HIV
Conditions
Keywords
HIV, autologous cell therapy, cyclophosphamide
Brief summary
The purpose of the study is to evaluate the safety, tolerability and effect on HIV viral load, of escalating doses of cyclophosphamide administered 1 day prior to SB-728-T infusion.
Detailed description
The objectives of the study are to augment HIV-specific T-cells and to reverse or decrease the progressive destruction of CD4+ T-cells that leads to clinical AIDS. Levels of engraftment vary from negligible to about 10% of the CD4+ T-cells in the vascular compartment. Preliminary analyses of HAART TI suggest that an anti-HIV effect may correlate with the level of SB-728-T engraftment. Concurrently, non-myeloablative lymphodepletion with cyclophosphamide has been demonstrated to enhance engraftment of adoptively transferred T-cells through a variety of mechanisms. The study is being undertaken to increase SB-728-T engraftment through the administration of low non-myeloablative doses of cyclophosphamide.
Interventions
GENETICSB-728-T
Infusion will be 5 to 30 billion ZFN modified CD4+ T cells 1 day following IV cyclophosphamide 200 mg
Sponsors
Sangamo Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
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 within 10 years of screening. * Must be willing to comply with study-mandated evaluations; including discontinuation of current antiretroviral therapy during the treatment interruption. * Must have received at least 6 months of continuous HAART therapy and have had undetectable VLs for the preceding 3 months. * On stable antiretroviral medication (no changes to treatment within 4 weeks of screening. * CD4+ T-cell count ≥500 cells/µL. * Undetectable HIV-1 RNA obtained at screening. * ANC ≥2500/µL * Platelet count ≥200,000/µL
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 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. * Subjects who are currently taking maraviroc or have received maraviroc within 6 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events | 28 days after the SB-728-T infusion of the last subject in each Cohort and up to 12 months | Number of Participants with Treatment related Adverse Events in subjects who received any portion of the SB-728-T infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | Up to 12 months after the last SB-728-T infusion | Effect of repeat doses of SB-728-T on engraftment following cyclophosphamide conditioning as measured by CCR5 Modified CD4 Cells in blood at Month 12. |
| Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | Up to 12 months after the last SB-728-T infusion | Effect of SB-728-T on plasma HIV-1 RNA levels following HAART interruption. The unit is log copies/mL, except for the Cohort 1, the unit is copies/mL. Cohort 1 mean and SD are 0. All 3 subjects had NO HIV-1 RNA DETECTED. |
| Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | Up to 12 months after the last SB-728-T infusion | Change from baseline to month 12 in CD4+ T-cell counts in peripheral blood after repeat treatments with SB-728-T. (i.e. month 12 value - baseline value) |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - IV Cyclophosphamide 200 mg SB-728-T: Infusion will be 5 to 30 billion ZFN modified CD4+ T cells 1 day following IV cyclophosphamide 200 mg | 3 |
| Cohort 2 - IV Cyclophosphamide 0.5 g/m2 SB-728-T: Infusion will be 5 to 30 billion ZFN modified CD4+ T cells up to 3 days following IV cyclophosphamide 0.5 g/m2 | 6 |
| Cohort 3 - IV Cyclophosphamide 1.0 g/m2 SB-728-T: Infusion will be 5 to 30 billion ZFN modified CD4+ T cells up to 3 days following IV cyclophosphamide 1.0 g/m2 | 11 |
| Cohort 4 - IV Cyclophosphamide 2.0 g/m2 SB-728-T: Infusion will be 5 to 30 billion ZFN modified CD4+ T cells up to 3 days following IV cyclophosphamide 2.0 g/m2 | 3 |
| Cohort 5 - IV Cyclophosphamide 1.5 g/m2 SB-728-T: Infusion will be 5 to 30 billion ZFN modified CD4+ T cells up to 3 days following IV cyclophosphamide 1.5 g/m2 | 3 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - IV Cyclophosphamide 200 mg | Cohort 2 - IV Cyclophosphamide 0.5 g/m2 | Cohort 3 - IV Cyclophosphamide 1.0 g/m2 | Cohort 4 - IV Cyclophosphamide 2.0 g/m2 | Cohort 5 - IV Cyclophosphamide 1.5 g/m2 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 44.7 years STANDARD_DEVIATION 8.08 | 43.2 years STANDARD_DEVIATION 6.11 | 41.5 years STANDARD_DEVIATION 12.13 | 35.3 years STANDARD_DEVIATION 10.21 | 50.0 years STANDARD_DEVIATION 1 | 42.5 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 8 Participants | 3 Participants | 2 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 6 Participants | 9 Participants | 2 Participants | 2 Participants | 21 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 10 Participants | 3 Participants | 3 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 11 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 11 / 11 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 0 / 6 | 0 / 11 | 1 / 3 | 0 / 3 |
Outcome results
Primary
Treatment-emergent Adverse Events
Number of Participants with Treatment related Adverse Events in subjects who received any portion of the SB-728-T infusion
Time frame: 28 days after the SB-728-T infusion of the last subject in each Cohort and up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - IV Cyclophosphamide 200 mg | Treatment-emergent Adverse Events | 3 participants |
| Cohort 2 - IV Cyclophosphamide 0.5 g/m2 | Treatment-emergent Adverse Events | 6 participants |
| Cohort 3 - IV Cyclophosphamide 1.0 g/m2 | Treatment-emergent Adverse Events | 11 participants |
| Cohort 4 - IV Cyclophosphamide 2.0 g/m2 | Treatment-emergent Adverse Events | 3 participants |
| Cohort 5 - IV Cyclophosphamide 1.5 g/m2 | Treatment-emergent Adverse Events | 3 participants |
Secondary
Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value)
Change from baseline to month 12 in CD4+ T-cell counts in peripheral blood after repeat treatments with SB-728-T. (i.e. month 12 value - baseline value)
Time frame: Up to 12 months after the last SB-728-T infusion
Population: Safety Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - IV Cyclophosphamide 200 mg | Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | 0.064 cells 10^9/L | Standard Deviation 0.1309 |
| Cohort 2 - IV Cyclophosphamide 0.5 g/m2 | Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | 0.149 cells 10^9/L | Standard Deviation 0.3736 |
| Cohort 3 - IV Cyclophosphamide 1.0 g/m2 | Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | -0.043 cells 10^9/L | Standard Deviation 0.1712 |
| Cohort 4 - IV Cyclophosphamide 2.0 g/m2 | Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | 0.153 cells 10^9/L | Standard Deviation 0.3247 |
| Cohort 5 - IV Cyclophosphamide 1.5 g/m2 | Change From Baseline to Month 12 in CD4+ T-cell Counts in Peripheral Blood After Repeat Treatments With SB-728-T. (i.e. Month 12 Value - Baseline Value) | 0.099 cells 10^9/L | Standard Deviation 0.3279 |
Secondary
Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood.
Effect of repeat doses of SB-728-T on engraftment following cyclophosphamide conditioning as measured by CCR5 Modified CD4 Cells in blood at Month 12.
Time frame: Up to 12 months after the last SB-728-T infusion
Population: Safety Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - IV Cyclophosphamide 200 mg | Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | 0.038 cells 10^9/L | Standard Deviation 0.0409 |
| Cohort 2 - IV Cyclophosphamide 0.5 g/m2 | Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | 0.061 cells 10^9/L | Standard Deviation 0.0447 |
| Cohort 3 - IV Cyclophosphamide 1.0 g/m2 | Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | 0.143 cells 10^9/L | Standard Deviation 0.1055 |
| Cohort 4 - IV Cyclophosphamide 2.0 g/m2 | Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | 0.085 cells 10^9/L | Standard Deviation 0.0197 |
| Cohort 5 - IV Cyclophosphamide 1.5 g/m2 | Effect of Escalating Doses of Cyclophosphamide on SB-728-T Engraftment as Measured by CCR5 Modified CD4 Cells in Blood. | 0.079 cells 10^9/L | Standard Deviation 0.0155 |
Secondary
Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption
Effect of SB-728-T on plasma HIV-1 RNA levels following HAART interruption. The unit is log copies/mL, except for the Cohort 1, the unit is copies/mL. Cohort 1 mean and SD are 0. All 3 subjects had NO HIV-1 RNA DETECTED.
Time frame: Up to 12 months after the last SB-728-T infusion
Population: Safety Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - IV Cyclophosphamide 200 mg | Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | 0 log copies/mL | Standard Deviation 0 |
| Cohort 2 - IV Cyclophosphamide 0.5 g/m2 | Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | 0.250 log copies/mL | Standard Deviation 0.5 |
| Cohort 3 - IV Cyclophosphamide 1.0 g/m2 | Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | 1.537 log copies/mL | Standard Deviation 1.3955 |
| Cohort 4 - IV Cyclophosphamide 2.0 g/m2 | Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | 0.667 log copies/mL | Standard Deviation 0.5774 |
| Cohort 5 - IV Cyclophosphamide 1.5 g/m2 | Effect of SB-728-T on Plasma HIV-1 RNA Levels Following HAART Interruption | 3.442 log copies/mL | Standard Deviation 1.1545 |