Human Immunodeficiency Virus (HIV)
Conditions
Brief summary
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.
Interventions
GENETICSB-728mR-T
-SB-728mR-T infusions of 2 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells)
DRUGCyclophosphamide
\- IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion
Sponsors
Sangamo Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Outcome Measure | 12 months | Number of Participants with Treatment related Adverse Events in subjects who received any portion of the SB-728mR-T infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Outcome Measure | 12 months | Effect of repeat doses of SB-728mR-T on engraftment following cyclophosphamide conditioning as measured by CCR5 Modified CD4 Cells at Month 12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 SB-728mR-T infusions of 2 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells)
Cyclophosphamide: - IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion | 3 |
| Cohort 2 SB-728mR-T infusions of 3 equal doses 14 days apart (total of up to 40 billion ZFN modified T-cells)
Cyclophosphamide: - IV cyclophosphamide 1 g/m2 two days prior to the first SB-728mR-T infusion | 5 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Subject moved from area and finds it difficult to return for visits. | 1 | 0 |
| Overall Study | Subject restarted HAART prior to month 18. | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 1 |
|---|---|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 10.09 | 46.9 years STANDARD_DEVIATION 13.35 | 59.0 years STANDARD_DEVIATION 8.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 5 |
Outcome results
Primary
Primary Outcome Measure
Number of Participants with Treatment related Adverse Events in subjects who received any portion of the SB-728mR-T infusion
Time frame: 12 months
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Primary Outcome Measure | 1 Participants |
| Cohort 2 | Primary Outcome Measure | 2 Participants |
Secondary
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.
Time frame: 12 months
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Secondary Outcome Measure | 0.090 cells 10^9/L | Standard Deviation 0.0015 |
| Cohort 2 | Secondary Outcome Measure | 0.162 cells 10^9/L | Standard Deviation 0.0818 |
Secondary
Secondary Outcome Measure
Effect of SB-728mR-T on plasma HIV-1 RNA levels following HAART interruption
Time frame: 12 months
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Secondary Outcome Measure | 3.218 log copies/mL | Standard Deviation 1.9243 |
| Cohort 2 | Secondary Outcome Measure | 1.228 log copies/mL | Standard Deviation 1.7029 |
Secondary
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)
Time frame: Baseline and 12 months
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Secondary Outcome Measure | -0.178 cells 10^9/L | Standard Deviation 0.0445 |
| Cohort 2 | Secondary Outcome Measure | 0.078 cells 10^9/L | Standard Deviation 0.2796 |