Abstract C31: Phase 1 study of AV-412, a novel irreversible EGFR inhibitor, administered daily in patients with advanced solid tumors

Abstract

Background: Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib is a frequent clinical phenomenon in non-small cell lung cancer (NSCLC). Approximately 50% patients (pts) with acquired resistance to EGFR TKIs demonstrate the T790M mutation in EGFR gene. AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models with acquired resistance to EGFR TKIs (bearing the T790M mutation), and is being developed for treatment of NSCLC. Methods: Pts with advanced, incurable solid tumors were enrolled in a phase 1 study and administered AV-412 orally once-a-day. Doses evaluated were: 50mg, 100mg, 150mg and 200mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose limiting toxicity (DLT), pharmacokinetics (PK) and activity of AV-412. Results: 24 pts were treated: 13 males/11 females, median age 61 yrs (range 32–73). ECOG PS 0 (17 pts) or 1 (7 pts). Tumor types (No. of pts) were colorectal (5), NSCLC (3), pancreatic (3), uterine (3), melanoma (2), ovarian (2), hepatocellular (1), breast (1), head and neck (1) and other (3). Mean number of prior treatments were 6 (range 1–15). Five (20.8%) pts had received prior therapy with an EGFR inhibitor. The median duration of treatment was 32.5 days (range 7 – 214 days). Two pts experienced DLT at 200mg (grade 3 nausea and vomiting, and grade 3 diarrhea), following which anti-emetic premedications were instituted in the study. The MTD of AV-412 was 150mg; 11 pts were treated at this dose. The most common treatment-related adverse events (all grades) were nausea (54.2%), diarrhea (45.8%), and vomiting (41.7%); hematologic abnormalities included lymphopenia, increased INR, anemia, and leucopenia (12.5% each), hepatic and renal abnormalities included increased ALT, increased AST, and proteinuria (12.5% each). Drug-related laboratory abnormalities were generally mild to moderate in severity. Preliminary PK data indicate dose proportional exposure. Three patients had disease stabilization > 16 weeks: 2 pts with colorectal cancer (116 days, 170 days) and a pt with ovarian cancer (172 days). Conclusions: AV-412 is well tolerated at a dose of 150 mg/day. The most frequent toxicities were nausea and diarrhea, which could be controlled with standard medications. This study is currently enrolling a cohort of patients with NSCLC to evaluate clinical activity of AV-412 in patients with EGFR mutations, and updated results will be available for presentation. A phase 1 study of intermittent dosing of AV-412 is also being conducted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C31.

Epidermal Growth Factor Receptor Inhibitor Treatment Timing does not Impact Survival in Stage 4 Colon Cancer Treatment: A Retrospective Study

“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] EGFR inhibitors have shown to have severe toxicities which can influence the patient's quality of life and may affect the decision to begin treatment with these medications. 7,8, [28][29][30][31][32][33][34][35][36][37] Inferior patient outcomes of EGFR inhibitor treatment in later lines might be an important determinant for the decision to choose a different chemotherapy to avoid the risk of these toxicities and potential treatment delays. It is also important for clinicians to have justifications for the use of EGFR inhibitors in later lines.…”

Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles

“…AV‐412 ( 30 ) potently inhibits recombinant EGFR (IC 50 1.4 nM), EGFR mutants; L858R (0.51 nM), T790M (0.79 nM), L858R/T790M (2.3 nM), and HER2 (19 nM) . Phase I clinical trials for advanced solid tumors have been completed , but no more trials are ongoing to date .…”