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

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ClinicalTrials.gov Identifier: NCT02500849
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : June 4, 2018
Sponsor:
Collaborator:
Sangamo Therapeutics
Information provided by (Responsible Party):
City of Hope Medical Center

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

Condition or disease Intervention/treatment Phase
HIV Genetic: SB-728mR-HSPC Infusion 3 days following busulfan conditioning Phase 1

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  (Clinical Trial)
Estimated Enrollment : 12 participants
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
Study Start Date : July 2015
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Busulfan

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 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




Primary Outcome Measures :
  1. Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level [ Time Frame: 18 months ]

Secondary Outcome Measures :
  1. 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:
  1. Detection of CCR5 modified HSPC in bone marrow [ Time Frame: Up to Month 12 ]
  2. Time to hematological recovery as measured by neutrophil and platelet engraftment time [ Time Frame: Up to Year 5 ]
  3. Changes in CD4+ T-cell percentage after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
  4. Changes in CD4+ T-cell number after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
  5. Changes in CD4/CD8 ratio after SB-728mR-HSPC infusion [ Time Frame: Up to Year 5 ]
  6. Detection of CCR5-modified PBMC in blood over time [ Time Frame: Up to Year 5 ]
  7. 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 ]
  8. Longitudinal changes of proviral DNA in PBMC [ Time Frame: 18 months ]
  9. Pharmacokinetic analysis of busulfan (AUC levels) [ Time Frame: pre-busulfan and at 15, 30, 60, 180 and 240 min after end of infusion ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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: Maricela 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         
Quest Clinical Research Recruiting
San Francisco, California, United States, 94115
Contact: Grace Gonzaga    415-353-0800    grace@questclinical.com   
Principal Investigator: Jay Lalezari, 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         
Sponsors and Collaborators
City of Hope Medical Center
Sangamo Therapeutics
Investigators
Principal Investigator: Amrita Y. Krishnan, MD City of Hope Medical Center

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02500849     History of Changes
Other Study ID Numbers: 14017
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: June 2018

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
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists