Trial registered on ANZCTR


Trial ID
ACTRN12615000763549
Ethics application status
Approved
Date submitted
29/06/2015
Date registered
23/07/2015
Date last updated
6/09/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A gene transfer study using chemotherapy for adults recently diagnosed with HIV-1 who are taking antiretroviral drugs
Scientific title
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)
Secondary ID [1] 286751 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV-1 infection 295110 0
AIDS 295531 0
Condition category
Condition code
Infection 295360 295360 0 0
Acquired immune deficiency syndrome (AIDS / HIV)
Inflammatory and Immune System 295806 295806 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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).
Intervention code [1] 291902 0
Treatment: Other
Intervention code [2] 292278 0
Treatment: Drugs
Comparator / control treatment
This study is part of the first stage of testing Cal-1 in humans. It is a requirement that all study participants are receiving standard of care antiretroviral therapy for their HIV infection.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295102 0
The safety and feasibility of introducing Cal-1 gene-transduced CD4+ lymphocyte and CD34+ bone marrow stem cells following chemotherapy conditioning with intravenous busulfan in HIV-1-infected adults receiving effective ART.

This is a composite outcome, assessing adverse events and correlations with the Cal-1 gene-transduced CD4+ lymphocyte and CD34+ bone marrow stem cell product dose and characteristics. This outcome is assessed by physical examinations and vital signs, complete blood counts, serum biochemistry, lymphocyte phenotyping, HIV-1 plasma viral load, and HIV-1 ART resistance genotype testing.
Timepoint [1] 295102 0
48weeks after receipt of the Cal-1-modified cells
Secondary outcome [1] 314778 0
Survival (engraftment, differentiation and contribution) of Cal-1-modified CD4+ lymphocytes and CD34+ bone marrow stem cells over time.

This is a composite outcome of survival, engraftment and contribution over time of the Cal-1-modified cells as measured by specialised tests that measure the presence and expression of Cal-1 in whole blood, specific types of white blood cells, bone marrow and gut tissue
Timepoint [1] 314778 0
Initially, up to 48 weeks after receipt of the Cal-1-modified cells, with the possibility of extension up to 100 weeks after receipt of the Cal-1-modified cells
Secondary outcome [2] 314779 0
The effect of Cal-1-modified CD4+ lymphocytes and CD34+ bone marrow stem cells on plasma viral load

This is a composite outcome based on measures of HIV plasma viral load and CD4+ lymphocytes during the period off anti-retroviral therapy (ART).
Timepoint [2] 314779 0
Study participants will stop their anti-retroviral therapy (ART) 26 weeks after the Cal-1-modified cell infusions, and will remain off ART up to 48 weeks after receipt of the Cal-1-modified cells, with the possibility of extension up to 100 weeks after receipt of the Cal-1-modified cells. The secondary outcomes are assessed throughout this period at study visits every month +/- 2 weeks.

Eligibility
Key inclusion criteria
1. HIV-1 diagnosis during early HIV-1 infection;

2. CD4+ T lymphocyte count >/= 500 cells/microlitre;

3. Plasma viral load < 50 copies/mL;

4. Commenced combination ART within six months of HIV-1 infection diagnosis;

5. Uninterrupted ART since initiation, and remaining on the first ART regimen;

6 HIV-1 resistance mutation testing, reporting susceptible virus to NRTI/NNRTI/PI drugs.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Abnormal haematology or biochemistry;

2. Detection of any CXCR4- or dual-tropic HIV-1;

3. Co-infection with hepatitis B, hepatitis C, or HTLV-1/2;

4. Latent tuberculosis infection;

5. CD4+ T lymphocyte count < 250 cells/microlitre at any time;

6. Zidovudine (AZT) within 12 weeks of study screening;

7. History of malignancy, chronic obstructive airways disease, seizure, haematological diseases, or heart failure;

8. Current or planned immunosuppressive or immunomodulatory medication;

9. Known hypersensitivity to G-CSF (Neupogen 'Registered Trademark'), plerixafor (Mozobil 'Registered Trademark'), busulfan, or any Escherichia coli-derived proteins;

10. Receipt of a vaccine for HIV-1, or any gene transfer product, at any time;

11. Individuals who will decline transfusions of any blood product;

12. Pregnancy or breastfeeding;

13. History of alcohol or drug dependence/abuse in the 12 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A total of six (6) participants will be enrolled; three (3) participants in each of 2 sequentially enrolled cohorts.

The two cohorts are differentiated according to the chemotherapy (busulfex) dose used for conditioning. Both cohorts will receive Cal-1-modified CD4+ and CD34+ cells.


Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Linear recruitment and assignment to each of the 2 study groups. Group 2 will commence after Group 1 enrolment is complete and safety data out to 12 weeks post-infusion reviewed by the independent safety monitoring board.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety
Statistical methods / analysis
The sample size of 6 participants has not been based on formal power calculations.

Numbers of individual clinical and laboratory adverse events, in numbers of participants, will be summarised by treatment, causality, and severity, both overall and by nominal study week. Clinical events will also be summarised and aggregated by body system.

Given the small number of participants, no formal efficacy analyses will be conducted, but it is anticipated that comparisons will be performed by subgroup (i.e. by dose of busulfan conditioning, doses of Cal-1-modified CD4+ and CD34+ cells) using one-sample t-tests or non-parametric equivalents as appropriate.



Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Actual
Recruitment outside Australia
Country [1] 8205 0
United States of America
State/province [1] 8205 0
California

Funding & Sponsors
Funding source category [1] 291302 0
Commercial sector/Industry
Name [1] 291302 0
Calimmune, Inc.
Address [1] 291302 0
5151 E. Broadway Blvd., Suite 700, Tucson, AZ 85711
Country [1] 291302 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Calimmune Australia Pty Limited
Address
Level 8, Lowy Packer Building
405 Liverpool Street,
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 289985 0
Commercial sector/Industry
Name [1] 289985 0
Calimmune, Inc.
Address [1] 289985 0
5151 E. Broadway Blvd., Suite 700, Tucson, AZ 85711
Country [1] 289985 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292869 0
St Vincent's Hospital HREC
Ethics committee address [1] 292869 0
390 Victoria St,
Darlinghurst NSW 2010
Ethics committee country [1] 292869 0
Australia
Date submitted for ethics approval [1] 292869 0
12/03/2015
Approval date [1] 292869 0
15/05/2015
Ethics approval number [1] 292869 0
HREC/15/SVH/67

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes
Due to lack of participant recruitment, study activity at St. Vincent's Hospital, Holdsworth House Medical Practice, and Taylor Square Private Clinic has been discontinued. There are efforts to open recruitment in the United States.

Contacts
Principal investigator
Name 57394 0
Prof Anthony Kelleher
Address 57394 0
The Kirby Institute
Wallace Wurth Building
UNSW
Kensington
NSW 2052
Country 57394 0
Australia
Phone 57394 0
+61 2 9385 9951
Fax 57394 0
Email 57394 0
akelleher@kirby.unsw.edu.au
Contact person for public queries
Name 57395 0
Mr Kyle McDonald
Address 57395 0
St Vincent's Hospital
390 Victoria Street
Darlinghurst
NSW 2010
Country 57395 0
Australia
Phone 57395 0
+61 2 8382 4978
Fax 57395 0
Email 57395 0
Kyle.McDonald@svha.org.au
Contact person for scientific queries
Name 57396 0
Dr Geoffrey Symonds
Address 57396 0
Calimmune Australia
Level 8, Lowy Packer Building
405 Liverpool Street,
Darlinghurst NSW 2010
Country 57396 0
Australia
Phone 57396 0
+61 2 8382 4915
Fax 57396 0
Email 57396 0
geoff.symonds@calimmuneinc.com