Clinical trial NCT02500849: Safety Study of Zinc Finger Nuclease CCR5-modified Hematopoietic Stem/Progenitor Cells in HIV-1 Infected Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: HIV
Keywords: 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
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: Sangamo Therapeutics
name: California Institute for Regenerative Medicine (CIRM)
First posted: 2015-07-17
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level
timeFrame: 18 months
Secondary outcomes:
measure: Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process
timeFrame: Approximately first 1-2 months on study
Other outcomes:
measure: Detection of CCR5 modified HSPC in bone marrow
timeFrame: Up to Month 12
measure: Time to hematological recovery as measured by neutrophil and platelet engraftment time
timeFrame: Up to Year 5
measure: Changes in CD4+ T-cell percentage after SB-728mR-HSPC infusion
timeFrame: Up to Year 5
measure: Changes in CD4+ T-cell number after SB-728mR-HSPC infusion
timeFrame: Up to Year 5
measure: Changes in CD4/CD8 ratio after SB-728mR-HSPC infusion
timeFrame: Up to Year 5
measure: Detection of CCR5-modified PBMC in blood over time
timeFrame: Up to Year 5
measure: HIV-1 RNA levels in plasma during the treatment interruption of antiretroviral medicines
timeFrame: ATI Day 0 and weeks 2, 4, 6, 8, 10, 12, 14, 16 and 28
measure: Longitudinal changes of proviral DNA in PBMC
timeFrame: 18 months
measure: Pharmacokinetic analysis of busulfan (AUC levels)
timeFrame: pre-busulfan and at 15, 30, 60, 180 and 240 min after end of infusion
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center
state: California
city: Los Angeles
country: United States
facility: Mills Clinical Research
state: California
city: San Francisco
country: United States
facility: Quest Clinical Research
state: California
city: Norwalk
country: United States
facility: Circle CARE Center, LLC
state: Connecticut
Study officials:
affiliation: City of Hope Medical Center
name: Amrita Y. Krishnan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: DiGiusto DL, Cannon PM, Holmes MC, Li L, Rao A, Wang J, Lee G, Gregory PD, Kim KA, Hayward SB, Meyer K, Exline C, Lopez E, Henley J, Gonzalez N, Bedell V, Stan R, Zaia JA. Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells. Mol Ther Methods Clin Dev. 2016 Nov 9;3:16067. doi: 10.1038/mtm.2016.67. eCollection 2016.