Human Immunodeficiency VirusPhase 1/2NCT01734850
Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-1 Infection
A Phase 1/2 study testing Busulfan, Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes in people with Human Immunodeficiency Virus, run by Calimmune, Inc. at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Human Immunodeficiency Virus
- What is being tested?
- Busulfan, Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 2 sitesUnited States
- Study dates
- Apr 2013to Nov 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
Show all 9Show fewer
- 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
Who cannot join
- 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
Show all 24Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
UCLA CARE Center
Los Angeles, California, 90035
Quest Clinical Research
San Francisco, California, 94115
About this study
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
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:
- Removing a protein named CCR5 from bone marrow and white blood cells
- Producing a protein named C46 on bone marrow and white blood cells
Read the 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:
- Binding of the virus to the cellular CCR5 co-receptor and
- 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.
- Conditions
- Human Immunodeficiency Virus
- Being tested
- Busulfan, Cal-1 modified HSPC, Cal-1 modified CD4+ T lymphocytes
- Keywords
- HIV-1
- Medical subject headings
- Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BusulfanDrug
Also called Busulfex
Intravenous busulfan
Cal-1 modified HSPCBiological
Also called LVsh5/C46 modified HSPC
Hematopoietic progenitor/stem cells (HSPC) modified with LVsh5/C46 (Cal-1)
Cal-1 modified CD4+ T lymphocytesBiological
Also called LVsh5/C46 modified CD4+ T lymphocytes
CD4+ T lymphocytes modified with LVsh5/C46 (Cal-1)
| Study group | Role | What they receive |
|---|---|---|
| No busulfan pre-conditioning | Experimental | Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes without busulfan preconditioning Receives: Biological: Cal-1 modified HSPC; Biological: Cal-1 modified CD4+ T lymphocytes |
| 1 x 4mg/kg busulfan preconditioning | Experimental | Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with single 4mg/kg busulfan dose administered as pre-conditioning for transplant Receives: Drug: Busulfan; Biological: Cal-1 modified HSPC; Biological: Cal-1 modified CD4+ T lymphocytes |
| 2 x 4mg/kg busulfan pre-conditioning | Experimental | Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with two 4mg/kg busulfan doses administered as pre-conditioning for transplant Receives: Drug: Busulfan; Biological: Cal-1 modified HSPC; Biological: Cal-1 modified CD4+ T lymphocytes |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Severe and Life-threatening Adverse Events (AEs)
Measured: Up to 48 weeks
Number of Participants With Severe or Life-threatening AEs Related to CSL202
Measured: Up to 48 weeks
Number of Participants With the Presence of Replication-competent Retrovirus
Measured: Up to 48 weeks
Number of Participants With Predominant Integration Site Analysis
Vector Integration Site Analysis performed only when Cal-1 Marking is >= 1%.
Measured: Up to 48 weeks
Mean Cell Dose for CD4+ Cells (Ttn)
Measured: Up to 48 weeks
Mean Cell Dose for CD34+ Cells (HSPCtn)
Measured: Up to 48 weeks
Percent Transduction Efficiency of CD4+ Cells (Ttn) and CD34+ Cells (HSPCtn) of Final Cell Product
Measured: Up to 48 weeks
Total Area Under the Curve (AUC) for Busulfan
Cohort 3: Total AUC = first dose AUC value + second dose AUC value
Measured: Up to 48 weeks
Secondary outcomes (9)
Percent Cal-1 Marking in Peripheral Blood
Measured: Up to 48 weeks
Cal-1 Marking in Gut-associated Lymphoid Tissue (GALT) (10-15 cm)
Samples were collected via endoscopic biopsy from the sigmoid colon: 10-15 cm from the anal margin
Measured: Up to 48 weeks
Cal-1 Marking in GALT (25-35 cm)
Samples were collected via endoscopic biopsy from the sigmoid colon: 25-35 cm from the anal margin
Measured: Up to 48 weeks
Cal-1 Marking in Bone Marrow
Measured: Up to 48 weeks
Cal-1 C46 Expression in Peripheral Blood
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
Measured: Up to 48 weeks
Cal-1 sh5 Expression in Peripheral Blood
sh5 relative expression will be analyzed by RT-qPCR and normalized to the expression of RNU38B microRNA
Measured: Up to 48 weeks
HIV Viral Load at Baseline Screening and Week 48 or at Anti-retroviral Therapy (ART) Re-commencement
Measured: Up to 48 weeks
CD4+ Count at Baseline Screening and Week 48 or at ART Re-commencement
Measured: Up to 48 weeks
Number of Participants With HIV-1 Tropism Shift
Shift from R5 to X4 or dual/mixed tropism
Measured: Up to 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2012 (estimated)
- Study startApr 2013
- Primary completionSep 2017
- Study completionNov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Human Immunodeficiency VirusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Calimmune, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ronald Mitsuyasu, M.D., Principal investigator, University of California, Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01734850
- Sponsor's protocol ID
- CAL-USA-11
- Status last verified
- Jul 2020
- First submitted
- 19 Nov 2012
- Last updated
- 6 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01734850
- Acronym / sponsor ID
- CAL-USA-11
- Conditions
- Human Immunodeficiency Virus
- Keywords
- HIV-1
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Calimmune, Inc.Industry (pharma, biotech, devices)
- Study start
- Apr 2013 (actual)
- Primary completion
- Sep 2017 (actual)
- Study completion
- Nov 2017 (actual)
- First posted
- 28 Nov 2012 (estimated)
- Results
- Posted 6 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Removing a protein named CCR5 from bone marrow and white blood cells
- 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:
- Binding of the virus to the cellular CCR5 co-receptor and
- 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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| No busulfan pre-conditioning | Experimental | Biological: Cal-1 modified HSPC, Biological: Cal-1 modified CD4+ T lymphocytesCal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes without busulfan preconditioning |
| 1 x 4mg/kg busulfan preconditioning | Experimental | Drug: Busulfan, Biological: Cal-1 modified HSPC, Biological: Cal-1 modified CD4+ T lymphocytesCal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with single 4mg/kg busulfan dose administered as pre-conditioning for transplant |
| 2 x 4mg/kg busulfan pre-conditioning | Experimental | Drug: Busulfan, Biological: Cal-1 modified HSPC, Biological: Cal-1 modified CD4+ T lymphocytesCal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes, with two 4mg/kg busulfan doses administered as pre-conditioning for transplant |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (24 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BusulfanAlso: BusulfexIntravenous busulfan | Drug | 1 x 4mg/kg busulfan preconditioning, 2 x 4mg/kg busulfan pre-conditioning |
| Cal-1 modified HSPCAlso: LVsh5/C46 modified HSPCHematopoietic progenitor/stem cells (HSPC) modified with LVsh5/C46 (Cal-1) | Biological | 1 x 4mg/kg busulfan preconditioning, 2 x 4mg/kg busulfan pre-conditioning, No busulfan pre-conditioning |
| Cal-1 modified CD4+ T lymphocytesAlso: LVsh5/C46 modified CD4+ T lymphocytesCD4+ T lymphocytes modified with LVsh5/C46 (Cal-1) | Biological | 1 x 4mg/kg busulfan preconditioning, 2 x 4mg/kg busulfan pre-conditioning, No busulfan pre-conditioning |
Primary outcome
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
9 secondary outcomes
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
Cal-1 Marking in GALT (25-35 cm)
Time frame: Up to 48 weeks
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
Cal-1 sh5 Expression in Peripheral Blood
Time frame: Up to 48 weeks
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ronald Mitsuyasu, M.D. principal investigator
University of California, Los Angeles
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Busulfan, Cal-1 modified HSPC and Cal-1 modified CD4+ T lymphocytes in people with Human Immunodeficiency Virus, run by Calimmune, Inc. at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Severe and Life-threatening Adverse Events (AEs) (time frame: Up to 48 weeks). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2020.