Abstract A184: A phase I study of 5-azacytidine (AZA) and erlotinib (E) for patients (pt) with advanced solid tumors

Abstract

Abstract Background: Erlotinib (E), a tyrosine kinase inhibitor of EGFR, is approved for non-small cell lung cancer. 5-Azacytidine (AZA) is approved for leukemia. AZA traps DNA methyltransferase (DMT) in a covalent complex with DNA resulting in a progressive loss of DNA methylation, at concentrations that do not cause major suppression of DNA synthesis. Hypomethylation reactivates previously quiescent genes and may restore the function of genes that control cell proliferation and differentiation, such as EGFR. Methods: A standard 3+3 phase I study of the combination of E and AZA was planned in patients with incurable solid tumors. E was given at full dose (150 mg/day continuously). Vidaza was given intravenously every 2 weeks at a starting dose of 75 mg/m2/day ×1 day. Increments were by number of AZA days: The second cohort received 2 consecutive days of Vidaza, the third, 3 days, the fourth, 4 days. One course was 4 weeks. Standard grade 3 and 4 DLTs (CTCAE version 3) were recorded on the first course of treatment. RECIST criteria were used to determine response. Results: 18 adult patients (pt) have been enrolled. Cohort 1: 6 pt; cohort 2, 3 pt; cohort 3, 6 pt; cohort 4, 3 pt. DLTs included eye infection (1 pt in cohort 1) and a neutropenic sepsis in cohort 3. Both cohorts were expanded. Overall AEs were: grade 3 rash, diarrhea, and hypokalemia (1 each (5%)); grade 1–2 rash (60%), nausea/vomiting (38%), diarrhea (38%), fatigue (33%), mouth sores and dysgeusia (22% each), hypokalemia (16%), transaminase increase (11%), neutropenia (5%), pneumonitis (5%), urticaria (5%). The maximum tolerated dose has not been reached at 75 mg/m2/day × 4 days every 2 weeks. Enrollment will continue until AZA 100 mg/m2/day × 4 days is reached. ORR is 5% with a clinical benefit rate of 40%, and the median number of courses given is 2 (range 1–6). Conclusions: The combination of E and AZA is well tolerated with no synergistic toxicities. The main AEs are rash and gastrointestinal. E+AZA has modest but definite activity in patients with refractory tumors, and long disease stabilization are observed in selected patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A184.