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Ph1 Study of FT538 Alone and With Vorinostat for Persistent Low-Level HIV Viremia

Primary Purpose

HIV-1-infection, ART, Cd4+ Lymphocyte Deficiency

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
FT538
Vorinostat
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV-1-infection focused on measuring FT538, ACC/AHA, ADCC, AE, AIDS, ASCVD, CAR, CFR, CIBMTR, CLIA, CNS, CRP, CRS, CSRC, DC, DLT, GALT, HDACi, HIV, ICANS, ICE, IL-15, pVL

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Male or female, age ≥18 and ≤65 years at the time of signing the consent form HIV-1 infection on continuous antiretroviral therapy (ART) for at least 12 months without any interruptions of greater than 14 consecutive days and without plans to modify ART before the End of Treatment visit. Two or more consecutive detectable HIV RNA levels of ≤200 copies/mL in the last 2 years, with at least one determination meeting this criterion in the previous 12 months. (If testing was not obtained within 42 days of planned dose 1, test will be repeated during subject screening to confirm status) Screening CD4+ T cell count ≥350 cells/ µl within 28 days of the 1st dose of FT538. Completion of initial COVID-19 vaccination series and/or documented COVID-19 infection with completion of treatment ≥ 3 months prior Patient weight of ≥ 50 kg due to FT538 fixed cell dosing and FT538 product pre-dosed packaging. Adequate organ function within 14 days of Day 1, defined as the following: Platelet counts >150,000/mm^3 Hemoglobin > 12.5 g/dL for men and > 11.5 g/dL for women. It is not acceptable for patients to be transfused within the prior month to meet this requirement. The use of Epogen is permitted. AST and ALT ≤ 3 x upper limit of institutional normal Estimated CrCl (eGFR) >50 mL/min/1.73m^2 Persons of childbearing potential or with partners of childbearing potential must be willing to abstain from heterosexual activity or to use a highly effective form of contraception from the time of study enrollment through at least 4 months after the last dose of FT538. Persons are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception. For Dose Cohort 4 (FT538 plus Vorinostat): Females of childbearing potential must use highly effective contraception from the time of study enrollment through 6 months after the last dose of vorinostat. Males with partners of childbearing potential must use highly effective contraception from the time of study enrollment through 3 months after the last dose of vorinostat or 4 months after the last dose of FT538, whichever is more conservative. Must agree to and sign the consent for the Master Long-Term Follow-Up study to fulfill the FDA recommended 15 years following exposure to the investigational gene therapy product. Voluntary written consent prior to the performance of any research related procedures. Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control for a minimum of 4 months after the last dose of FT538. If of childbearing potential, a negative pregnancy test is required within 14 days prior to the 1st dose of FT538 or within 7 days prior to the 1st dose of vorinostat if treated in Dose Cohort 4. Known allergy to the following FT538 components: albumin (human) or DMSO. Currently receiving or likely to require systemic immunosuppressive therapy (e.g., prednisone >5 mg daily) for any reason within 5 days before the 1st dose of FT538 and 14 days after the last dose of FT538 - inhaled and topical steroids are permitted. Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months - minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) is permitted. Prior history of solid organ transplant or hematopoietic stem cell transplant. Receipt of any investigational agent (not approved by the FDA for any indication) within 28 days prior to the first dose of FT538. Note that participation in prior HIV cure studies, including those involving IL-2 or N803, is permitted as long as experimental therapy completed >28 days prior. Chronic liver disease defined as Class B and C on the Child-Pugh scale. Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines, including a previous diagnosis of any of the following within the previous 12 months: (a) acute myocardial infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial revascularization, (e) stroke, (f) transient ischemic attack (TIA), or (g) peripheral arterial disease presumed to be of atherosclerotic origin. Moderate-severe obstructive lung disease. In subjects reporting a history of mild obstructive lung disease at screening, pulmonary function test (PFT) to be obtained and patient excluded from study if the FEV1 is <80% of predicted. Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease or receipt of medications for these conditions in the 2-year period leading up to study enrollment. Known concurrent or recent (defined as having received treatment within the last 3 months) infection with: Latent or active TB infection prior to completing a standard regimen of anti-TB therapy; defined as meeting PPD criteria for TB exposure or a positive quantiferon gold test collected at screening Active fungal infection requiring systemic antifungal therapy Chronic active hepatitis B or C. For Hepatitis B this will be defined as HBs antigen + and for Hepatitis C this will be defined as Hepatitis C antibody positive and Hepatitis C PCR+. COVID-19; defined as a positive SARS-CoV-2 PCR test at screening or a history of COVID-19 diagnosed within the last 3 months. Clinical vaccination administered within 6 weeks of the 1st dose of FT538. Presence of any social issues that, per investigator judgement, are likely to interfere with study conduct or may cause increased risk to patient. Patient history of alcohol or substance abuse that, per investigator judgement, are likely to interfere with study conduct or may cause increased risk to patient Any medical condition or clinical laboratory abnormality that, per investigator judgement, precludes safe participation in and completion of the study or that could affect compliance with protocol conduct or interpretation of results.

Sites / Locations

  • Masonic Cancer Center at University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Determine the safety and feasibility of administering FT538 monotherapy

Characterize the toxicities and impact of FT538 and vorinostat

Arm Description

Administering FT538 monotherapy as an intravenous infusion once every 14 days for 4 consecutive doses and in combination with twice weekly vorinostat for the reduction of the HIV reservoir.

To characterize the toxicities associated with FT538 monotherapy and with vorinostat in this patient population. To determine the impact of FT538 on the persistence of low-level HIV viremia, defined as detectable HIV-1 RNA of ≤200 copies/mL despite good ART adherence.

Outcomes

Primary Outcome Measures

Determine the safety and feasibility of administering FT538 monotherapy.
At screen and baseline visits, all grades of signs and symptoms that occurred 30 days prior to the visit will be recorded. At all subsequent visits, all grades of signs and symptoms that occurred since the previous visit must be recorded as part of an Adverse Event (AE) assessment.

Secondary Outcome Measures

Characterize the toxicities associated with FT538 monotherapy and vorinostat.
flow cytometric analysis for NK cell degranulation (CD107a).
Determine the impact of FT538 on the persistence of low-level HIV viremia
Defined as patients with detectable HIV-1 RNA of ≤200 copies/mL despite good ART adherence.

Full Information

First Posted
December 9, 2022
Last Updated
August 1, 2023
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT05700630
Brief Title
Ph1 Study of FT538 Alone and With Vorinostat for Persistent Low-Level HIV Viremia
Official Title
MT2022-06: Phase I Study of FT538 Monotherapy and in Combination With Vorinostat for the Treatment of Persistent Low-Level HIV Viremia
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 15, 2024 (Anticipated)
Primary Completion Date
July 26, 2024 (Anticipated)
Study Completion Date
August 21, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a single center Phase I clinical trial of FT538 administered intravenously (IV) once every 14 days for 4 consecutive doses for the reduction of the HIV reservoir in lymphoid tissue of HIV-infected individuals receiving standard of care (SOC) antiretroviral therapy (ART). As this is an early 1st in human study and the 1st for HIV-infected individual, the safety of FT538 is confirmed prior to the addition of oral vorinostat to explore the concept of "Kick and Kill".

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-1-infection, ART, Cd4+ Lymphocyte Deficiency, Lymphoid Tissue; Infection, Interleukin
Keywords
FT538, ACC/AHA, ADCC, AE, AIDS, ASCVD, CAR, CFR, CIBMTR, CLIA, CNS, CRP, CRS, CSRC, DC, DLT, GALT, HDACi, HIV, ICANS, ICE, IL-15, pVL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Determine the safety and feasibility of administering FT538 monotherapy
Arm Type
Experimental
Arm Description
Administering FT538 monotherapy as an intravenous infusion once every 14 days for 4 consecutive doses and in combination with twice weekly vorinostat for the reduction of the HIV reservoir.
Arm Title
Characterize the toxicities and impact of FT538 and vorinostat
Arm Type
Experimental
Arm Description
To characterize the toxicities associated with FT538 monotherapy and with vorinostat in this patient population. To determine the impact of FT538 on the persistence of low-level HIV viremia, defined as detectable HIV-1 RNA of ≤200 copies/mL despite good ART adherence.
Intervention Type
Biological
Intervention Name(s)
FT538
Intervention Description
FT538 is an investigational off-the-shelf cryopreserved NK cell product derived from an iPSC that contains three functional modifications: 1) a novel high affinity, non-cleavable CD16 (Fc receptor) that maintains CD16 on the cell surface and remains fully functional after NK cell activation, thus augmenting ADCC; 2) an IL-15 receptor fusion that promotes NK cell activity and enhances cell persistence; and 3) the knock-out of CD38 expression prevent anti-CD38 antibody-induced fratricide.
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Intervention Description
Vorinostat is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of cutaneous T-cell lymphoma and, under investigation in HIV as disruptor of HIV latency.
Primary Outcome Measure Information:
Title
Determine the safety and feasibility of administering FT538 monotherapy.
Description
At screen and baseline visits, all grades of signs and symptoms that occurred 30 days prior to the visit will be recorded. At all subsequent visits, all grades of signs and symptoms that occurred since the previous visit must be recorded as part of an Adverse Event (AE) assessment.
Time Frame
26 months
Secondary Outcome Measure Information:
Title
Characterize the toxicities associated with FT538 monotherapy and vorinostat.
Description
flow cytometric analysis for NK cell degranulation (CD107a).
Time Frame
30 months
Title
Determine the impact of FT538 on the persistence of low-level HIV viremia
Description
Defined as patients with detectable HIV-1 RNA of ≤200 copies/mL despite good ART adherence.
Time Frame
30 months
Other Pre-specified Outcome Measures:
Title
Characterize FT538 and Vorinostat Relationship with HIV RNA
Description
Ultrasensitive qPCR diagnostics will be used to quantify ratio of HIV RNA to single-copy levels.
Time Frame
30 months
Title
FT538 impact on frequency and phenotype of viral cells in PBMC lymphocyte subsets.
Description
Detection of viral antigens using an ultra-sensitive p24 system.
Time Frame
30 months
Title
Optional lymphoid tissue collection
Description
To determine the impact of FT538 on the frequency, location, and phenotype of viral RNA-positive and DNA-positive cells in lymphoid tissues (inguinal lymph node and colonic)
Time Frame
30 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female, age ≥18 and ≤65 years at the time of signing the consent form HIV-1 infection on continuous antiretroviral therapy (ART) for at least 12 months without any interruptions of greater than 14 consecutive days and without plans to modify ART before the End of Treatment visit. Two or more consecutive detectable HIV RNA levels of ≤200 copies/mL in the last 2 years, with at least one determination meeting this criterion in the previous 12 months. (If testing was not obtained within 42 days of planned dose 1, test will be repeated during subject screening to confirm status) Screening CD4+ T cell count ≥350 cells/ µl within 28 days of the 1st dose of FT538. Completion of initial COVID-19 vaccination series and/or documented COVID-19 infection with completion of treatment ≥ 3 months prior Patient weight of ≥ 50 kg due to FT538 fixed cell dosing and FT538 product pre-dosed packaging. Adequate organ function within 14 days of Day 1, defined as the following: Platelet counts >150,000/mm^3 Hemoglobin > 12.5 g/dL for men and > 11.5 g/dL for women. It is not acceptable for patients to be transfused within the prior month to meet this requirement. The use of Epogen is permitted. AST and ALT ≤ 3 x upper limit of institutional normal Estimated CrCl (eGFR) >50 mL/min/1.73m^2 Persons of childbearing potential or with partners of childbearing potential must be willing to abstain from heterosexual activity or to use a highly effective form of contraception from the time of study enrollment through at least 4 months after the last dose of FT538. Persons are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception. For Dose Cohort 4 (FT538 plus Vorinostat): Females of childbearing potential must use highly effective contraception from the time of study enrollment through 6 months after the last dose of vorinostat. Males with partners of childbearing potential must use highly effective contraception from the time of study enrollment through 3 months after the last dose of vorinostat or 4 months after the last dose of FT538, whichever is more conservative. Must agree to and sign the consent for the Master Long-Term Follow-Up study to fulfill the FDA recommended 15 years following exposure to the investigational gene therapy product. Voluntary written consent prior to the performance of any research related procedures. Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control for a minimum of 4 months after the last dose of FT538. If of childbearing potential, a negative pregnancy test is required within 14 days prior to the 1st dose of FT538 or within 7 days prior to the 1st dose of vorinostat if treated in Dose Cohort 4. Known allergy to the following FT538 components: albumin (human) or DMSO. Currently receiving or likely to require systemic immunosuppressive therapy (e.g., prednisone >5 mg daily) for any reason within 5 days before the 1st dose of FT538 and 14 days after the last dose of FT538 - inhaled and topical steroids are permitted. Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months - minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) is permitted. Prior history of solid organ transplant or hematopoietic stem cell transplant. Receipt of any investigational agent (not approved by the FDA for any indication) within 28 days prior to the first dose of FT538. Note that participation in prior HIV cure studies, including those involving IL-2 or N803, is permitted as long as experimental therapy completed >28 days prior. Chronic liver disease defined as Class B and C on the Child-Pugh scale. Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines, including a previous diagnosis of any of the following within the previous 12 months: (a) acute myocardial infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial revascularization, (e) stroke, (f) transient ischemic attack (TIA), or (g) peripheral arterial disease presumed to be of atherosclerotic origin. Moderate-severe obstructive lung disease. In subjects reporting a history of mild obstructive lung disease at screening, pulmonary function test (PFT) to be obtained and patient excluded from study if the FEV1 is <80% of predicted. Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease or receipt of medications for these conditions in the 2-year period leading up to study enrollment. Known concurrent or recent (defined as having received treatment within the last 3 months) infection with: Latent or active TB infection prior to completing a standard regimen of anti-TB therapy; defined as meeting PPD criteria for TB exposure or a positive quantiferon gold test collected at screening Active fungal infection requiring systemic antifungal therapy Chronic active hepatitis B or C. For Hepatitis B this will be defined as HBs antigen + and for Hepatitis C this will be defined as Hepatitis C antibody positive and Hepatitis C PCR+. COVID-19; defined as a positive SARS-CoV-2 PCR test at screening or a history of COVID-19 diagnosed within the last 3 months. Clinical vaccination administered within 6 weeks of the 1st dose of FT538. Presence of any social issues that, per investigator judgement, are likely to interfere with study conduct or may cause increased risk to patient. Patient history of alcohol or substance abuse that, per investigator judgement, are likely to interfere with study conduct or may cause increased risk to patient Any medical condition or clinical laboratory abnormality that, per investigator judgement, precludes safe participation in and completion of the study or that could affect compliance with protocol conduct or interpretation of results.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joshua Rhein
Phone
612-624-9452
Email
rhei0005@umn.edu
Facility Information:
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joshua Rhein
Phone
612-624-9452
Email
rhei0005@umn.edu

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Research related samples will be managed using established protocols in the Schacker Laboratory.

Learn more about this trial

Ph1 Study of FT538 Alone and With Vorinostat for Persistent Low-Level HIV Viremia

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