Yali Zhu

Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors

Purpose: To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen. Experimental Design: In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m2 or 175 mg/m2 administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient. Results: Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m2. Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses. Conclusions: When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m2 of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.

Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib

Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR‐ABL‐positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib‐resistant cells and increases imatinib‐induced apoptosis in vitro in cells from imatinib‐resistant patients.

Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer☆

OBJECTIVES Dinaciclib (MK-7965, formerly SCH 727965), a novel, small-molecule inhibitor of cyclin-dependent kinases, has been shown to induce apoptosis in preclinical studies of human tumor cell lines, including non-small cell lung cancer (NSCLC) cells. Erlotinib, an epidermal growth factor receptor inhibitor, is approved for the treatment of advanced NSCLC as second- or third-line therapy. This phase 2, randomized, multicenter, open-label study compared dinaciclib with erlotinib in patients with previously treated NSCLC. MATERIALS AND METHODS The study was comprised of 2 parts: in part 1, patients were randomized to either intravenous (IV) dinaciclib (50 mg/m2) or oral erlotinib (150 mg) using an adaptive Bayesian design that adjusted the randomization ratio in favor of the more active arm, and in part 2, patients who had progressed on erlotinib were permitted to cross over to receive dinaciclib at the same dosage as in part 1. Patients were followed until disease progression or death, initiation of nonstudy cancer treatment, discontinuation, or withdrawal of consent. The primary efficacy end point was time-to-progression (TTP) in part 1 and objective response rate (ORR) in part 2. RESULTS Based on Kaplan-Meier estimates, the median TTP was 1.49 months (95% confidence interval [CI]: 1.31, 2.63) following initial treatment with dinaciclib, compared with 1.58 months (95% CI: 1.38, 2.83) with erlotinib. No objective responses were observed following initial treatment with dinaciclib. Common severe (grade 3 or 4) drug-related adverse effects included neutropenia, leukopenia, vomiting, and diarrhea. CONCLUSIONS Dinaciclib, administered IV, was well tolerated at the 50 mg/m2 dose, but does not have activity as monotherapy in previously treated NSCLC. Evaluation of dinaciclib in combination with other agents for other indications including breast cancer and multiple myeloma is in progress.

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARY Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin. Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130 mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14 days: lovastatin 20 mg; lovastatin 20 mg plus ezetimibe 5, 10, or 20 mg; lovastatin 40 mg plus ezetimibe 10 mg; or placebo. Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20 mg combined with lovastatin 20 mg caused a significantly ( p < 0.01) greater reduction in LDL-C than lovastatin 20 mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10 mg plus lovastatin 20 mg, 56.0% with ezetimibe 10 mg plus lovastatin 40 mg, 33.2% with lovastatin alone, and 17.3% with placebo. Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10 mg appears to be the optimal dose when co-administered with lovastatin 20 mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.

The Influence of Multiple-Dose Vorapaxar, an Oral PAR-1 Receptor Antagonist, on the Single-Dose Pharmacokinetics and Pharmacodynamics of Digoxin

Vorapaxar is a novel orally active thrombin receptor antagonist selective for the PAR‐1 receptor. This open‐label, single‐center, fixed‐sequence, 2‐period, 2‐treatment study assessed the pharmacokinetics and pharmacodynamics of single‐dose digoxin in the presence/absence of multiple‐dose vorapaxar. Eighteen healthy adult subjects received two treatments in a fixed sequence separated by ≥8‐day washout: (A) digoxin 0.5 mg (Day 1); (B) vorapaxar 2.5 mg/day Days 1–6 and single‐dose vorapaxar 40 mg administered with single‐dose digoxin 0.5 mg Day 7. The geometric mean ratio (%; GMR) for the two treatments (digoxin alone and digoxin plus vorapaxar) and 90% confidence intervals (CIs) for and AUCtf and Cmax of digoxin were calculated. Pharmacodynamics of digoxin was assessed by measuring changes in electrocardiogram (ECG) parameters. The GMR (90% CIs) estimates for digoxin AUCtf and Cmax were 105% (91, 121) and 154% (130, 181), respectively. Except for differences in peak plasma concentrations, the pharmacokinetics of digoxin were similar between the two treatments. Coadministration of vorapaxar plus digoxin had no effect on digoxin Tmax or ECG parameters. The results of this study suggest that the coadministration of vorapaxar and digoxin is unlikely to cause a clinically significant drug–drug interaction.

A Phase I Multicenter Study of Continuous Oral Administration of Lonafarnib (SCH 66336) and Intravenous Gemcitabine in Patients With Advanced Cancer

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median Tmax values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m2 is the maximum tolerated dose with acceptable safety and tolerability.

Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies

Background:Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity.Methods:In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography.Results:Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m−2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred.Conclusions:Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

Effects of age and gender on the pharmacokinetics of lonafarnib (L) following a single oral dose

L (SCH 66336), a tricyclic farnesyl protein transferase inhibitor, is being developed for the treatment of various cancers. A single‐dose study in healthy volunteers was conducted to evaluate the effects of age and gender on L pharmacokinetics (PK). Subjects, stratified by age and gender into 4 groups (young male, young female, elderly male, and elderly female), received 100 mg L orally in the morning. Plasma samples were collected and L concentrations were determined by LC‐MS/MS. Mean (%CV) PK parameters and statistical results are: (see Table 1 )

PI-15Pharmacokinetics of lonafarnib, a farnesyl protein transferase inhibitor, in pediatric patients with brain tumors

Lonafarnib (L, SCH 66336) is an oral farnesyl protein transferase inhibitor (FPTI). Ras mutations or over‐expression have been identified in both adult and pediatric brain tumors. Pre‐clinical studies have demonstrated that both ras mutant and non‐mutated tumors that signal through this pathway can be effectively inhibited by FPTI. In addition to assessment of the dosing‐limiting toxicities and maximally tolerated dose (MTD), an objective of this Phase 1 study was to assess the pharmacokinetics (PK) of L in children with brain tumors.

Lack of pharmacokinetic (PK) interactions between lonafarnib (L) and imatinib (I)

L (SCH 66336), an oral farnesyl protein transferase inhibitor, is being developed for the treatment of hematologic malignancies. In vitro data suggest that L can inhibit proliferation of I‐resistant cells and increases I‐induced apoptosis. An objective of this Phase 1 study was to evaluate the potential for a PK interaction between L and I.