A gene transfer study using chemotherapy for adults recently diagnosed with HIV-1 who are taking antiretroviral drugs
An adaptive phase I/II, dose-ranging study to evaluate the safety and feasibility of busulfan conditioning prior to transplant of CD4+ T lymphocytes and CD34+ haematopoietic stem/progenitor cells (HSPCs) transduced with LVSH5/C46 (CAL-1), in adults diagnosed at primary HIV-1 infection who are established on effective combination antiretroviral therapy (ART)
Calimmune Australia Pty Limited
6 participants
Sep 25, 2015
Interventional
Conditions
Summary
The gene transfer product Cal-1 aims to protect CD4+ T lymphocytes and blood cells from CD34+ bone marrow stem cells from HIV-1 infection. The protective effect may suppress the HIV-1 RNA plasma viral load and maintain the CD4+ T lymphocyte count in a treated individual, thereby decreasing or delaying (either partially or completely) the need for ART. The purpose of this study is to help determine whether Cal-1, as well as the method used to deliver Cal-1, is safe in people. Cal-1 is an experimental treatment for HIV-1 infection. This means that Cal-1 is not an approved treatment for HIV-1 in Australia. Cal-1 has already been tested in the laboratory and in animals, this study is part of the first stage of testing Cal-1 in people. We aim to collect preliminary information on whether Cal-1 can protect the person’s immune system from the effects of HIV by reducing HIV-1 viral load and/or preventing further decline in T cell counts.
Eligibility
Inclusion Criteria6
- HIV-1 diagnosis during early HIV-1 infection;
- CD4+ T lymphocyte count >/= 500 cells/microlitre;
- Plasma viral load < 50 copies/mL;
- Commenced combination ART within six months of HIV-1 infection diagnosis;
- Uninterrupted ART since initiation, and remaining on the first ART regimen;
- HIV-1 resistance mutation testing, reporting susceptible virus to NRTI/NNRTI/PI drugs.
Exclusion Criteria13
- Abnormal haematology or biochemistry;
- Detection of any CXCR4- or dual-tropic HIV-1;
- Co-infection with hepatitis B, hepatitis C, or HTLV-1/2;
- Latent tuberculosis infection;
- CD4+ T lymphocyte count < 250 cells/microlitre at any time;
- Zidovudine (AZT) within 12 weeks of study screening;
- History of malignancy, chronic obstructive airways disease, seizure, haematological diseases, or heart failure;
- Current or planned immunosuppressive or immunomodulatory medication;
- Known hypersensitivity to G-CSF (Neupogen 'Registered Trademark'), plerixafor (Mozobil 'Registered Trademark'), busulfan, or any Escherichia coli-derived proteins;
- Receipt of a vaccine for HIV-1, or any gene transfer product, at any time;
- Individuals who will decline transfusions of any blood product;
- Pregnancy or breastfeeding;
- History of alcohol or drug dependence/abuse in the 12 months.
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Interventions
LVsh5/C46 (Cal-1) is an experimental treatment for HIV-1 infection. It is designed to disrupt HIV-1 infection in two ways: First, it removes a protein named CCR5 from your white blood and bone marrow cells. Second, it produces a protein named C46 to block the entry of HIV-1 into cells. Cal-1 is delivered into your white blood and bone marrow cells using a modified, inactive virus called a ‘lentiviral vector’. Once inside your cells, the changes made by Cal-1 to those cells are permanent and may make those cells resistant to HIV-1. This will improve the immune system, as HIV-1 usually kills white blood cells. There are multiple experimental parts to this study. These include: 1. the laboratory procedures to insert LVsh5/C46 (Cal-1) into bone marrow cells (specifically, CD34+ stem cells and white blood cells (specifically, CD4+ T cells) and then culture these cells to increase the number; 2. the effect of infusing Cal-1-modified cells in humans; 3. using chemotherapy before infusion of Cal-1-modified cells to aid take-up of the stem cells by your bone marrow. There are three parts to this study: Part A – your medical history (including history of your HIV-1 infection and treatment) will be reviewed and screening tests performed to confirm that you are eligible to participate; Part B – The collection of white blood cells (CD4+ T cells) and bone marrow (CD34+) stem cells are collected using a process called leukapheresis. The collection of CD34+ bone marrow cells requires 5 days treatment with drugs (Neupogen (Registered Trademark) and Mozobil (Registered Trademark) that move the cells from your bone marrow into your blood . Your CD4+ T cells and CD34+ bone marrow cells are taken to a specialised laboratory where they are modified with Cal-I. You will be asked to stop taking your antiretroviral drugs for a supervised 4-week period before and during this process. Once these cells are collected you will resume taking your antiretroviral drugs. Part C – you will receive 1 or 2 doses of chemotherapy as an intravenous infusion of Busulfex (Registered Trademark), followed by infusions of Cal-1-modified cells 2 days later. After the infusion, you will have regular study visits for approximately 1 year to monitor the presence and activity of Cal-1, the effect of the Busulfex chemotherapy as well as your overall health. At 26 weeks after receiving the cells, you will again stop taking your antiretroviral drugs. If your viral load and CD4+ counts remain below safety limits, you may continue off ART and continue to be monitored for up to 1 additional year There are two different treatment Groups planned, each with three participants. The only planned difference between Groups 1 and 2 is the dose of chemotherapy used. There is only a single dose of each Cal-1-modified cell type (the actual doses being dependent on the cell numbers harvested, and subsequent yields from the laboratory procedures for each individual study participant).
Locations(4)
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ACTRN12615000763549