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

HIV Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02500849
• Other study ID #: 14017
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: March 10, 2016
• Est. completion date: August 13, 2024

Study information

• Verified date: January 2024
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 12
• Est. completion date: August 13, 2024
• Est. primary completion date: September 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• HIV

Intervention

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

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California
United States	Mills Clinical Research	Los Angeles	California
United States	UCLA CARE Center	Los Angeles	California
United States	Circle CARE Center, LLC	Norwalk	Connecticut
United States	Quest Clinical Research	San Francisco	California

Sponsors (3)

Lead Sponsor	Collaborator
City of Hope Medical Center	California Institute for Regenerative Medicine (CIRM), Sangamo Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Detection of CCR5 modified HSPC in bone marrow		Up to Month 12
Other	Time to hematological recovery as measured by neutrophil and platelet engraftment time		Up to Year 5
Other	Changes in CD4+ T-cell percentage after SB-728mR-HSPC infusion		Up to Year 5
Other	Changes in CD4+ T-cell number after SB-728mR-HSPC infusion		Up to Year 5
Other	Changes in CD4/CD8 ratio after SB-728mR-HSPC infusion		Up to Year 5
Other	Detection of CCR5-modified PBMC in blood over time		Up to Year 5
Other	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
Other	Longitudinal changes of proviral DNA in PBMC		18 months
Other	Pharmacokinetic analysis of busulfan (AUC levels)		pre-busulfan and at 15, 30, 60, 180 and 240 min after end of infusion
Primary	Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level		18 months
Secondary	Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process		Approximately first 1-2 months on study