Safety Study of Zinc Finger Nuclease CCR5-modified Hematopoietic Stem/Progenitor Cells in HIV-1 Infected Patients

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and feasibility of administering SB-728mR-HSPC after conditioning with busulfan.

Detailed Description
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The objective of the study is to evaluate the safety and feasibility of giving autologous SB-728mR-HSPC to HIV-1 (R5) infected patients who are being treated with cART and have undetectable virus but suboptimal CD4+ cell levels. To strengthen the possibility that CCR5-disrupted HSPCs engraft, patients will receive either a two- or three-day (Cohort 1 or Cohort 2) course of busulfan (dose targeting AUC of 4000 µM/day) before being infused with the genetically modified cells. At 9-12 months after SB-728mR-HSPC infusion, subjects who are aviremic with CD4 cell counts ≥600 cells/µL and have ≥1% CCR5-modified CD4 cells within the peripheral blood detected by pentamer PCR will undergo an ATI.

Official Title
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A Pilot Study to Evaluate the Feasibility, Safety and Engraftment of Zinc Finger Nuclease (ZFN) CCR5 Modified CD34+ Hematopoietic Stem/Progenitor Cells (SB-728mR-HSPC) in HIV-1 (R5) Infected Patients

Conditions
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HIV

Intervention / Treatment
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* Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Maximum age 75 years for cohort 1 and 65 years for cohort 2. HIV-1 R5 seropositive with no evidence of CXCR4-tropic virus. On cART with undetectable HIV-1 (<20 gc/ml HIV-1 RNA) for at least 12 months prior to screening evaluations. CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL. No psychosocial conditions that would hinder study compliance and follow-up. Absence of clinically significant cardiomyopathy, congestive heart failure. Secondary Eligibility Criteria (for registration): Complete G-CSF/Plerixafor mobilization of HSPC. Collect ≥7.5 x 10^6 CD34+ cells/kg in two aphereses. The SB-728mR-HSPC product passed all release testing Exclusion Criteria: Use of AZT or maraviroc in the cART regimen. History of significant hematologic diseases such as leukemia, myelodysplasia, coagulopathy, and thromboembolism. Any AIDS-related opportunistic infection occurring within the past year such as tuberculosis, cryptococcosis and for which treatment has been unsuccessful as determined by the Principal Investigator. AIDS-related syndromes, infectious or otherwise, if perceived to cause excessive risk for morbidity post-HSPC infusion, as determined by the Principal Investigator. Patients with active HBV or HCV infection, i.e., HBV DNA and HCV RNA in blood, are excluded. Those with inactive, but past infection with HBV (positive HBV surface antigen or HBV surface antibody) or inactive HCV (positive HCV antibody), must have no cirrhosis, as determined by abdominal ultrasound with elastography. Active CMV retinitis or other active CMV-related organ dysfunction. CXCR4-tropic virus. Pregnant or nursing women. Any history of HIV-associated encephalopathy; dementia of any kind; seizures in the past 12 months; any perceived inability to directly provide informed consent. Participants may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy. Participation in prior investigational drug or medical device study within the previous 45 days. Current or history of immunomodulatory agent or steroid use. Prior therapy with HIV vaccine or gene therapy product. History of alcohol or substance abuse for the previous 12 months. Participants with active malignancies. However, participants with skin cancers, namely basal cell or squamous cell carcinoma, and malignancies treated with curative intent having no known active disease present for ≥2 years, may be eligible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1:<br>target busulfan AUC levels: 8,000 µM*min (+/- 1,000) | Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning<br> <br> * Other names: busulfan;|
| Experimental: Cohort 2:<br>busulfan AUC levels: 12,000 µM*min (+/- 1,000) | Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning<br> <br> * Other names: busulfan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process |  | Approximately first 1-2 months on study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, Acquired Immunodeficiency Syndrome, HIV Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases, Immunologic Deficiency Syndromes, Immune System Diseases, Busulfan, Pharmacologic Actions