Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory CLL patients with intact organ function and WBC < 200 × 109/L. Five separate dose levels (5 mg/m2, 7 mg/m2, 10 mg/m2, 14 mg/m2, and 17 mg/m2) were explored dosing on a weekly schedule × 3 with one week off (4 week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two DLTs at the 17 mg/m2 dose (TLS and pneumonia). The phase II expansion occurred at 14 mg/m2 with sixteen patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the MTD was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities, and tumor lysis syndrome. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.

We applied model‐based meta‐analysis of viral suppression as a function of drug exposure and in vitro potency for short‐term monotherapy in human immunodeficiency virus type 1 (HIV‐1)‐infected treatment‐naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class‐specific models relating viral load kinetics from monotherapy studies to potency normalized steady‐state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long‐term efficacy in combination therapy, in order to set steady‐state trough concentration targets of 6.17‐ and 2.15‐fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose–response of new antiretrovirals to inform early clinical trial design.

A791 between 2010 and 2015 were conducted. For each CAV appraisal, information regarding the level of evidence and clinical effectiveness was collected. Results: Twenty antiviral drugs (47 indications) were assessed. All obtained a favourable opinion for reimbursement with 11 a major to moderate CAV, 14 a minor and 22 no CAV. No one obtained a major CAV. The majority of studies [46% (22/47)] were non-active comparator studies based on virological response and supported an important to moderate CAV in 32% (7/22), as sofosbuvir that granted the highest CAV level (important CAV). Among the 19 comparative trials, 68% (13/19) were of superiority design supporting a major to moderate CAV in 31% (4/13) of the cases. A higher proportion of important to moderate CAV were observed in trials using a relevant primary endpoint (26%) versus no one for a study using an exploratory endpoint such as pharmacokinetic endpoint. ConClusions: A high proportion (53%) of CAV is recognized in virology compared to the other therapeutic areas (15%) while non-active comparator studies are made. This report shows that HAS appraisals remain multi-factorial. HAS' expectations in terms of level of evidence take into account the medical need, therapeutic area specificity and a rapid evolution of the therapeutic strategy. The emergence of anti-viral drug resistance can also influence the CAV appraisal.