Safety and Immune Response to Vicriviroc in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents

Safety and Immune Response to Vicriviroc in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents

Phase I/II Open-Label Study to Evaluate the PK, Safety, Tolerability and Antiviral Activity of Vicriviroc, a Novel CCR5 Antagonist in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents

Complications with current HIV antiretroviral therapy have left many children and adolescents with limited therapeutic options due to drug resistance. The purpose of this study is to test the effectiveness and safety of Vicriviroc (VCV), an HIV entry inhibitor and CCR5 co-receptor antagonist.

Highly active antiretroviral therapy (HAART) that includes a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) has become the standard treatment of HIV-infected adults and children. When effective, HAART decreases the viral population, increases the body's immune responses, and leads to decreased disease progression and increased survival. However, several factors including poor adherence, drug toxicities, and drug resistance complicate HIV management and allow for children and adolescents to develop resistance to multiple drug classes, leaving them with very limited therapeutic options. Fortunately, drugs with new mechanisms of action, such as HIV entry inhibitors, demonstrate activity even in people with resistance to the currently available reverse transcriptase and protease inhibitors. The purpose of this study is to test the effectiveness and safety of Vicriviroc (VCV), an HIV entry inhibitor. Vicriviroc targets the CCR5 chemokine receptor, which HIV uses to bind and enter CD4+ cells. This study is a two-stage, age-stratified, non-comparative study to explore the safety, tolerability, pharmacokinetic profile and antiviral activity of the investigational CCR5 inhibitor Vicriviroc in HIV-infected treatment experienced children and adolescents. In Step I participants will be screened for the co-receptor CCR5 to assess whether they can enter Step II. Only participants with CCR5-tropic virus are eligible for Step II - the main portion of the study to evaluate the study outcome measures. Those participants who continue to Step II will be assigned to one of four age-stratifies cohorts which will receive varying forms, either liquid or tablet, of Vicriviroc: Cohort I: 12 years to less than 19 years of age, to receive tablet formulation of VCV Cohort II: 6 years to less than 12 years of age, to receive tablet formulation of VCV Cohort III: 6 years to less than 12 years of age, to receive liquid formulation of VCV Cohort IV: 2 years to less than 6 years of age, to receive liquid formulation of VCV Dose strengths of 20 mg and 30 mg will be used, or in liquid formulation at a concentration of 1mg/mL. Step II is composed of Stage I and Stage II. Stage I is a dose ranging study designed to explore how the body responds to different doses of vicriviroc, including safety factors associated with dosage. After optimal dosage information and safety measures have been assessed for the different cohorts in Stage I, Stage II will open. Stage II will evaluate the long term safety, tolerability and effectiveness of vicriviroc. The study, including Steps I and II will last for approximately 48 weeks. Follow-up for all subjects exposed to vicriviroc will last for 5 years after initial exposure. Visits will be every 3 months for subjects on study provided vicriviroc and every 6 months for subjects who discontinue vicriviroc. The study was terminated shortly after the initiation, when the drug company decided to discontinue development of the study drug. As of study termination, nine participants had enrolled under Cohort I in Step I, but only 4 participants had CCR5 tropism and received the study medication under Step II. All 4 participants had limited post-baseline data.

Administered orally in either tablet or liquid form at a dosage of approximately 0.8/mg/kg every 24 hours, with a ritonavir boosted protease inhibitor containing background regimen

The protocol required reporting of signs and symptoms and laboratory abnormalities of >=Grade 2 and all grades of fever. The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs. Expedited adverse event reporting followed Version 2.0 of the DAIDS Expedited Adverse Event Manual.The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules is to be determined by the Study Team. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.

Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RCC website at (http://rcc.tech-res.com/). All grade 3 and higher signs, symptoms, and laboratory toxicities were included.

For Stage I subjects who are enrolled in Step II, the average of the pre-dose and 24 hour post dose sample from the intensive PK evaluations of said subjects will be used as the estimate of Cmin. The whole cohort will fail the PK targets if the population target (median vicriviroc Cmin should be =>200 ng/mL) is not met, and that nearly all of subjects' Cmin failed to be > 100 ng/mL.

Number of Participants Who Failed to Achieve =>1-log Drop From Baseline in HIV-1 Viral Load and HIV-1 Viral Load of =>400 Copies/mL (Virologic Failures)

Plasma HIV RNA (RNA) concentrations were determined at entry and at regular intervals using the HIV-1 MONITOR Test, version 1.5 (Roche Molecular Diagnostics) or RealTime HIV-1 (Abbott Molecular). The primary definition of virologic success will require subjects to have achieved and maintained 1-log drops from baseline of HIV-1 RNA or HIV-1 RNA <400 copies/mL.

Among all patients enrolled in Step I, the prevalence of detectable coreceptor phenotype, R5 tropic, R5/X4 mixed and X4 tropic viruses will be evaluated. The extent to which coreceptor phenotype in Step I is associated with Step I CD4 cell count, HIV RNA, and age will be evaluated. The association of Step I coreceptor phenotype and nadir CD4, HIV subtype, number of ART regimens, and years of ART will be evaluated. At the time of virologic failure, the extent of change from Step I and/or baseline R5 tropic virus to R5/X4 mixed or to X4 tropic virus as detected by the TrofileTM assay will be evaluated.

Change in CD4 count from baseline to weeks 24 will be presented both in the aggregate and broken down by age cohort.

Change in CD4 percent from baseline to weeks 24 will be presented both in the aggregate and broken down by age cohort.

Number of subjects with changes in genotypic and phenotypic drug resistance to the OBT and to vicriviroc (envelope sequence) from baseline to Week 24 and/or virologic failure will be presented both in the aggregate and broken down by age cohort.

Changes in HIV RNA (copies/mL) from baseline to Week 24 will be presented both in the aggregate and broken down by age cohort.

Inclusion Criteria: Confirmed HIV infection Treatment experienced subjects: Children or adolescents on an unchanged therapeutic regimen for at least 12 weeks and experiencing virologic failure OR participants on no treatment for 4 weeks or more but with history of virologic failure on a prior therapeutic regimen. Likely to have virus that is sensitive to at least one ritonavir boosted protease inhibitor HIV viral load greater than or equal to 1,000 copies/ml within 90 days prior to Step I entry Able to swallow study medication, in tablets or liquid form specific to age-assigned cohort Parent, legal guardian or participant able and willing to provide signed informed consent and to have the participant followed at the clinic site Willing to use effective methods of contraception Inclusion Criteria for Step II (In addition to the inclusion criteria for Step I): Participant's plasma HIV tested at Step I must be R5 tropic Genotypic sensitivity enabling the participant to take optimized background therapy (OBT) consisting of at least a ritonavir-based protease inhibitor. More information on this criterion can be found in the study protocol. Exclusion Criteria: Presence of any currently active AIDS defining illness or history of malignancy History of a seizure disorder that requires current anti-seizure medication for control or at risk for seizures. Those with a history of febrile seizures alone are not excluded. Certain abnormal laboratory values. More information on this criterion can be found in the protocol. Any vaccinations 14 days prior to Step I, or scheduled to occur within 14 days prior to entry into Step II, and the week 24 and 48 visits in Step II Allergy or sensitivity to study drug or its ingredients Taking any Step II disallowed medications (see protocol) and unable or unwilling to discontinue them at least one week prior to entering Step II Use of NNRTIs other than etravirine 21 days prior to Step II entry Pregnancy or breastfeeding. Infants who are receiving breastmilk are allowed to enroll. Exclusion Criteria for Step II All exclusion criteria for Step I Participants harboring dual or mixed tropic virus (R5/X4) or X4 virus or non phenotypable virus Current or anticipated use of any disallowed medications Use of efavirenz, nevirapine, and delavirdine for 21 days prior to Step II entry Pregnant within 3 days of Step II entry

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