-Hodgkin Lymphoma in AIDS Patients Using Peripheral Blood Stem/Progenitor Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs|
- Procedure related toxicity as determined by adverse events (AE) grading scale using the Common Terminology Criteria for Adverse Events CTCAE) version v4.03 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]Tables will be created to summarize these toxicities and side effects.
- Time to Absolute Neutrophil Count (ANC) >= 500/uL [ Time Frame: First 30 days ] [ Designated as safety issue: Yes ]
- Time to platelet recovery to >= 50,000/uL [ Time Frame: First 90 days ] [ Designated as safety issue: Yes ]
- Evidence for and duration of vector-marked PBMC/marrow cells [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]PCR-based assay on PBMC
- Expression of the RNA transgenes in lineage-specific progeny of the transduced cells [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]PCR-based assay on FACS-sorted cells
- Effect of ATI on HIV markers and CD4 count [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]HIV proviral DNA, HIV RNA single copy, and 2-LTR circle DNA from PBMCs
- Pharmacokinetics of busulfan [ Time Frame: Day -2 at 0 hours (pre-infusion); 3 hours (just before end of infusion); and at 4, 5, and 6 hours and day -1 at 24 hours ] [ Designated as safety issue: No ]Cmax, CLsys, Vd, t1/2's, AUC
- Ability to obtain suitable numbers of transduced HSPC for engraftment [ Time Frame: Pre-infusion of the investigational drug ] [ Designated as safety issue: No ]The number and type of cells will be determined by fluorescence activated cell sorting (FACS) analysis of the final cell product. The minimum target number of CD34+ cells for collection is 7.5 x 10e6 cells/kg and, in the final transduced cell product, the number of CD34+ cells must be >= 2.0 x 10e6 CD34+ cells/kg with total viability >= 70%.
- Feasibility of product manufacturing as evidenced by product release [ Time Frame: Pre-infusion of the investigational drug ] [ Designated as safety issue: No ]Release assays
|Study Start Date:||June 2014|
|Estimated Primary Completion Date:||June 2031 (Final data collection date for primary outcome measure)|
Experimental: Treatment (gene therapy)
Patients receive busulfan IV over 3 hours on day -2 followed by lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells IV on day 0.
Other Names:Biological: lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells
Other Name: lentivirus-transduced hematopoietic progenitor cellsOther: pharmacological study
Correlative studiesOther: laboratory biomarker analysis
I. To demonstrate the safety and feasibility of recombinant (r)HIV7-short hairpin RNA targeted to the HIV-1 tat/rev (shI)-trans-active response element (TAR)-chemokine cysteine-cysteine receptor 5 ribozyme (CCR5RZ)-treated hematopoietic stem progenitor cells (HSPC) (lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells) infusion in AIDS patients completing treatment for NHL and non-myeloablative conditioning with busulfan.
II. To demonstrate the engraftment of gene-modified progeny cells following such treatment.
III. To determine if selection of these gene-modified progeny cells occurs during analytical treatment interruption (ATI) of combination anti-retroviral therapy (cART).
I. To evaluate the pharmacokinetics of busulfan in patients with AIDS-related lymphoma (ARL).
II. To determine the effects of HIV-1 infection on the presence of gene-marked peripheral blood mononuclear cells (PBMC) as measured by woodchuck post-transcriptional regulatory element (WPRE) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) performed before, during, and after ATI.
OUTLINE: Patients receive busulfan intravenously (IV) over 3 hours on day -2 followed by lentivirus vector rHIV7-shI-TAR-CCR5RZ-transduced hematopoietic progenitor cells IV on day 0.
After completion of study treatment, patients are followed up at 1, 7, 14, and 21 days and 1, 2, 3, 6, 9, 12, 18, and 24 months and then annually for 13 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01961063
|United States, California|
|City of Hope Medical Center||Recruiting|
|Duarte, California, United States, 91010|
|Contact: Amrita Y. Krishnan 626-256-4673 AKrishnan@coh.org|
|Principal Investigator: Amrita Y. Krishnan|
|Principal Investigator:||Amrita Krishnan||City of Hope Medical Center|