ABSTRACT
PURPOSE: This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off x 3wks q4wks; S2). RESULTS: Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2-4) and tremors (Grade 2-3). In S2, DLTs included tremors (Grade 2-3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. CONCLUSION: The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Quinazolines/administration & dosage , Receptor, trkA/antagonists & inhibitors , Adolescent , Adult , Aged , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/metabolism , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/blood , Pyrazoles/pharmacokinetics , Quinazolines/blood , Quinazolines/pharmacokinetics , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887. RESULTS: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. PATIENTS AND METHODS: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated. CONCLUSION: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.
Subject(s)
Antineoplastic Agents/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Cyclin-Dependent Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrroles/adverse effects , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , CDC2 Protein Kinase/antagonists & inhibitors , CDC2 Protein Kinase/metabolism , Cohort Studies , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic useABSTRACT
A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.
