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3524 Background: CP-868,596 is an orally available, highly specific inhibitor of platelet-derived growth factor receptors (PDGFR). PDGF and its receptor play an important role in angiogenesis, modulation of tumor interstitial fluid pressure (IFP), and influence cell growth, migration, and survival through signal-transduction pathways. Methods: The safety, tolerability and pharmacokinetics (PK) of daily oral CP-868,596 administered in 4-week cycles were assessed in patients with advanced solid malignancies. Original dose escalation cohorts were 100, 200, 280 and 340 mg QD administered on an empty stomach. Prevalence of persistent Grade 1 nausea and vomiting led to amendments that include “with food” cohorts. Safety assessments included adverse events (AEs), clinical laboratories, and ECG monitoring. PK blood samples were collected after a single dose and at steady state. PK parameters were estimated by non compartmental techniques. Results: Data is available for all 59 patients enrolled in the trial (29 M/30F); mean age (range): 58.6 (18–80). The most common treatment related AEs were nausea (67.8%), vomiting (55.9%) and diarrhea (25.4%). The MTD with coadministration of anti-emetics on an empty stomach was 200 mg/day. Coadministration of CP-868,596 with food resulted in a decrease of nausea and vomiting. The recommended phase 2 dose is 100 mg BID given with food. CP-868,596 was rapidly absorbed after oral administration. Median Tmax ranged from 1 to 4 hours. Cmax and AUC of CP-868,596 increased with dose more-than proportionally. Moderate accumulation occurred with a mean AUC accumulation ratio of 1.4–4.0. The mean terminal t1/2 ranged from 11.6 to 16.8 hours and was similar across all dose levels. The effect of food on PK appeared to be dose-dependent in this parallel cohort design with a limited number of patients (n=3–8). Analysis of safety data showed increasing liver enzymes with increasing PK exposures. No objective responses were seen. Conclusion: Daily administration of CP-868,596 appears to be safe and well tolerated. DLTs were: N/V (2), elevated ALT/GGT (2/2), increased Mg (1), Hematuria (1), and Insomnia (1). Mean steady state serum concentrations in all dose cohorts exceeded the preclinically predicted minimal efficacious exposure (16 ng/mL). No significant financial relationships to disclose.
Lewis et al. (Wed,) studied this question.