Phase I accelerated dose-escalation, pharmacokinetic (PK) and pharmacodynamic study of PF-03814735, an oral aurora kinase inhibitor, in patients with advanced solid tumors: Preliminary results

Abstract

2517 Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes and have been linked to tumorigenesis. Aurora kinase A is commonly amplified in solid tumors and has been established as an oncogene. Aurora B is over-expressed in tumors and leads to defects in mitosis and increased invasiveness. PF-03814735 is a novel oral ATP-competitive, reversible inhibitor of Aurora A and B kinases with a broad spectrum of preclinical activity. Methods: This is an accelerated dose-escalation study to identify the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose, and to obtain proof-of-mechanism (by assessment of pH3 inhibition in tumor biopsies and FDG-PET) with PF-03814735 administered daily for 5 or 10 consecutive days in 3-week cycles. Results: Twenty patients received a median of 2 cycles (1–4) across 7 dose levels from 5 to 100 mg/day for 5 days. Tumor types included colorectal (5), breast (3), NSCLC (4), SCLC (2), bladder, melanoma, ovarian, renal, head and neck and cancer of unknown primary (1 each). The dose was doubled in single patient cohorts until treatment-related grade 2 diarrhea occurred in one patient at 40 mg/day. Afterwards, cohorts included 3–7 patients with 20–50% dose increments per cohort. In the first 16 patients, the most common treatment-related adverse events were mild to moderate diarrhea (50%), vomiting (25%), anorexia, fatigue, and nausea (19% each). Dose-limiting febrile neutropenia was observed in 2/7 patients treated at 100mg/day. No objective response has been reported. One ovarian cancer patient has received 4 cycles at 80 mg/day. One head and neck cancer patient has received 4 cycles at 100 mg/d and continues. Serum exposure of PF-03814735 (Cmax and AUC) increased in a dose-proportional manner at all dose levels. After a single dose, the total clearance of PF-03814735 is 1195±393 mL/hr and median terminal half-life is 19.1 hr. PK of PF-3814735 is linear. Conclusions: The MTD was defined as 80 mg/day for five days. This dose level is currently being expanded to obtain proof-of-mechanism data at the recommended phase II dose. Dose escalation on the 10-day treatment schedule is occurring simultaneously. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer