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

• ClinicalTrials.gov Identifier: NCT02500849
• Recruitment Status: Active, not recruiting
• First Posted: July 17, 2015
• Last Update Posted: December 17, 2020
• Sponsor: City of Hope Medical Center
• Collaborators: Sangamo Therapeutics; California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): City of Hope Medical Center

Tracking Information

• First Submitted Date: March 16, 2015
• First Posted Date: July 17, 2015
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: March 10, 2016
• Estimated Primary Completion Date: March 10, 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 15, 2015): Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level [ Time Frame: 18 months ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: July 15, 2015): Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process [ Time Frame: Approximately first 1-2 months on study ]
• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 15, 2015)

• Detection of CCR5 modified HSPC in bone marrow [ Time Frame: Up to Month 12 ]
• Time to hematological recovery as measured by neutrophil and platelet engraftment time [ Time Frame: Up to Year 5 ]
• Changes in CD4+ T-cell percentage after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
• Changes in CD4+ T-cell number after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
• Changes in CD4/CD8 ratio after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
• Detection of CCR5-modified PBMC in blood over time [ Time Frame: Up to Year 5 ]
• HIV-1 RNA levels in plasma during the treatment interruption of antiretroviral medicines [ Time Frame: ATI Day 0 and weeks 2, 4, 6, 8, 10, 12, 14, 16 and 28 ]
• Longitudinal changes of proviral DNA in PBMC [ Time Frame: 18 months ]
• Pharmacokinetic analysis of busulfan (AUC levels) [ Time Frame: pre-busulfan and at 15, 30, 60, 180 and 240 min after end of infusion ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV

Intervention

Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning

Other Name: busulfan

Study Arms

• Experimental: Cohort 1:
  target busulfan AUC levels: 8,000 µM*min (+/- 1,000)
  Intervention: Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning
• Experimental: Cohort 2:
  busulfan AUC levels: 12,000 µM*min (+/- 1,000)
  Intervention: Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning

• Publications *: 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. eCollection 2016.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 15, 2015): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 10, 2021
• Estimated Primary Completion Date: March 10, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02500849
• Other Study ID Numbers: 14017
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: City of Hope Medical Center
• Study Sponsor: City of Hope Medical Center

Collaborators

• Sangamo Therapeutics
• California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: Amrita Y. Krishnan, MD; City of Hope Medical Center

• PRS Account: City of Hope Medical Center
• Verification Date: December 2020