Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NCT01734850
Previous Study | Return to List | Next Study

Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-1 Infection

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: NCT01734850
Recruitment Status : Completed
First Posted : November 28, 2012
Results First Posted : August 6, 2020
Last Update Posted : August 6, 2020
Sponsor:
Information provided by (Responsible Party):
Calimmune, Inc.

Tracking Information
First Submitted Date  ICMJE November 19, 2012
First Posted Date  ICMJE November 28, 2012
Results First Submitted Date  ICMJE June 25, 2020
Results First Posted Date  ICMJE August 6, 2020
Last Update Posted Date August 6, 2020
Actual Study Start Date  ICMJE April 2013
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2020)
  • Number of Participants With Severe and Life-threatening Adverse Events (AEs) [ Time Frame: Up to 48 weeks ]
  • Number of Participants With Severe or Life-threatening AEs Related to CSL202 [ Time Frame: Up to 48 weeks ]
  • Number of Participants With the Presence of Replication-competent Retrovirus [ Time Frame: Up to 48 weeks ]
  • Number of Participants With Predominant Integration Site Analysis [ Time Frame: Up to 48 weeks ]
    Vector Integration Site Analysis performed only when Cal-1 Marking is >= 1%.
  • Mean Cell Dose for CD4+ Cells (Ttn) [ Time Frame: Up to 48 weeks ]
  • Mean Cell Dose for CD34+ Cells (HSPCtn) [ Time Frame: Up to 48 weeks ]
  • Percent Transduction Efficiency of CD4+ Cells (Ttn) and CD34+ Cells (HSPCtn) of Final Cell Product [ Time Frame: Up to 48 weeks ]
  • Total Area Under the Curve (AUC) for Busulfan [ Time Frame: Up to 48 weeks ]
    Cohort 3: Total AUC = first dose AUC value + second dose AUC value
Original Primary Outcome Measures  ICMJE
 (submitted: November 22, 2012)
Feasibility and safety of the introduction of Cal-1 into HSPC and CD4+ T lymphocyte cell populations, and the associated delivery procedures. [ Time Frame: 48 weeks ]
Baseline demographic and clinical information, treatment, and duration of follow-up will be summarized by group and overall. Severity of clinical adverse events (AEs) and laboratory safety parameters will be graded according to DAIDS criteria. Numbers of individual AEs, in numbers of subjects, will be summarized by severity and treatment. AEs will also be summarized and aggregated by body system for clinical events. The worst severity of each clinical and laboratory AE, for each subject, will be summarized by treatment. All grade 3 and 4 AEs, and any other events that lead to a subject ceasing trial follow-up, will be listed by treatment, with duration and resolution. Feasibility measures include the number of manufacturing procedures successfully completed (i.e. complying with all release criteria); number of gene modified cells, as affected by CD4+ and CD34+ purity, transduction efficiency, and viability; and the number of target cells harvested.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2020)
  • Percent Cal-1 Marking in Peripheral Blood [ Time Frame: Up to 48 weeks ]
  • Cal-1 Marking in Gut-associated Lymphoid Tissue (GALT) (10-15 cm) [ Time Frame: Up to 48 weeks ]
    Samples were collected via endoscopic biopsy from the sigmoid colon: 10-15 cm from the anal margin
  • Cal-1 Marking in GALT (25-35 cm) [ Time Frame: Up to 48 weeks ]
    Samples were collected via endoscopic biopsy from the sigmoid colon: 25-35 cm from the anal margin
  • Cal-1 Marking in Bone Marrow [ Time Frame: Up to 48 weeks ]
  • Cal-1 C46 Expression in Peripheral Blood [ Time Frame: Up to 48 weeks ]
    C46 relative expression will be analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and normalized to the expression of β2-microglobulin (β2M) mRNA
  • Cal-1 sh5 Expression in Peripheral Blood [ Time Frame: Up to 48 weeks ]
    sh5 relative expression will be analyzed by RT-qPCR and normalized to the expression of RNU38B microRNA
  • HIV Viral Load at Baseline Screening and Week 48 or at Anti-retroviral Therapy (ART) Re-commencement [ Time Frame: Up to 48 weeks ]
  • CD4+ Count at Baseline Screening and Week 48 or at ART Re-commencement [ Time Frame: Up to 48 weeks ]
  • Number of Participants With HIV-1 Tropism Shift [ Time Frame: Up to 48 weeks ]
    Shift from R5 to X4 or dual/mixed tropism
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2012)
The benefit of busulfan conditioning in impacting efficacy of Cal-1 in controlling HIV-1 infection [ Time Frame: 48 weeks ]
Log10 HIV-1 RNA, CD4+ T lymphocyte count, CD4+ %, CD4:CD8 ratio, measures of Cal-1 marking/expression and thymopoiesis will be plotted over time for each individual subject, and will be summarized for each nominal study week. Changes in Log10 HIV-1 RNA and CD4+ T lymphocyte count from baseline will be formally compared in all subjects. Associations between feasibility and safety measures and secondary outcomes include:
  • Number of gene-modified cells infused and peripheral blood marking, plasma HIV RNA and CD4+ T cell counts
  • Integration profile of the Ttn and HSPCtn products and observations in integration analysis of peripheral blood post infusion
  • HSPCtn methylcellulose colony forming units and peripheral blood subpopulation marking
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-1 Infection
Official Title  ICMJE An Adaptive Phase I/II Study of the Safety of CD4+ T Lymphocytes and CD34+ Hematopoietic Stem/Progenitor Cells Transduced With LVsh5/C46, a Dual Anti-HIV Gene Transfer Construct, With and Without Conditioning With Busulfan in HIV-1 Infected Adults Previously Exposed to ART
Brief Summary

This is an early phase research study looking at whether an experimental gene transfer, LVsh5/C46 (also known as Cal-1), is safe and if it can protect the immune system from the effects of HIV without the use of antiretroviral drugs.

Cal-1 is an experimental gene transfer agent designed to inhibit HIV infection through 2 active parts:

  1. Removing a protein named CCR5 from bone marrow and white blood cells
  2. Producing a protein named C46 on bone marrow and white blood cells
Detailed Description

It is estimated that 33 million individuals are currently infected with HIV. HIV/AIDS is a disease that impairs immune function, primarily by decreasing CD4+ T lymphocytes. The progression can be contained by daily dosing with antiretroviral therapy (ART) but there are side effects that can be treatment limiting, and the development of HIV drug resistance can force the physician to modify the ART regimen. There are no effective vaccines currently available for HIV.

LVsh5/C46 (also known as Cal-1) is a dual therapeutic, self-inactivating lentiviral vector that encodes for both a short hairpin RNA against the HIV-1 co-receptor CCR5 (sh5) and a HIV-1 fusion inhibitor, C46 and inhibits two processes required for HIV-1 infection:

  1. Binding of the virus to the cellular CCR5 co-receptor and
  2. Fusion of the virus with the host cell

The rationale is that Cal-1 introduced into hematopoietic progenitor/stem cells (HSPC) and mature CD4+ T lymphocytes will protect these cells and their progeny cells from HIV-1 infection and its pathogenic sequelae. This may provide a continuous means of controlling HIV-1 after a single or infrequent dose(s), thereby decreasing or delaying (partially or completely) the need for antiretroviral drug therapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Human Immunodeficiency Virus
Intervention  ICMJE
  • Drug: Busulfan
    Intravenous busulfan
    Other Name: Busulfex
  • Biological: Cal-1 modified HSPC
    Hematopoietic progenitor/stem cells (HSPC) modified with LVsh5/C46 (Cal-1)
    Other Name: LVsh5/C46 modified HSPC
  • Biological: Cal-1 modified CD4+ T lymphocytes
    CD4+ T lymphocytes modified with LVsh5/C46 (Cal-1)
    Other Name: LVsh5/C46 modified CD4+ T lymphocytes
Study Arms  ICMJE
  • Experimental: No busulfan pre-conditioning
    Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes without busulfan preconditioning
    Interventions:
    • Biological: Cal-1 modified HSPC
    • Biological: Cal-1 modified CD4+ T lymphocytes
  • Experimental: 1 x 4mg/kg busulfan preconditioning
    Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with single 4mg/kg busulfan dose administered as pre-conditioning for transplant
    Interventions:
    • Drug: Busulfan
    • Biological: Cal-1 modified HSPC
    • Biological: Cal-1 modified CD4+ T lymphocytes
  • Experimental: 2 x 4mg/kg busulfan pre-conditioning
    Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with two 4mg/kg busulfan doses administered as pre-conditioning for transplant
    Interventions:
    • Drug: Busulfan
    • Biological: Cal-1 modified HSPC
    • Biological: Cal-1 modified CD4+ T lymphocytes
Publications * Not Provided

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: July 22, 2020)
13
Original Estimated Enrollment  ICMJE
 (submitted: November 22, 2012)
12
Actual Study Completion Date  ICMJE November 2017
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Prior to any study-related procedures, signed informed consent indicating that they understand the purpose, risks and procedures required for the study and are willing to participate in the study
  • Individuals aged 18 to 65 years of age (inclusive) at time of consent
  • Documented HIV-1 infection ≥ 6 months prior to Screening 1
  • Previous treatment with antiretroviral agents that had a demonstrated suppressive effect (defined as plasma HIV RNA ≤ 50 copies/ml)
  • A documented viable ART regimen option, as determined by the Investigator, taking into account prior ART experience and HIV geno/phenotyping analyses
  • Not taking antiretroviral therapy for ≥ 6 weeks prior to Screening 1, for one or more of the following reasons:

    i) Concerns over short-term or long-term toxicities associated with antiretroviral agents, or ii) Treatment fatigue from the daily regimen of life-long therapy

  • Plasma HIV-1 viral RNA ≥ 5,000 copies/mL and ≤ 100,000 copies/ml at Screening 1 and Screening 2
  • CD4+ T lymphocyte count ≥ 500 cells/µl at Screening 1 and Screening 2

Exclusion Criteria:

  • Abnormal hematology at Screening 1: Absolute neutrophil count (ANC) < 1.5 x 109/L, Platelet count < 100 x 109/L, Hemoglobin < 10 g/dL
  • Abnormal biochemistry at Screening 1: Alanine aminotransferase (ALT) > 2.5 x Upper Limit of Normal (ULN), Total bilirubin > 1.5 x ULN, Serum creatinine > 1.5 x ULN
  • Detection of any CXCR4-tropic HIV-1 at Screening 1
  • Evidence of co-infection with hepatitis B virus, hepatitis C virus, West Nile Virus, or HTLV-1 as detected at Screening 2
  • Evidence of active TB infection determined by positive QuantiFERON®-TB Gold/IGRA test result and clinical confirmation at Screening 2
  • ART or other antiretroviral therapy within 6 weeks of Screening 1 or any time during the pre-infusion period
  • Documented history of CD4+ T lymphocyte count < 250 cells/µl
  • Any previous or current AIDS-defining illnesses (CDC Category C), including AIDS-related dementia, with the exception of Kaposi's sarcoma confined to the skin
  • History of malignancy or systemic chemotherapy within the last 5 years (i.e., subjects with prior malignancy must be disease-free for 5 years), except curatively-treated basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical or anal intra-epithelial neoplasia
  • History of steroid-dependent asthma in the past 5 years
  • History of seizure
  • Any clinical history of hematologic diseases including leukemia, myelodysplasia, myeloproliferative disease, thromboembolic disease, sickle cell disorder, thrombocytopenia or leukopenia
  • Class II-IV heart failure, according to the New York Heart Association classification
  • Inadequate venous access for apheresis, as assessed at Screening 1
  • Current or planned systemic immunosuppressive or immunomodulatory medication
  • Taking warfarin, aspirin or any medication that is likely to affect platelet function or other aspects of blood coagulation, and unable to safely cease this medication for a period of 1 week prior, during, and 1 week after administration of G-CSF (a total period of 19 days)
  • Participation in any study involving any investigational drug or medical device within 30 days prior to Screening 1
  • Receipt of a vaccine for HIV-1 or any gene transfer product at any time
  • Prior treatment with recombinant G-CSF or busulfan or other stem-cell mobilizing or modulating agent within the previous 12 months
  • Known hypersensitivity to busulfan, G-CSF (Neupogen™) or E. coli-derived proteins
  • Subjects who will not accept transfusions of blood products
  • Pregnant or breast-feeding at any time between Screening 1 and Baseline (infusion)
  • History of alcohol or drug abuse within the 12 months prior to Screening 1
  • Inability to understand and provide informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 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 NCT01734850
Other Study ID Numbers  ICMJE CAL-USA-11
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Calimmune, Inc.
Study Sponsor  ICMJE Calimmune, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ronald Mitsuyasu, M.D. University of California, Los Angeles
PRS Account Calimmune, Inc.
Verification Date July 2020

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