Abstract
BackgroundAST1306 is an orally active irreversible small molecule inhibitor of EGFR (erbB1), HER2 (erbB2) and HER4 (erbB4) signaling. This is a phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306. In addition the effects of food on PK was tested.MethodsA modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.ResultsSeventy-one patients were enrolled, with breast (n = 22) and lung cancers (n = 14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n = 1), 1500 mg BID (n = 1), 800 mg TID (n = 1) and 1200 mg TID (n = 2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean Tmax was prolonged, Cmax was increased, and AUC0-∞ was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for ≥ 6 months was achieved in 7 patients.ConclusionsBased on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.
Highlights
The epidermal growth factor family of membrane receptor tyrosine kinases consists of the epidermal growth factor receptor (EGFR; erbB1) and human epidermal growth factor receptor (HER) 2, HER3 and HER4 [1]
This is exemplified by the development of resistance to EGFR tyrosine kinase inhibitor (TKI), through emergence of a secondary T790M EGFR mutation in nonsmall-cell lung carcinoma (NSCLC) [3], which occurs in 50% of the patients with lung adenocarcinoma [4]
Irreversible erbB family blocker may be beneficial to the patients with EGFR-TKI resistant NSCLC and trastuzumab resistant HER2-positive metastatic breast cancer (MBC) [5]
Summary
The epidermal growth factor (erbB) family of membrane receptor tyrosine kinases consists of the epidermal growth factor receptor (EGFR; erbB1) and human epidermal growth factor receptor (HER) 2 (erbB2), HER3 (erbB3) and HER4 (erbB4) [1]. A number of small-molecule tyrosine kinase inhibitors (TKIs) (e.g., gefitinib, erlotinib, lapatinib) and antibodies (eg, trastuzumab, cetuximab, panitumumab) targeting the erbB family have been developed to treat breast, colorectal, lung, gastric and head and neck squamous cell cancers [2]. Despite the improvements achieved in patients treated with reversible inhibitors of EGFR or EGFR and HER2, primary and acquired resistances to these agents remain a clinical challenge. This is exemplified by the development of resistance to EGFR tyrosine kinase inhibitor (TKI), through emergence of a secondary T790M EGFR mutation in nonsmall-cell lung carcinoma (NSCLC) [3], which occurs in 50% of the patients with lung adenocarcinoma [4]. In addition the effects of food on PK was tested
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