Purpose: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients.Experimental Design: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics.Results: Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving ≥15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the doselimiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease ≥4 months. PD-0325901 exposure was generally dose proportional. Doses ≥2 mg BID consistently caused ≥60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (≥50%) in Ki-67.Conclusions: PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use. Clin Cancer Res; 16(6); 1924-37. ©2010 AACR.The RAS-mitogen-activated protein kinase (MAPK) pathway has emerged as a critical signaling network involved in the regulation of cell growth and survival. The RAS-MAPK cascade mediates proliferative and antiapoptotic signaling from growth factors and oncogenic factors (such as gain-of-function RAS and RAF mutant phenotypes) that promote tumor growth, progression, and metastasis. The RAS-MAPK pathway is constitutively active in several solid tumor types (1-4).MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) occupies a pivotal position in the RAS-MAPK pathway and serves as a focal point for several mitogenic signaling pathways activated by known oncogenes (e.g., BRAF, ErbB, and RAS; refs. 5-7). Although MEK has not been identified as an oncogene itself, constitutively active MEK has been shown in >30% of primary tumor cell lines tested (including colon, lung, breast, pancreas, ovary, and kidney; ref. 2). Constitutively active MEK shows transforming ability and has resulted in highly tumorigenic cell lines in vitro (6, 7). MEK is a dual-specificity kinase and phosphorylates its only known substrates, ERK1/2 (MAPK), on both a tyrosine and threonine residue. Note: This article is part of a two-part st...

Purpose AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. Experimental design In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750–1,000 mg/m2 on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). Results Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n= 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m2 and AZD7762 9 mg cohort). Conclusions The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m2 was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.