The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART
|First Received Date ICMJE||March 17, 2011|
|Last Updated Date||January 15, 2014|
|Start Date ICMJE||March 2011|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||To compare RCVL in HIV-infected patients on stable ART, before and after a single exposure to VOR, after a pair of exposures to VOR, and after multiple exposures to VOR. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
HIV RNA expression per 1 million resting CD4+ cells (RCVL) after the second of a pair of VOR doses, in participants who exhibited an increase in HIV RNA expression per 1 million resting CD4+ cells after a single 400 mg dose of VOR (HIV RNA per million resting CD4+ T cells). We will compare the HIV RNA expression per 1 million resting CD4+ cells obtained at the leukapheresis after paired VOR doses to the level obtained at baseline leukapheresis on stable ART.
|Original Primary Outcome Measures ICMJE
||To compare HIV RNA expression within resting CD4+ cells in HIV-infected patients on stable ART before and after a single exposure to VOR [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
The frequency of detectable HIV RNA expression within resting CD4+ T cells will increase after VOR exposure in vivo.
|Change History||Complete list of historical versions of study NCT01319383 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||a) safety, tolerability, and PK profile of VOR; b) alterations in global histone acetylation and histone acetylation of the host p21 gene promoter, c) changes on plasma HIV-1 RNA. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
A single oral administration of VOR in combination with ART to patients with HIV-1 infection will be safe and tolerable.
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART|
|Official Title ICMJE||A Phase I/II Investigation of the Effect of Vorinostat (VOR) on HIV RNA Expression in the Resting CD4+ T Cells of HIV-Infected Patients Receiving Stable Antiretroviral Therapy|
The purpose of this study is to compare HIV RNA expression and infection within resting (CD4)+ cells in HIV-infected patients on stable ART before and after a single exposure to Vorinostat (VOR), after exposure to short intervals of VOR, and after repeated short interval exposure to VOR dosed over several weeks.
This is a Phase I-II single-center study in participants (ppts) with HIV-1 infection receiving stable ART, with plasma HIV RNA < 50 copies/mL. Baseline ART will be maintained throughout the study. Participants will be screened for study entry, and then undergo an initial leukapheresis evaluation at study entry to obtain resting CD4+ T cells for quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL) at a baseline evaluation. All participants who enter the study will receive VOR at assigned study visits, and undergo repeat leukapheresis to measure the effects of VOR exposure.
Participants with and without an ex vivo response to VOR (baseline leukapheresis [Visit 2.0]) will be evaluated for an in vivo response to the single dose of VOR 400 mg. Participants who completed Step 1 in protocol v3.0 and v5.0 are eligible to enroll directly into Step 2 after being consented to Version 6.0 and completing Step 1, Visits 1 and 2 of this protocol. The leukapheresis at Visit 2 will be optional based on prior ascertainment of baseline parameters. Omission of the leukapheresis at visit 2 will be determined by study PI. Enrollment and completion of required research assays will be completed at this study visit. Enrollment into Step 1 will continue until 12 evaluable participants have successfully completed multiple doses of VOR (Step 3), or until the study-stopping rules are met.
Step 1 includes four visits: screening (visit 1), enrollment and baseline Leukapheresis (Visit 2), single dose administration of VOR (visit 3) and safety follow up (Visit 4). It is estimated that up to 30 eligible participants may be screened and enrolled to provide a total of 12 evaluable participants who complete Step 3. VOR 400 mg will be administered as a single dose at study Visit 3. Each participant will only receive 400 mg VOR at this one time point. An abbreviated pharmacokinetics (PK) as well as a leukapheresis procedure will be part of Visit 3. It is anticipated that Step 1 will occur over a minimum of 8 weeks. All participants must complete Step 1 prior to moving to Step 2. All participants will be assessed after the Visit 3 leukapheresis for an in vivo response to the 400 mg of VOR.
Progression from Step 1 (single dose) to Step 2 (paired doses) will be based on each participant's increase in RCVL following their first dose of 400 mg VOR (Visit 3), compared to that measured at baseline (Visit 2). Progression from Step 2 (paired doses) to Step 3 (multiple doses) will be based on each participant's increase in RCVL following the 3rd dose of 400 mg VOR (Visit 6), compared to that measured at baseline (Visit 2).
The goal of this study is to determine the optimal interval between two doses of VOR (Step 2), and the response of RCI (and secondarily RCLV) to repeated doses at this interval (Step 3).
Step 2 will be initiated at least 4 weeks after the completion of the Step 1 safety follow up visit (Visit 4). If greater than 60 days elapse between Visit 4 and Visit 5, participants will repeat screening Visit labs to qualify for continued study participation. In Step 2, two paired doses of VOR 400 mg will be administered. The interval between the 2 paired doses can be as short as 48 hours, and as much as 4 days apart from each other, and participants will be assessed via a 3rd leukapheresis for in vivo response to the second of the paired doses of 400 mg VOR. The first three (3) participants will first be assessed for an in-vivo response after the 2nd dose of the paired doses given 48 hours (2 days) apart. Subsequent participants will be assessed for responses to paired doses separated by 48 hours, or the interval may be lengthened to as much 96 hours (4 days), as dictated by the accumulated responses observed in subsequent participants.
If at least 2 of the 3 participants with 48-hour intervals respond (defined as a significant within-subject increase in cell-associated HIV RNA, see Fig 3), then 3 subsequent participants will receive 48-hour intervals. If 2 of these 3 respond 4 of 6 total), then 3 additional participants will receive 48-hour intervals. If among the first 6 evaluable participants receiving 48-hour intervals there are 3 non-responders, then subsequent participants will receive 72-hour intervals. Participants receiving 72-hour intervals will then be assessed in the same way as those receiving 48-hour intervals, to either continue additional participants at 72-hour intervals or to increase to 96-hour intervals. Step 2 will enroll until a total of 12 evaluable subjects with a measureable increase in cell-associated HIV RNA are obtained, and these volunteers have advanced to Step 3.
Our preliminary results from version 5.0 are consistent with the hypothesis that the complex cellular effects of HDAC inhibitor exposure require more than 24 hours to resolve. We observed what appears to be an antagonistic effect where a VOR dose blunts the effect of the next dose when two doses are given within 24 hours of each other. The purpose of Step 2 is to establish the optimal dosing interval in which a response to Vorinostat is sustained. Step 2 will study dosing intervals; starting with a 48-hour interval and moving to longer intervals between doses depending on the effect observed with the ultimate goal to determine the shortest interval that yields an optimal effect of VOR.
If a participant fails to respond in their initial Step 2 dosing interval, they can be eligible to repeat Step 2. They can re-enter or repeat Step 2 one time only. They will only re-enter Step 2 to test a longer dosing interval. Again, if > 60 days elapses between the final safety visit of step 2 (Visit 7) and their re-entry to Step 2, they will re-screen (visit 1 only) to qualify to continue in the study.
After a period of at least 6 weeks, to allow data analysis, participants who demonstrate an in vivo response to the 2nd of the paired dose of VOR will proceed to Step 3 and receive 10 doses of VOR 400 mg administered at the same interval at which cell-associated HIV-RNA induction was observed in Step 2. If greater than 60 days elapse between Visit 7 and Visit 8, participants will repeat the screening visit labs to qualify for continued participation in the study. At the completion of 10 doses, participants will then be assessed via a 4th and final leukapheresis for in vivo response to the serial dosing of VOR.
It is anticipated that Step 3 will occur over a minimum of 4 weeks; however this may vary among participants based on their Step 2 dosing interval stage. Accumulated blood volumes and the timing between leukapheresis procedures will determine the length of time between each stepsParticipants completing this protocol (version 6.0), who respond initially in Step 2 will receive a total of 5200 mg of Vorinostat. Participant completing the study, who repeat Step 2, will receive a total of 6000 mg of Vorinostat. For reference, participants who completed the previous version (5.0) received a total of 10,000 mg of Vorinostat without clear evidence of any durable drug-associated toxicity thus far.
The change in the frequency of HIV-1 infection per million resting CD4 + cells will be measured after repeated short interval dosing with VOR in Step 3. This 4th leukapheresis (Visit 12) will be compared to the baseline leukapheresis done at Visit 2. If the VOR 400 mg dosing in Step 3 is interrupted due to toxicity or intolerance, then the leukapheresis will be performed as soon as possible after the VOR interruption. This is justified as if a depletion of resting cell infection can occur; new resting cell infection is unlikely to occur in the presence of ART. Test dosing in this Step will continue until the study's stopping (lack of response in five) or toxicity rules are met.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||HIV-1 Infection|
|Intervention ICMJE||Drug: Vorinostat
Drug administration - Step 1 - 400mg Vorinostat will be given as single doses by mouth at visits 2 and 5.
Step II - 400 mg VOR for 3 consecutive days a week (for a maximum of 8 weeks).
|Study Arm (s)||Experimental: Vorinostat
Step 1 - Screening (Visit 1), Enrollment (Visit 2) and Single Dose Vorinostat 400 mg (Visits 3 & 4)
Step 2 - Visits 5 and 6 - Paired Doses of Vorinostat 400 mg and Leukapheresis.
Step 3: Visits 8 - 13 Multiple Doses of Vorinostat 400 mg and Leukapheresis
Intervention: Drug: Vorinostat
|Publications *||Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||30|
|Estimated Completion Date||March 2016|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Hematological: Absolute Neutrophil Count (ANC) ≥ 1,500/mcL Platelets ≥ 125,000/mcL Hgb ≥ 12 g/dL
Coagulation: Prothrombin Time or International Normalized Ratio (INR) ≤ 1.5x upper limit of normal (ULN)
Chemistry: K+ levels Within normal limits Mg++ levels > Lower limits of normal (LLN) but <1.5 x ULN Glucose Screening serum glucose(fasting/non-fasting) below 120 mg/dl.
Renal: Serum creatinine/calculated creatinine clearance* ≤ 1.3 X ULN OR ≥ 60 mL/min for participants with creatinine levels > 1.3 X ULN
Hepatic: Serum total bilirubin Total bilirubin < 1.5 times ULN. If total bilirubin is elevated, direct bilirubin will be measured and the participant will be eligible if the direct bilirubin is < 2 X ULN.
Aspartate amino transferase (AST) (SGOT) and Alanine amino transferase (ALT) (SGPT)≤ 2.0 X ULN Lipase <1.6 X ULN Alkaline Phosphatase ≤ 2.5 X ULN
*Creatinine clearance should be calculated per institutional standard.
11. Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within the last 30 days. Potential participants may enroll after a 30-day washout period.
12. Known hypersensitivity to the components of VOR or its analogs. 13. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. Pregnancy or breast feeding, or expecting to father children within the projected duration of the study.
15. Inability to communicate effectively with study personnel.
|Ages||18 Years to 65 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01319383|
|Other Study ID Numbers ICMJE||CID 0807, 1U01AI095052-01|
|Has Data Monitoring Committee||Yes|
|Responsible Party||David Margolis, MD, University of North Carolina, Chapel Hill|
|Study Sponsor ICMJE||University of North Carolina, Chapel Hill|
|Information Provided By||University of North Carolina, Chapel Hill|
|Verification Date||January 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP