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

• 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: Calimmune, Inc.
• Information provided by (Responsible Party): Calimmune, Inc.

Tracking Information

• First Submitted Date: November 19, 2012
• First Posted Date: November 28, 2012
• Results First Submitted Date: June 25, 2020
• Results First Posted Date: August 6, 2020
• Last Update Posted Date: August 6, 2020
• Actual Study Start Date: April 2013
• Actual Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-1 Infection
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Human Immunodeficiency Virus

Intervention

• 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

• 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

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01734850
• Other Study ID Numbers: CAL-USA-11
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Calimmune, Inc.
• Study Sponsor: Calimmune, Inc.
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ronald Mitsuyasu, M.D.; University of California, Los Angeles

• PRS Account: Calimmune, Inc.
• Verification Date: July 2020