Administration of Venetoclax to Promote Apoptosis of HIV-infected Cells and Reduce the Size of the HIV Reservoir Among People Living With HIV on ART

NCT05668026 | Recruiting Phase 1 DMC

• 2 other identifiers: AMB-0012022-001677-31
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

In summary, there is a compelling rationale for investigating venetoclax as an intervention to sensitise virus-expressing cells to apoptosis and thereby reduce the size of the latent HIV reservoir. While this concept may ultimately need to be tested in the setting of concomitant latency reversal, the investigators propose to initially establish the safety of venetoclax in PLWH on ART. The investigators will use this study to also investigate effects of venetoclax monotherapy on proapoptotic pathways, immune effector function and HIV persistence in PLWH on ART and through these studies establish the rationale for subsequent studies testing venetoclax in combination with an LRA.

Conditions

HIV-1-infection

Keywords

HIV-1; bcl-2 inhibitor; venetoclax; anti-apoptotic protein

Outcome Measures

Primary Outcomes (1)

• To determine the safety of venetoclax in PLWH on ART

  Incidence of treatment-emerging adverse events (AEs) \>=grade 3 probably or definitely related to study treatment. Safety defined as all other treatment-emerging AEs, graded according to severity and assessed as either not related or possibly, probably or definitely related to study treatment.

  0-140 days

Secondary Outcomes (2)

• To determine the effect of venetoclax on HIV persistence in PLWH on ART

  0-140 days

• To determine the effect of venetoclax on proapoptotic pathways in PLWH on ART

  0-140 days

Study Arms (1)

Single-arm

EXPERIMENTAL

Study participants will receive venetoclax daily for 14 days followed by 21 days off defined as one cycle. This dosing will then be repeated for two additional cycles.

Drug: Venetoclax

Interventions

Venetoclax DRUG

In this study participants will receive venetoclax 200 mg, 400 mg or 800 mg once daily for 14 days in the dose-escalation phase. In the expansion cohort, the selected max-tolerated dose will be given for three cycles, each consisting of venetoclax daily for 14 days followed by 14 days off.

Single-arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented HIV-1 infection
• Age 18-65 years, both included
• Receiving combination ART for at least 2 years and being on the same ART regimen for at least 4 weeks at the screening visit
• HIV-1 plasma RNA \<50 copies/mL for \>2 years (documented on at least 2 occasions within the 2 years) and \<20 copies/mL at screening. Episodes of a single HIV plasma RNA 50-500 copies/mL will not exclude participation if the subsequent HIV plasma RNA was \<50 copies/mL
• CD4+ T cell count \>500 cells/yL at screening and at least two CD4+ T cell counts \>500 cells/yL in the 24 months prior to screening
• Ability and willingness to provide informed consent and to continue ART throughout the study
• For potential study participants who anticipate receiving a SARS-CoV-2 vaccine within the study period, enrolment and commencement of study therapy will be postponed until 4 weeks after completing SARS-CoV-2 vaccination, whereas screening procedures can be initiated before or concurrently with SARS-CoV-2 vaccination.
• A female, may be eligible to enter and participate in the study if she:
• Is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
• Is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
• Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications
• Any intrauterine device (IUD) with published data showing that the expected failure rate is \<1% per year
• Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject
• Approved hormonal contraception (Where other medications to be used in the study (e.g., efavirenz and darunavir) are known, or are likely, to significantly interact with systemic contraceptives, resulting in decreased efficacy of the contraceptive, then alternative methods of non-hormonal contraception are recommended)
• Any other method with published data showing that the expected failure rate is \<1% per year

You may not qualify if:

• Current or previous use of a BCL-2 antagonist or other pro-apoptotic agent used as cancer therapy
• Any concomitant disease where venetoclax treatment is indicated
• Current use of any moderate or strong CYP3A4 inhibitors (such as ketoconazole, voriconazole, posaconazole, itraconazole, ritonavir, cobicistat and clarithromycin)
• Current use of any HIV protease inhibitor (due to CYP3A4 inhibition)
• Current use of any strong inhibitor of the P-gp drug efflux pump (this includes cobicistat, ritonavir, azithromycin and clarithromycin)
• current use of drugs that are P-gp substrates (such as TDF, TAF and dolutegravir) is allowed but will require venetoclax dosing at least 6 hours after intake of those drugs
• for study participants receiving TDF or TAF we will perform enhanced renal monitoring by quantifying estimated glomerular filtration rate (eGFR) at each study visit during venetoclax administration
• Current use of strong CYP3A4 inducers (such as carbamazepine, phenytoin, rifampicin and St. John's wort); moderate CYP3A4 inducers (such as bosentan, efavirenz, etravirine, modafinil and nafcillin) may be used but should be avoided as much as possible
• Receipt of immunomodulating agents (excluding immunisation) or systemic chemotherapeutic agents within 28 days prior to study entry
• Any other current or prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study
• Known hypersensitivity to the components of venetoclax or its analogues
• Any significant acute medical illness in the past 4 weeks
• Any evidence of an active AIDS-defining opportunistic infection
• Individuals who intend to modify their ART regimen within the study period
• Current or recent gastrointestinal disease or gastrointestinal surgery that may impact the absorption of the investigational drug

Sponsors & Collaborators

• University of Aarhus: lead
• The Peter Doherty Institute for Infection and Immunity: collaborator
• Walter and Eliza Hall Institute of Medical Research: collaborator
• The Alfred: collaborator
• Aarhus University Hospital: collaborator

Study Sites (1)

Aarhus University Hospital

Aarhus, Denmark

RECRUITING

MeSH Terms

Interventions

venetoclax

Study Officials

• Thomas A Rasmussen

  Department of Infectious Diseases, Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

• Sharon R Lewin

  The Peter Doherty Institute for Infection and Immunity (Doherty Institute), University of Melbourne

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jesper D Gunst

CONTACT

23886636; jesdam@rm.dk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Dose-escalation study and an expansion cohort based on dose-limiting toxicities.

Study Record Dates

• First Submitted: December 19, 2022
• First Posted: December 29, 2022
• Study Start: April 1, 2024
• Primary Completion: March 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 1, 2025

Record last verified: 2024-04

Locations

DK (1)