A phase Ib study of CUDC-101, a multitargeted inhibitor of EGFR, HER2, and HDAC, in patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer.

Abstract

e13101 Background: CUDC-101 is a small molecule EGFR/HER2 receptor tyrosine kinase and HDAC inhibitor that has shown promising activity in cancer cell lines and tumor xenograft models. A previous Phase 1 study showed 275 mg/m2 to be the maximum tolerated dose when given daily for 5 days every 2 weeks (QDx5). Dose limiting toxicity included transient creatinine elevation. This expansion Phase 1b study was conducted to further evaluate safety and tolerability of the QDx5 and of a three dose per week (3x/week) schedule for 3 weeks every 4 weeks. Methods: Eligible patients (pts) ≥18 years with advanced breast, gastric, head and neck, NSCLC or liver cancer (n = 10/tumor type); adequate marrow and organ function; and an ECOG PS ≤2 were assigned to receive CUDC-101 (275 mg/m2) on QDx5 or 3x/week schedule. NSCLC patients required documented EGFR exon 19 or 21 mutation/deletion with recent acquired resistance to erlotinib. Study parameters included safety (CTCAE v.3), antitumor response (RECIST v1.1), PK (blood and urine) and PD (tumor biopsy and CTC) assessments. Results: A total of 46 pts were treated (23/dose schedule), including 25 (54%) males, mean age 62 yrs, PS 0/1/2 (33/56/11%), and a median of 3 prior regimens (range, 0-7). The overall incidence and severity of treatment-related AEs were similar between the 2 dose schedules, including fatigue, transiently increased creatinine, nausea, vomiting, decreased appetite, anemia and asthenia, each occurring in <20% of all pts and mostly Grade ≤ 2. Grade 3 AEs were reported in 4 pts. Overall, 15 (33%) pts had SD as their best response: 4 pts had SD for >14 weeks, including 1 with head and neck (QDx5), and 2 with liver (1 lasting 47 weeks) and 1 gastric cancer (all 3 on 3x/week). Paired tumor biopsies were available for one pt showing target inhibition. CTC and PK analyses are ongoing. Conclusions: CUDC-101 was well tolerated using either dosing schedule, with preliminary evidence of antitumor activity. The more convenient 3x/week schedule was selected for an ongoing Phase 1 combination study.