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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: HIV
• Intervention / Treatment: Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning

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
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Los Angeles, California, United States, 90035
      • UCLA CARE Center
    • Los Angeles, California, United States, 90069
      • Mills Clinical Research
    • San Francisco, California, United States, 94115
      • Quest Clinical Research
  • Connecticut
    • Norwalk, Connecticut, United States, 06850
      • Circle CARE Center, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level	18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process	Approximately first 1-2 months on study

Other Outcome Measures

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

Collaborators and Investigators

• 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

Publications and helpful links

General 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. doi: 10.1038/mtm.2016.67. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2016
• Primary Completion (Actual): September 20, 2020
• Study Completion (Estimated): August 13, 2024

Study Registration Dates

• First Submitted: March 16, 2015
• First Submitted That Met QC Criteria: July 15, 2015
• First Posted (Estimated): July 17, 2015

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Immune System Diseases; Acquired Immunodeficiency Syndrome; Virus Diseases; HIV Infections; Gene therapy; Sexually Transmitted Diseases, Viral; Immunologic Deficiency Syndromes; Pharmacologic Actions; Busulfan; Sexually Transmitted Diseases; RNA Virus Infections; Retroviridae Infections
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Busulfan
• Other Study ID Numbers: 14017