Phase I study of the novel, oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK): Evaluating the pharmacokinetic effect of a high-fat meal in patients with hormone-refractory prostate cancer (HRPC)

Abstract

4689 Background: PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptors, important mediators of tumor growth and metastasis. This phase I study in patients (pts) with HRPC assessed the effect of food on the pharmacokinetics (PK) of PTK/ZK and evaluated safety and preliminary efficacy (defined as changes in serum prostate-specific antigen [PSA] levels). Methods: Pts with HRPC received 1,000 mg/day PTK/ZK and were randomized to fed or fasted conditions on days 15, 18, 22, and 25. Blood was collected over 24 hr to assess the PK of PTK/ZK and PSA levels. Results: Of 23 pts treated, 1 pt discontinued due to disease-related adverse event (AE), and 3 due to drug-related AEs. PK data from 19 evaluable pts showed that administration of PTK/ZK with food resulted in a delay in absorption (Tmax increased from 2.0 to 4.0 hr; P < .001), decreased Cmax by 12% (fed:fasted ratio of 0.88; 90% CI = 0.72, 1.08), and increased AUC by 27% (fed:fasted ratio of 1.27; 90% CI = 1.07, 1.52). PK variability was moderate with intrapatient CV% of 21% - 25% and interpatient CV% of 42% for Cmax and AUC; variability was slightly higher under fed conditions. Commonly reported AEs were mostly grades 1/2: nausea (70%), dizziness (52%), headache (52%), hypertension (39%), vomiting (39%), arthralgia (35%), fatigue (30%), constipation (26%), anorexia (17%), back pain (17%), bone pain (13%), and cough (13%). Grade 3 AEs (> 5%) were hypertension (17%) and syncope (9%). The incidence of AEs was similar on fasting and fed days. Overall median time to PSA progression (TTP) was 2 mo. One pt had a 68% reduction from baseline in serum PSA level and TTP of 12 mo; 2 other pts demonstrated > 40% reductions in PSA and TTP of 4 and 5 mo, respectively. Conclusions: The small food effect observed in this study was not associated with higher frequency or severity of AEs on fed vs fasted days, suggesting that the small but statistically significant food effect is not clinically significant, and that PTK/ZK may be taken with or without food. PTK/ZK also exhibited clinical activity in pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Schering AG