CCR5-modified CD4+ T Cells for HIV Infection

NCT03666871 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: TRAILBLAZER
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

A Comparative Study of Autologous CD4+ T Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 versus ex vivo Expanded Unmodified Autologous CD4+ T Cells in Treated HIV-1 Infected Subjects

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (3)

• Difference in the magnitude of change in intact provirus from before infusion to 96 weeks after infusion between the two study arms.

  Difference in the magnitude of change in intact provirus from before infusion to 96 weeks after infusion between the two study arms.

  96 weeks

• Difference in the proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment between the two study arms.

  Difference in the proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment between the two study arms.

  96 weeks

• Proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment in each of the study arms.

  Proportion of participants who experience a grade ≥3 adverse event that is considered possibly, probably, or definitely related to study treatment in each of the study arms.

  24 months

Secondary Outcomes (8)

• Difference in the magnitude of change in intact provirus from before infusion to 48 weeks after infusion between the two study arms.

  48 weeks

• Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 48 visit.

  48 weeks

• Change in the log10 copy-number of intact proviruses per million CD4+ T cells from the first leukapheresis visit to the week 96 visit.

  96 weeks

• Peripheral CD4+ T cell count at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in each study arm.

  96 weeks

• Frequency of pentamer PCR-positive CD4+ T cells in peripheral blood at each of the follow-up time points after infusion of ex vivo expanded CD4+ T cells in the CCR5-modified study arm

  96 weeks

Study Arms (2)

Arm 1

EXPERIMENTAL

Arm 1 (n=20) will be pretreated with cyclophosphamide 1 g/m2 and will receive a single intravenous infusion of 0.5 to 4x1010 ex vivo expanded autologous CD4+ T cells that have been transduced with a zinc finger nuclease designed to cleave CCR5.

Biological: SB-728-T

Arm 2

ACTIVE COMPARATOR

Arm 2 (n=10) will be pretreated with cyclophosphamide 1 g/m2 and will receive a single intravenous infusion of 0.5 to 4x1010 ex vivo expanded autologous CD4+ T cells that have not been modified by zinc finger nucleases.

Biological: Expanded unmodified autologous CD4+ T cells

Interventions

SB-728-T BIOLOGICAL

Autologous CD4+ T cells with ex vivo modification of the CCR5 gene by zinc finger nucleases

Arm 1

Expanded unmodified autologous CD4+ T cells BIOLOGICAL

Autologous CD4+ T cells without ex vivo modification of the CCR5 gene by zinc finger nucleases

Arm 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent signed and dated by study subject.
• Men or women, including trans men or women, ≥18 and ≤70 years of age.
• For persons born male who have not been surgically sterilized, willingness to abstain from sexual activity that could result in conception for 90 days after the cyclophosphamide administration visit.
• HIV-1 infection, documented by any FDA-approved ELISA, EIA, or rapid antibody detection method, and confirmed by a second FDA-approved antibody-based test or by a positive FDA-approved HIV RNA detection assay. FDA-approved HIV-1 RNA detection assay alone constitutes proof of HIV-1 infection assuming there is documentation of \>199 copies/mL of HIV-1 RNA in the absence of antiretroviral therapy.
• Adequate venous access for leukapheresis, as documented by standard clinical procedures at each site.
• The following laboratory values at screening:
• Absolute neutrophil count (ANC) \> 1500/mm3
• Hemoglobin level ≥11 g/dL
• Platelet count ≥150,000/mm3
• Serum creatinine \<1.5 mg/dL
• AST and ALT ≤2.5 times the upper limit of normal
• CD4+ T cell count \> 350 cells/mm3
• HIV-1 RNA \<50 copies/mL performed with an ultrasensitive HIV-1 PCR assay.
• Urine red blood cell (RBC) counts within the normal range used by each institution.
• INR ≤1.5 and PTT ≤2xULN

You may not qualify if:

• Women and persons born female regardless of gender identity with childbearing potential. These participants are considered to be of childbearing potential if they are postmenarchial, have an intact uterus and at least one ovary, and have had at least one menstrual period in the past two years. Participants who have had a documented bilateral tubal ligation or a hysterectomy are not considered to be of childbearing potential.
• Plasmid DNA products
• RNA products
• Poxvirus-vectored products
• Adenovirus-vectored products
• Replication-negative adeno-associated virus-vectored products
• Prophylactic or therapeutic HIV vaccines that use one of these delivery mechanisms
• Allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).
• An antiretroviral regimen including maraviroc or any CCR5 inhibitor within 4 weeks prior to screening.
• Acute or chronic hepatitis C infection, defined as a positive plasma HCV RNA using any FDA-approved qualitative or quantitative test in a participant with a positive HCV antibody (HCV RNA testing is not required in participants with a negative HCV antibody) at screening. Participants who have completed a course of antiviral treatment for hepatitis C and have a confirmed plasma HCV RNA level below the limit of detection of the assay 12 weeks or longer after completion of therapy will be eligible. Note: Individuals that have undetectable HCV RNA in the absence of treatment that cleared infection spontaneously are also considered eligible to participate.
• Acute or chronic hepatitis B infection, defined as a positive HBV surface antigen or a positive HBV DNA at screening.
• Any prior AIDS-defining condition within the past 5 years, except a history of CD4+ T cell count below 200 cells/mm3.
• NOTE: The terms "AIDS encephalopathy" and "wasting syndrome" are often recorded on medical records to indicate constellations of signs and symptoms that may not formally meet the current diagnostic criteria for AIDS-related dementia or AIDS-associated wasting syndrome, respectively. Therefore, the principal investigators will determine whether in their opinion, a reported history of these conditions truly corresponds to an AIDS-defining syndrome meeting this criterion.
• Any active cancer or malignancy within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin or low-grade (0 or 1) anal or cervical intraepithelial neoplasia.
• Diagnosis of New York Heart Association (NYHA) grade 3 or 4 congestive heart failure, uncontrolled angina or uncontrolled arrhythmias.

Sponsors & Collaborators

• University of Cincinnati: lead
• University of California, San Francisco: collaborator
• Case Western Reserve University: collaborator

Study Sites (1)

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Carl Fichtenbaum, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, double-blind

Study Record Dates

• First Submitted: September 7, 2018
• First Posted: September 12, 2018
• Study Start: June 12, 2019
• Primary Completion: January 31, 2024
• Study Completion: February 28, 2024
• Last Updated: May 21, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: After acceptance of primary and secondary manuscripts. Available for 3 years after above.
• Access Criteria: Contact the Study Principal investigator to obtain information. Requests will be reviewed by the core team for approval.

Locations

US (1)