Phase I study of AV-412, a novel, irreversible EGFR inhibitor, administered intermittently in patients with advanced solid tumors.

Abstract

3103 Background: AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models bearing the L858R/T790M mutation. A daily dosing study identified a maximally tolerated dose (MTD) of 150 mg/day [AACR-NCI-EORTC 2009]. The goals of this study were to determine the MTD, safety, dose limiting toxicity (DLT), pharmacokinetics (PK), and activity of AV-412 administered on two intermittent dosing schedules. Methods: Patients (pts) with incurable solid tumors were enrolled and administered AV-412 orally three times a week (TIW). Once the MTD was identified, a once weekly (OW) schedule was evaluated. Doses ranged from 100-200 mg TIW to 200-500 mg OW. Results: 36 patients were treated: 26 males/10 females, median age 60 years (range 27-80). ECOG PS 0/1 (21/15 pts). Tumor types were colorectal (17), pancreatic (4), appendiceal (3), esophageal (2), NSCLC (2), and other (8). Median number of prior treatments were 4 (range 0-14). Twenty-four pts (66.7%) received a prior EGFR inhibitor. The median duration of treatment was 49 days (range 1- 99). Two pts experienced DLT in cycle 1 at 200 mg TIW (grade 3 nausea and vomiting, and grade 3 diarrhea), therefore the MTD was 100 mg. In the OW schedule, two pts experienced DLT in cycle 1 at 500 mg (grade 3 acute renal failure, and grade 3 diarrhea) and 400 mg OW was declared the MTD. Common treatment-related adverse events (all grades) were nausea (69.4%), diarrhea (55.6%), vomiting (41.7%), and fatigue (27.8%). Treatment-related skin rash was rare (2.7%). Preliminary PK data showed less than dose proportional exposure and high interpatient variability. Preliminary efficacy data revealed 8 pts had stable disease with a median duration of 7.7 weeks. Conclusions: AV-412 is well tolerated at 400 mg once weekly. The OW schedule was able to achieve a higher MTD and Cmax when compared to daily dosing. Additional studies are under discussion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO AVEO