Repeat Doses of SB-728mR-T After Cyclophosphamide Conditioning in HIV-Infected Subjects on HAART

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of repeat doses of T-cell immunotherapy (SB-728mR-T) following cyclophosphamide conditioning. CCR5 is a major co-receptor for HIV entry into T-cells. Disruption of CCR5 by zinc finger nuclease (SB-728mR), blocks HIV entry into the T-cells, therefore, protects the T-cells from HIV infection. Safety (primary outcome) and anti-viral effect (secondary outcome) of zinc finger nuclease-mediated CCR5 disrupted autologous T-cells (SB-728mR-T) will be evaluated in the study.

Official Title
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A Phase 1/2, Open-Label Study to Assess the Safety and Tolerability of Repeat Doses of Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Subjects Following Cyclophosphamide Conditioning

Conditions
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Human Immunodeficiency Virus (HIV)

Intervention / Treatment
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* Genetic: SB-728mR-T
* Genetic: SB-728mR-T
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 years of age or older with documented HIV diagnosis. Must be willing to comply with study-mandated evaluations; including discontinuation of current antiretroviral therapy during the treatment interruption. Initiated HAART therapy within (≤) 1 year of HIV diagnosis or suspected infection. Undetectable HIV-1 RNA for at least 2 months prior to screening and at screening. CD4+ T-cell count ≥500 cells/µL. Absolute neutrophil count (ANC) ≥ 2500/mm3. Platelet count ≥ 200,000/mm3. Exclusion Criteria: Acute or chronic hepatitis B or hepatitis C infection. Active or recent (in prior 6 months) AIDS defining complication. Any cancer or malignancy within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin or low grade (0 or 1) anal or cervical dysplasia. Current diagnosis of NYHA grade 3 or 4 CHF, uncontrolled angina or uncontrolled arrhythmias. History or any features on physical examination indicative of a bleeding diathesis. Received HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector. Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents within 30 days prior to screening. Use of Aspirin, dipyridamole, warfarin or any other medication that is likely to affect platelet function or other aspects of blood coagulation during the 2 week period prior to leukapheresis. Currently participating in another clinical trial or participation in such a trial within 30 days prior to screening visit. Currently taking maraviroc or have received maraviroc within 6 months prior to screening.

Ages Eligible for Study
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Minimum Age: 18 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> | Genetic: SB-728mR-T<br>* -SB-728mR-T infusions of 2 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells)<br>Drug: Cyclophosphamide<br>* - IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion<br>|
| Experimental: Cohort 2<br> | Genetic: SB-728mR-T<br>* - SB-728mR-T infusions of 3 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells)<br>Drug: Cyclophosphamide<br>* - IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome Measure | Number of Participants with Treatment related Adverse Events in subjects who received any portion of the SB-728mR-T infusion | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcome Measure | Effect of repeat doses of SB-728mR-T on engraftment following cyclophosphamide conditioning as measured by CCR5 Modified CD4 Cells at Month 12. | 12 months | 
| Secondary Outcome Measure | Effect of SB-728mR-T on plasma HIV-1 RNA levels following HAART interruption | 12 months | 
| Secondary Outcome Measure | Change from baseline to month 12 in CD4+ T-cell counts in peripheral blood after repeat treatments with SB-728mR-T. (i.e. month 12 value - baseline value) | Baseline and 12 months |