Clinical Trials

MainTitle

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

This study is currently recruiting participants. (see Contacts and Locations)

Verified September 2017 by City of Hope Medical Center

Sponsor
City of Hope Medical Center

Collaborator
Sangamo Therapeutics

Information provided by (Responsible Party)
City of Hope Medical Center
ClinicalTrials.gov Identifier
NCT02500849

First received: March 16, 2015
Last updated: September 1, 2017
Last Verified: September 2017
History of Changes
Purpose

Purpose

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

Condition Intervention Phase
HIV

Genetic : SB-728mR-HSPC Infusion 3 days following busulfan conditioning
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures

  • Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level [ Time Frame: 18 months ]
Secondary Outcome Measures:
  • Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process [ Time Frame: Approximately first 1-2 months on study ]
Other Outcome Measures:
  • 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 ]

Estimated Enrollment: 12
Study Start Date: July 2015
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

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

Eligibility

Ages Eligible for Study: 18 Years to 75 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

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.

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02500849

Contacts

Contact:   Rodica Stan, PhD 626-218-8330 rstan@coh.org

Locations

United States, California
City of Hope Medical Center Not yet recruiting
Duarte, California, United States, 91010
Contact: Rodica Stan, PhD    626-218-8330    rstan@coh.org
Principal Investigator: Amrita Y. Krishnan, MD
UCLA CARE Center Recruiting
Los Angeles, California, United States, 90035
Contact: Maricella Gonzalez    310-557-3729    mmgonzalez@mednet.ucla.edu
Principal Investigator: Ronald Mitsuyasu, MD
Mills Clinical Research Recruiting
Los Angeles, California, United States, 90069
Contact: Sandro Antunes    310-550-2271    Sandro.Antunes@millsclinicalresearch.com
Principal Investigator: Anthony Mills, MD
Palmtree Clinical Research, Inc. Recruiting
Palm Springs, California, United States, 92262
Contact: Erik Hernandez    760-902-9615    ehernandez@palmtreeclinical.com
Principal Investigator: Richard A. Loftus, MD
Quest Clinical Research Recruiting
San Francisco, California, United States, 94115
Contact: Nora Darago    415-353-0800    ndarago@estudysite.com
Principal Investigator: Sandra S. Win, MD
United States, Connecticut
Circle CARE Center, LLC Recruiting
Norwalk, Connecticut, United States, 06850
Contact: Greg Ulrich, RN    203-852-9525    gulrich@whcccc.org
Contact: Patricia R Garton, APRN    203-852-9525    tgarton@whcccc.org
Principal Investigator: David Rubin, MD
United States, Florida
Gary J. Richmond, MD, PA Recruiting
Fort Lauderdale, Florida, United States, 33316
Contact: Vernon F. Appleby, RN    954-524-2250 ext 211    vfappleby@earthlink.net
Principal Investigator: Gary J. Richmond, MD

Sponsors and Collaborators

City of Hope Medical Center
Sangamo Therapeutics

Investigators

Principal Investigator: Amrita Y. Krishnan, MD City of Hope Medical Center
More Information

More Information


Responsible Party: City of Hope Medical Center  
ClinicalTrials.gov Identifier: NCT02500849   History of Changes  
Other Study ID Numbers: 14017  
Study First Received: March 16, 2015  
Last Updated: September 1, 2017  

Keywords provided by City of Hope Medical Center:

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

Additional relevant MeSH terms:
Busulfan

ClinicalTrials.gov processed this data on December 15, 2017
This information is provided by ClinicalTrials.gov.