First-in-human study of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer: Update on safety and pharmacokinetics and initial report on pharmacodynamic responses and clinical benefit.

B229 Background: PF-00299804 is an orally bioavailable, potent, irreversible small molecule inhibitor of the HER tyrosine kinases Her 1, 2 and 4. A first-in-man phase I dose escalation study is ongoing. Preliminary results were reported at ASCO 2007. An expanded data set exploring clinical benefit and pharmacodynamics in cohorts enriched for specific genetic characteristics is included in the current report.
 Methods: Assessments were made of the safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles at doses ranging from 0.5 to 60 mg. In an expanded cohort within the phase I dose escalation study additional patients were recruited at the predicted recommended phase 2 dose (RP2D) for continuous dosing. Cohorts of patients dosed at the predicted RP2D were enriched for molecular variations of HER family receptors in multiple tumor types, as well as for wild type K-ras in refractory NSCLC patients. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG-PET/CT was performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Spearman correlations were assessed between AEs and dose, as well as AEs and PK parameters (Cmax, AUC, and Ctrough).
 Results: The most common AEs were diarrhea, fatigue, nausea, and rash. As previously reported, 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Other DLTs observed include diarrhea, rash, and pleuritic pain. The MTD was reached at 45 mg QD which was selected as the recommended phase 2 dose (R2PD). The terminal half life was ~85 hr, supporting once-daily dosing. Correlation was observed between severity of rash and dose as well as PK parameters. Objective tumor responses as assessed using RECIST criteria were observed in two patients with advanced refractory NSCLC. Both patients had failed at least 6 regimens of prior therapy; one patient who had progressed on erlotinib treatment had an exon 20 insertion mutation in EGFR. Data on these and on efficacy assessments within additional patients with other tumor types will be reported.
 Conclusions: Daily administration of PF-00299804 appears safe and tolerable across multiple dose levels up to 45mg/d. Rash-, Diarrhea, fatigue, and nausea, are the most frequent AEs, with rash severity correlating with dose and PK parameters. 45 mg/d has been declared the MTD and is being explored in expanded cohorts enriched for genetic variation in HER family receptors as well as in NSCLC patients wild type for K-ras. Clinical and biological activity of PF-00299804 was observed including objective responses in two patients with advanced refractory NSCLC including one erlotinib failure with EGFR mutation. Explorations of relationships between response and tumor molecular profiles will be reported.