HIV Infections
Conditions
Brief summary
A Comparative Study of Autologous CD4+ T Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 versus ex vivo Expanded Unmodified Autologous CD4+ T Cells in Treated HIV-1 Infected Subjects
Detailed description
This is a randomized clinical trial comparing the effect of infusing expanded autologous CD4+ T cells with or without ex vivo modification of the CCR5 gene by zinc finger nucleases among HIV-infected patients with plasma HIV RNA levels \<50 copies/mL for at least 48 weeks and CD4+ T cell counts greater than 350 cells/µL. The main hypothesis is that the infusion of modified CD4+ T cells will lead to a reduction in the size of the replication-competent HIV reservoir, that is greater than that resulting from infusion of unmodified CD4+ T cells. A total of 30 participants will be randomized to receive one infusion of 0.5 - 4 x 1010 ex vivo expanded autologous CD4+ T cells that have been either modified by transduction with a zinc finger nuclease designed to cleave CCR5 (arm 1, n=20) or unmodified (arm 2, n=10). All participants will be pre-treated with cyclophosphamide at a dose of 1 g/m2 before infusion. The primary outcome measure the difference in the magnitude of change in intact provirus from before infusion to 96 weeks after infusion between the two study arms.
Interventions
BIOLOGICALSB-728-T
Autologous CD4+ T cells with ex vivo modification of the CCR5 gene by zinc finger nucleases
BIOLOGICALExpanded unmodified autologous CD4+ T cells
Autologous CD4+ T cells without ex vivo modification of the CCR5 gene by zinc finger nucleases
Sponsors
University of California, San Francisco
Case Western Reserve University
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind
Intervention model description
Randomized, double-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent signed and dated by study subject. 2. Men or women, including trans men or women, ≥18 and ≤70 years of age. 3. For persons born male who have not been surgically sterilized, willingness to abstain from sexual activity that could result in conception for 90 days after the cyclophosphamide administration visit. 4. HIV-1 infection, documented by any FDA-approved ELISA, EIA, or rapid antibody detection method, and confirmed by a second FDA-approved antibody-based test or by a positive FDA-approved HIV RNA detection assay. FDA-approved HIV-1 RNA detection assay alone constitutes proof of HIV-1 infection assuming there is documentation of \>199 copies/mL of HIV-1 RNA in the absence of antiretroviral therapy. 5. Adequate venous access for leukapheresis, as documented by standard clinical procedures at each site. 6. The following laboratory values at screening: 1. Absolute neutrophil count (ANC) \> 1500/mm3 2. Hemoglobin level ≥11 g/dL 3. Platelet count ≥150,000/mm3 4. Serum creatinine \<1.5 mg/dL 5. AST and ALT ≤2.5 times the upper limit of normal 6. CD4+ T cell count \> 350 cells/mm3 7. HIV-1 RNA \<50 copies/mL performed with an ultrasensitive HIV-1 PCR assay. 8. Urine red blood cell (RBC) counts within the normal range used by each institution. 9. INR ≤1.5 and PTT ≤2xULN 7. Willing to comply with study-mandated evaluations. 8. All participants must have received combination antiretroviral therapy, and had plasma HIV RNA levels \<50 copies/mL for at least 48 weeks. Subjects who had intermittent isolated episodes of detectable low-level viremia \<500 copies RNA/mL flanked by values \<50 copies/mL will remain eligible. 9. On stable antiretroviral medication (no changes to treatment and no missed dose for \>7 continuous days within 4 weeks of screening) and willing to continue on current antiretroviral therapy, unless a change is medically indicated, for the duration of the study. Note: Changes in formulation or a single within-class, single-agent change are permitted in the last 48 weeks but not within 12 weeks of study entry.
Exclusion criteria
1. Women and persons born female regardless of gender identity with childbearing potential. These participants are considered to be of childbearing potential if they are postmenarchial, have an intact uterus and at least one ovary, and have had at least one menstrual period in the past two years. Participants who have had a documented bilateral tubal ligation or a hysterectomy are not considered to be of childbearing potential. 2. Previous gene therapy using an integrating vector. NOTE: For the purposes of the TRAILBLAZER protocol, only therapies that a) are expected to modify the host genome durably or broadly, and b) are delivered using a vector defined by FDA as having a propensity for integration or the potential for latency/reactivation meet this exclusion criterion. The following are examples of products and vectors that DO NOT meet this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the magnitude of change in intact provirus from before infusion to 96 weeks after infusion between the two study arms. | 96 weeks | Difference in the magnitude of change in intact provirus from before infusion to 96 weeks after infusion between the two study arms. |
| Difference in the proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment between the two study arms. | 96 weeks | Difference in the proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment between the two study arms. |
| Proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment in each of the study arms. | 24 months | Proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment in each of the study arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral CD4+ T cell count at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in each study arm. | 96 weeks | Peripheral CD4+ T cell count at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in each study arm. |
| Frequency of pentamer PCR-positive CD4+ T cells in peripheral blood at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in the CCR5-modified study arm | 96 weeks | Frequency of pentamer PCR-positive CD4+ T cells in peripheral blood at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in the CCR5-modified study arm |
| Difference in the magnitude of change in intact provirus from before infusion to 48 weeks after infusion between the two study arms. | 48 weeks | Difference in the magnitude of change in intact provirus from before infusion to 48 weeks after infusion between the two study arms. |
| Frequency of pentamer PCR-positive CD4+ T cells in cell suspensions of lymph node biopsy tissue | 96 weeks | Frequency of pentamer PCR-positive CD4+ T cells in cell suspensions of lymph node biopsy tissue |
| Frequency of pentamer PCR-positive CD4+ T cells in CSF | 96 weeks | Frequency of pentamer PCR-positive CD4+ T cells in CSF |
| Frequency of pentamer PCR-positive CD4+ T cells in cell suspensions of rectal biopsy tissue | 96 weeks | Frequency of pentamer PCR-positive CD4+ T cells in cell suspensions of rectal biopsy tissue |
| Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 48 visit. | 48 weeks | Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 48 visit. |
| Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 96 visit. | 96 weeks | Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 96 visit. |
Countries
United States
Outcome results
None listed