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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV I Infection
• Intervention / Treatment: Drug: Romidepsin; Biological: Vacc-4x; Biological: rhuGM-CSF

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 Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus University Hospital, Skejby Sygehus

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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 Names: Istodax®
Other: 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 Names: Istodax®; Biological: Vacc-4x; Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.; Other Names: 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 Names: Leukine®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	Safety and tolerability evaluation as measured by adverse events (AE) and serious adverse events (SAE).	3 weeks
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.	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.	Day 161/175

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	Day 56/84
Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	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).	287 days
Part B: Level of HIV-1 Transcription.	At day 105, 112 and 119 patients receive romidepsin and 4 hours after each administration HIV transcription is measured as unspliced HIV-1 RNA.	Day 105, 112 and 119

Collaborators and Investigators

• Sponsor: Bionor Immuno AS
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Lars Jørgen Østergaard, MD, PhD, Aarhus University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: March 3, 2014
• First Submitted That Met QC Criteria: March 17, 2014
• First Posted (Estimate): March 19, 2014

Study Record Updates

• Last Update Posted (Actual): March 1, 2017
• Last Update Submitted That Met QC Criteria: January 11, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Antibiotics, Antineoplastic; Romidepsin
• Other Study ID Numbers: BPC01-001; 2013-004747-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD 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.