Safety and Efficacy of Romidepsin and the Therapeutic Vaccine Vacc-4x for Reduction of the Latent HIV-1 Reservoir (REDUC)

• ClinicalTrials.gov Identifier: NCT02092116
• Recruitment Status: Completed
• First Posted: March 19, 2014
• Results First Posted: March 1, 2017
• Last Update Posted: March 1, 2017
• Sponsor: Bionor Immuno AS
• Collaborator: Celgene Corporation
• Information provided by (Responsible Party): Bionor Immuno AS

Study Description

Brief Summary:

The REDUC trial's objective is to address one of the core issues with the treatment of HIV, which is that some HIV infected cells hide in so-called latent reservoirs. The reservoirs are unaffected by conventional HIV medication and invisible to the immune system. HDACi have the potential to activate these latently infected cells. This will make the HIV infected cells visible to the immune system; the immune response generate by Vacc-4x will be able to attack and eliminate the infected cells.

Condition or disease	Intervention/treatment	Phase
HIV I Infection	Drug: Romidepsin; Biological: Vacc-4x; Biological: rhuGM-CSF	Phase 1; Phase 2

Detailed Description:

The study is divide into two parts. In Part A the safety and tolerability of romidepsin will be evaluated and the effect of romidepsin treatment on HIV-1 transcription in HIV-infected patients virologically suppressed on cART will be determined.

In Part B the effect of treatment with Vacc-4x + rhuGM-CSF and romidepsin treatment on the HIV-1 latent reservoir in HIV-infected patients virologically suppressed on cART will be measured.

Six patients will be enrolled for part A and the safety and tolerability profile evaluated before enrolling 20 patients in B.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Phase I/IIa Study to Evaluate the Safety and Effect of Therapeutic HIV-1 Immunization Using Vacc-4x + rhuGM-CSF and HIV-1 Reactivation Using Romidepsin on the Viral Reservoir in Virologically Suppressed HIV-1 Infected Adults on cART
• Study Start Date: March 2014
• Actual Primary Completion Date: August 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

Arm	Intervention/treatment
Part A; Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14. Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.	Drug: Romidepsin; Latency reversing agent; Other Name: Istodax®
Part B; Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8). A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir. A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).	Drug: Romidepsin; Latency reversing agent; Other Name: Istodax®; Biological: Vacc-4x; Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.; Other Name: A combination of Vacc-10, Vacc-11, Vacc-12 and Vacc-13; Biological: rhuGM-CSF; Granulocyte macrophage colony stimulating factor as a local adjuvant; Other Name: Leukine®

Outcome Measures

Primary Outcome Measures :

1. Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: 3 weeks ]
   Safety and tolerability evaluation as measured by adverse events (AE) and serious adverse events (SAE).
2. Part B: Changes From Baseline in HIV-1 Reservoir (Total HIV-1DNA; Integrated HIV-1 DNA in Unfractionated CD4+ T Cells and Replication Competent Provirus. [ Time Frame: Day 161/175 ]

   Total HIV-1 DNA and integrated HIV-1 DNA were analysed by MMRM analysis (copies/10^6 CD4+ T cells). To estimate the frequency of infectious units per 10^6 resting memory CD4+ T cells a quantitative viral outgrowth assay (qVOA) was used.

   Blood samples were obtained at Day 0, Day 105 and Day 161.

Secondary Outcome Measures :

1. Part A: Changes From Baseline in HIV-1 Reservoir (Total HIV-1DNA; Integrated HIV-1 DNA in Unfractionated CD4+ T Cells and Replication Competent Provirus. Estimates of Change From Baseline of the Size of the Latent HIV-1 Reservoir in CD4+ Cells. [ Time Frame: Day 56/84 ]

   Total HIV-1 DNA and integrated HIV-1 DNA were analysed by MMRM analysis (copies/10^6 CD4+ T cells). To estimate the frequency of infectious units per 10^6 resting memory CD4+ T cells a quantitative viral outgrowth assay (qVOA) was used.

   Total HIV-1 DNA was measured at Day 84

2. Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: 287 days ]
   Safety and tolerability evaluation of romidepsin and Vacc-4x in combination with GM-CSF as measured by adverse events (AE) and serious adverse events (SAE).
3. Part B: Level of HIV-1 Transcription. [ Time Frame: Day 105, 112 and 119 ]
   At day 105, 112 and 119 patients receive romidepsin and 4 hours after each administration HIV transcription is measured as unspliced HIV-1 RNA.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age >18 years
2. Currently receiving cART and having received cART for a minimum of 1 year
3. HIV-1 plasma RNA <50 copies/mL for at least 1 year (excluding viral load blips)
4. CD4 T cell count ≥500 cells/mm3

Exclusion Criteria:

1. CD4 T cell count nadir <200 cells/mm3
2. Previous treatment with an HDACi (Histone deacetylase inhibitor) within the previous 6 months
3. Any evidence of an active AIDS-defining opportunistic infection, active HBV or HCV co-infection, significant cardiac disease, malignancy, transplantation, insulin dependent diabetes mellitus or other protocol defined excluded medical condition
4. Use of any protocol defined contraindicated medication or vaccination
5. Unacceptable values of the hematologic and clinical chemistry parameters as defined in the protocol.
6. Males or females who are unwilling or unable to use protocol defined methods of contraception

Contacts and Locations

Locations

Denmark

Aarhus University Hospital, Skejby Sygehus

Aarhus N, Denmark, 8200

Sponsors and Collaborators

Bionor Immuno AS

Celgene Corporation

Investigators

• Principal Investigator: Lars Jørgen Østergaard, MD, PhD; Aarhus University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Leth S, Schleimann MH, Nissen SK, Hojen JF, Olesen R, Graversen ME, Jorgensen S, Kjaer AS, Denton PW, Mork A, Sommerfelt MA, Krogsgaard K, Ostergaard L, Rasmussen TA, Tolstrup M, Sogaard OS. Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial. Lancet HIV. 2016 Oct;3(10):e463-72. doi: 10.1016/S2352-3018(16)30055-8. Epub 2016 Jul 7.

Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK, Kjaer AS, Schleimann MH, Denton PW, Hey-Cunningham WJ, Koelsch KK, Pantaleo G, Krogsgaard K, Sommerfelt M, Fromentin R, Chomont N, Rasmussen TA, Ostergaard L, Tolstrup M. The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog. 2015 Sep 17;11(9):e1005142. doi: 10.1371/journal.ppat.1005142. eCollection 2015 Sep.

• Responsible Party: Bionor Immuno AS
• ClinicalTrials.gov Identifier: NCT02092116
• Other Study ID Numbers: BPC01-001; 2013-004747-23 ( EudraCT Number )
• First Posted: March 19, 2014
• Results First Posted: March 1, 2017
• Last Update Posted: March 1, 2017
• Last Verified: January 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Participants have not provided informed consent for their anonymized individual data to be made available beyond that described in the patient information sheet.

Additional relevant MeSH terms:

Romidepsin; Antibiotics, Antineoplastic; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action