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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.

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

Condition or disease Intervention/treatment Phase
Human Immunodeficiency Virus Drug: Busulfan Biological: Cal-1 modified HSPC Biological: Cal-1 modified CD4+ T lymphocytes Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 2013
Actual Primary Completion Date : September 2017
Actual Study Completion Date : November 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Busulfan

Arm Intervention/treatment
Experimental: No busulfan pre-conditioning
Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes without busulfan preconditioning
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

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
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

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
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




Primary Outcome Measures :
  1. Number of Participants With Severe and Life-threatening Adverse Events (AEs) [ Time Frame: Up to 48 weeks ]
  2. Number of Participants With Severe or Life-threatening AEs Related to CSL202 [ Time Frame: Up to 48 weeks ]
  3. Number of Participants With the Presence of Replication-competent Retrovirus [ Time Frame: Up to 48 weeks ]
  4. 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%.

  5. Mean Cell Dose for CD4+ Cells (Ttn) [ Time Frame: Up to 48 weeks ]
  6. Mean Cell Dose for CD34+ Cells (HSPCtn) [ Time Frame: Up to 48 weeks ]
  7. Percent Transduction Efficiency of CD4+ Cells (Ttn) and CD34+ Cells (HSPCtn) of Final Cell Product [ Time Frame: Up to 48 weeks ]
  8. 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


Secondary Outcome Measures :
  1. Percent Cal-1 Marking in Peripheral Blood [ Time Frame: Up to 48 weeks ]
  2. 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

  3. 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

  4. Cal-1 Marking in Bone Marrow [ Time Frame: Up to 48 weeks ]
  5. 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

  6. 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

  7. HIV Viral Load at Baseline Screening and Week 48 or at Anti-retroviral Therapy (ART) Re-commencement [ Time Frame: Up to 48 weeks ]
  8. CD4+ Count at Baseline Screening and Week 48 or at ART Re-commencement [ Time Frame: Up to 48 weeks ]
  9. Number of Participants With HIV-1 Tropism Shift [ Time Frame: Up to 48 weeks ]
    Shift from R5 to X4 or dual/mixed tropism



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT01734850


Locations
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United States, California
UCLA CARE Center
Los Angeles, California, United States, 90035
Quest Clinical Research
San Francisco, California, United States, 94115
Sponsors and Collaborators
Calimmune, Inc.
Investigators
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Principal Investigator: Ronald Mitsuyasu, M.D. University of California, Los Angeles
  Study Documents (Full-Text)

Documents provided by Calimmune, Inc.:
Study Protocol  [PDF] July 8, 2015
Statistical Analysis Plan  [PDF] December 15, 2017

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Responsible Party: Calimmune, Inc.
ClinicalTrials.gov Identifier: NCT01734850    
Other Study ID Numbers: CAL-USA-11
First Posted: November 28, 2012    Key Record Dates
Results First Posted: August 6, 2020
Last Update Posted: August 6, 2020
Last Verified: July 2020
Keywords provided by Calimmune, Inc.:
HIV-1
Additional relevant MeSH terms:
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Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists