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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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HIV I Infection

Intervention / Treatment
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* Drug: Romidepsin
* Biological: Vacc-4x
* Biological: rhuGM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Currently receiving cART and having received cART for a minimum of 1 year HIV-1 plasma RNA <50 copies/mL for at least 1 year (excluding viral load blips) CD4 T cell count ≥500 cells/mm3 Exclusion Criteria: CD4 T cell count nadir <200 cells/mm3 Previous treatment with an HDACi (Histone deacetylase inhibitor) within the previous 6 months 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 Use of any protocol defined contraindicated medication or vaccination Unacceptable values of the hematologic and clinical chemistry parameters as defined in the protocol. Males or females who are unwilling or unable to use protocol defined methods of contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Part A<br>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<br>* Latency reversing agent<br>* Other names: Istodax®;|
| Other: Part B<br>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<br>* Latency reversing agent<br>* Other names: Istodax®;Biological: Vacc-4x<br>* Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.<br>* Other names: A combination of Vacc-10, Vacc-11, Vacc-12 and Vacc-13;Biological: rhuGM-CSF<br>* Granulocyte macrophage colony stimulating factor as a local adjuvant<br>* Other names: Leukine®;|

What is the study measuring?
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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 |