Phase 1b study of oral CP-868,596, a highly specific PDGFR inhibitor, in combination with docetaxel.

A238 Background: CP-868,596 is a highly specific inhibitor of the platelet-derived growth factor receptor (PDGFR) tyrosine kinase, with nanomolar potency. PDGFR inhibition is antiangiogenic and may modulate tumor interstitial pressure, both of which may increase the efficacy of chemotherapy. The primary objective of this study was to assess the safety and tolerability of CP-868,596 in combination with Doc (docetaxel). Methods: Phase 1 dose escalation study of CP-868,596 given orally, twice daily in combination with docetaxel in 21 day cycles. Endpoints included safety, tolerability, PK and antitumor activity. Patients received 100 mg BID of CP-868,596 given on an empty stomach over 14 days, followed by a cohort dose (60 or 100 mg BID given with food) for 7 days. On day 22, Doc (75 mg/m 2 or 100 mg/m 2 IV) was administered. Safety assessments included adverse events (AEs) and clinical laboratories. PK samples for each patient were collected on Day 15 (CP-868,596 only) and for CP-868,596 and Doc on Days 21-23 . PK parameters were estimated by non compartmental techniques. Results: 33 pts were treated with demographics M:F = 24:9; 97% Caucasian, median age 55 (range 25-78); PS 0-1 97%. Primary tumor sites: NSCLC (24.2%), G.I. malignancy (21.2%), Sarcoma (21.2%), Prostate (12.1%), and Other (21.1%). AEs possibly related to CP-868,596 in over 10% of pts included nausea, diarrhea, vomiting and lethargy. AEs were generally CTC grade 1-2 and reversible. DLTs included febrile neutropenia (2), and nausea and vomiting (2). Cmax and AUC 0-12hr of CP-868,596 (n=11) were not different when administered at 100 mg BID with food either as a single agent or combined with docetaxel (75 mg/m 2 ). Evidence of antitumor activity was observed, including one patient with a clinical response to single-agent CP-868,596. Conclusions: CP-868,596 at the RP2D of 100 mg BID can be combined with Doc at both 75 and 100 mg/m 2 without a significant increase in toxicity. PK interactions between CP-868,596 and docetaxel was not evident in the preliminary analysis. Clincial response was observed.