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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02500849
Recruitment Status : Active, not recruiting
First Posted : July 17, 2015
Last Update Posted : May 1, 2019
Sponsor:
Collaborators:
Sangamo Therapeutics
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE March 16, 2015
First Posted Date  ICMJE July 17, 2015
Last Update Posted Date May 1, 2019
Study Start Date  ICMJE July 2015
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE 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  ICMJE Safety Study of Zinc Finger Nuclease CCR5-modified Hematopoietic Stem/Progenitor Cells in HIV-1 Infected Patients
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV
Intervention  ICMJE Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning
Other Name: busulfan
Study Arms  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2015)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2022
Estimated Primary Completion Date April 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02500849
Other Study ID Numbers  ICMJE 14017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE
  • Sangamo Therapeutics
  • California Institute for Regenerative Medicine (CIRM)
Investigators  ICMJE
Principal Investigator: Amrita Y. Krishnan, MD City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP