A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

Abstract

Background: AST1306 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.

Methods: A 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.

Results: Seventy-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 T(max) was prolonged, C(max) was increased, and AUC(0-∞) 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.

Conclusions: Based 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.

Figure 1

Waterfall plot of best responses, as percentage decrease in tumor size by RECIST, of the target lesions in patients. Fifty-five patients had measurable disease by RECIST and had at least 1 evaluation. The numbers above or below the bars represent the number of months the responders and patients with SD lasting ≥ 6 months received AST1306. * No EGFR or HER2 status; † EGFR exon 19/exon 20 double mutation; ‡ HER2 positive.

Figure 2

A 67-year old female patient diagnosed with MBC who had experienced treatment failure after 2 chemotheraphy and 2 hormonal regimens, but did not receive trastuzumab. She had confirmed PR at the 1500 mg BID dose level of AST1306, but withdrew from the study after 9 months due to continuous grade 2 diarrhea. A) CT imaging of the metastatic lesion prior to starting therapy, and B) shows the response to AST1306 two cycles after starting therapy. C and D shows continued response three and ten cycles after starting therapy.