Study to Evaluate the Safety and Effect of HIVconsv Vaccines in Combination With Histone Deacetylase Inhibitor Romidepsin on the Viral Rebound Kinetic After Treatment Interruption in Early Treated HIV-1 Infected Individuals

An Open Label Phase I Trial to Evaluate the Safety and Effect of HIVconsv Vaccines in Combination With Histone Deacetylase Inhibitor Romidepsin on the Viral Rebound Kinetic After Treatment Interruption in Early Treated HIV-1 Infected Individuals (BCN02-Romi)

The BCN02-Romi study aims to evaluate a combined "kick and kill" strategy using the most immunogenic candidate vaccine available so far (HIVconsv) with the strongest latency reversal agent available at present time (romidepsin) in a cohort of early-treated HIV positive individuals.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: MVA.HIVconsv vaccine; Drug: Romidepsin

Detailed Description

The combined use of therapeutic vaccination and specific drugs that can reactivate latent virus from the reservoir (Kick and kill strategies) hold the promise to achieve functional cure and viral eradication of HIV infection. The present project consists of a proof-of-concept clinical trial in a cohort of 24 early treated HIV-1 infected individuals rolled-over from the BCN01 vaccine clinical trial in which participants received the most immunogenic vaccines tested to date, ChAd and modified vaccinia Ankara (MVA).HIVconsv vaccines. All individuals will be given a booster immunization with MVA.HIVconsv in combination with romidepsin (RMD), a potent histone deacetylation inhibitor (HDACi) and will later undergo a monitored antiretroviral pause. HIVconsv vaccines have specifically been designed to stimulate a broad and potent cytotoxic T cell (CTL) response towards the most conserved viral regions of the HIV-1 proteome, which have recently been suggested to have a crucial role when targeting HIV variants harboured in the latent reservoir with mutations to escape T-cell immune responses. The study includes the development of a population pharmacokinetic/pharmacodynamic (PK/PD) substudy to analyse the in vivo effects of RMD in the induction of HIV expression in resting cells, deeply investigate any unintended effect on the CTL function as well as predict the relationship between RMD exposure and such effects. The investigators' results will allow investigators to optimize RMD dosing, to evaluate the clinical efficacy of this eradication strategy after the cART interruption and to identify better correlates of control of rebound viremia after cessation of treatment.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Clinic Hospital
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Germans Trias I Pujol Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject included in ChAd-MVA.HIVconsv_BCN01 study with complete follow-up and included in BCN01-RO extension study.
2. Optimal virological suppression for at least 3 years.cop/ml).
3. Being on a non-boosted integrase-inhibitor based regimen (raltegravir or dolutegravir) for at least 4 weeks at screening visit.

4. Haematological and biochemical laboratory parameters as follows:

   • Haemoglobin > 10g/dl
   • Platelets > 100.000/dl
   • Alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
   • Creatinine ≤ 1.3 x ULN
5. CD4 T cell count ≥500 cells/mm3

Exclusion Criteria:

1. Positive pregnancy test.
2. Presence of resistance drug mutations in the screening genotype
3. History of autoimmune disease other than HIV-related auto-immune disease.
4. Treatment for cancer or lymphoproliferative disease within 1 year of study entry
5. Any other prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study
6. Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MVA.HIVconsv plus romidepsin	Drug: MVA.HIVconsv vaccine; Dose: 2x10e8 pfu, Interval: weeks 0 and 9.; Drug: Romidepsin; Dose: 5mg/m2 over 4hours, Interval: weeks 3, 4 and 5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with grade >=3 adverse events assessed by Division of AIDS (DAIDS) grading table	Grade >=3 adverse events	Through study completion, maximum 75 weeks
Number of participants with serious adverse events	Serious adverse events	Through study completion, maximum 75 weeks
Viral reservoir measured by total HIV-1 DNA copies per 10e6 CD4+ T cells	Total HIV-1 DNA copies per 10e6 CD4+ T cells	From baseline to visit week 6 (romidepsin 3 + 1 week)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Romidepsin Cmax	RMD plasma concentrations will be measured by Liquid chromatography-mass spectrometry (LC-MS/MS)	week 3
Romidepsin Cmax	RMD plasma concentrations will be measured by LC-MS/MS	week 4
Romidepsin Cmax	RMD plasma concentrations will be measured by LC-MS/MS	week 5
Romidepsin Cmin	RMD plasma concentrations will be measured by LC-MS/MS	week 3
Romidepsin Cmin	RMD plasma concentrations will be measured by LC-MS/MS	week 4
Romidepsin Cmin	RMD plasma concentrations will be measured by LC-MS/MS	week 5
Romidepsin area under curve (AUC)	RMD plasma concentrations will be measured by LC-MS/MS	week 3
Romidepsin AUC	RMD plasma concentrations will be measured by LC-MS/MS	week 4
Romidepsin AUC	RMD plasma concentrations will be measured by LC-MS/MS	week 5
HIV-1 expression in resting CD4+ T-cells measured by CA-RNA and single-copy assay (SCA)		week 6
Levels of Histone H3 acetylation in lymphocytes		week 6
CTL toxicity assessment based on viability, activation or exhaustion (most relevant marker according to previous studies)		week 6
HIVconsv-specific T cell responses will be measured by IFNg ELISPOT using peptide pools covering different HIV proteins and HIVcons sequences.		week 6
Viral suppressive capacity of CD8+ T cells in vitro, using a flow cytometric assay		Baseline
Viral suppressive capacity of CD8+ T cells in vitro, using a flow cytometric assay		Week 17
Proportion of individuals who initiate a MAP following the futility analysis		Week 17
Proportion of individuals who maintain sustained plasma viral load (pVL) <2,000 copies/ml		Week 29
Proportion of individuals in whom cART is reinitiated due to viral rebound		Up to 51 weeks
Emergence of viral resistance during MAP phase	Description of viral resistance emerged, genotype.	Up to 51 weeks
Proportion of patients with viral suppression 6 months after treatment resumption.		24 weeks after treatment resumption (up to 75 weeks).

Collaborators and Investigators

• Sponsor: IrsiCaixa
• Collaborators: Hospital Clinic of Barcelona; University of Oxford; Germans Trias i Pujol Hospital; Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia; Hospital de Sant Pau; HIVACAT; BCN Checkpoint

Publications and helpful links

General Publications

• Munoz-Moreno JA, Carrillo-Molina S, Martinez-Zalacain I, Miranda C, Manzardo C, Coll P, Meulbroek M, Hanke T, Garolera M, Miro JM, Brander C, Clotet B, Soriano-Mas C, Molto J, Mothe B; BCN02-Neuro Substudy Group. Preserved central nervous system functioning after use of romidepsin as a latency-reversing agent in an HIV cure strategy. AIDS. 2022 Mar 1;36(3):363-372. doi: 10.1097/QAD.0000000000003121.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): October 30, 2017

Study Registration Dates

• First Submitted: November 9, 2015
• First Submitted That Met QC Criteria: November 25, 2015
• First Posted (Estimate): November 30, 2015

Study Record Updates

• Last Update Posted (Actual): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 16, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: HIV infection; HIV reservoir; Therapeutic Vaccines; Early treatment; Romidepsin; HDACi; HIVconsv; Population PK/PD analysis
• Additional Relevant MeSH Terms: Antineoplastic Agents; Antibiotics, Antineoplastic; Romidepsin
• Other Study ID Numbers: BCN02-Romi