A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer

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Abstract
3011 Background: Oral PD 0325901 is a potent inhibitor of the dual-specificity kinases, MEK1/2 (MAPK/ERK/Kinase), thereby preventing phosphorylation and subsequent activation of mitogen-activated protein kinase (pMAPK/pERK). Methods: The Phase 1 component of this Phase 1–2 study tested oral PD 0325901 administered QD or BID for 21 days repeated every 4 weeks in patients with breast, colon, nonsmall cell lung cancer (NSCLC) or melanoma. Tumor tissue was assessed by immunohistochemistry (IHC) for pERK at baseline (BL) and Day 15 of Cycle 1. Pharmacokinetic (PK) samples were obtained on Days 1 and 21 in all patients and also on Day 1 of Cycle 2 in patients participating in a 2-way crossover food effect component. Due to elevated serum phosphorus with corresponding soft tissue mineralization observed in rats, serum Ca, P and (Ca x P) product were monitored closely. Results: From February through November 2004, 30 patients received 74 (range 1–8) cycles of PD 0325901 administered at 1mg QD, or at 1mg, 2mg, 4mg, 8mg, 15mg, 20mg or 30mg BID. In decreasing frequency, common toxicities included rash, fatigue, diarrhea, nausea, and vomiting. Acneiform rash involving face, trunk and arms was dose limiting (DLT) in one patient at 30mg BID. Transient and reversible visual effects including blurred vision and halos occurred in 5 patients receiving ≥15mg BID. There was no notable effect on serum (C x P) product. Mean Cmax and AUC increased with dose and administration of PD 0325901 with food appeared to delay Tmax, decrease Cmax, and had a variable effect on AUC. Doses ≥ 2mg BID consistently suppressed tumor pERK by an average of 84% relative to BL and doses ≥15 mg BID yielded average steady state plasma concentrations >270ng/ml predicted necessary for near maximal pERK suppression in xenograft models. Responses included 1 PR (melanoma) and 5 SD (4 melanoma, 1 NSCLC). Conclusion: PD 0325901 is well tolerated, suppresses pERK in tumor tissue, and demonstrated objective response in melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer

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