A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors

3091 Background: BIBW 2992 is a highly potent irreversible dual EGFR /HER2 receptor tyrosine kinase inhibitor. This is the first trial performed in the United States with this compound. Methods: Patients with refractory solid tumors (historically known to express EGFR and/or HER2) with normal end-organ function and PS 0–1 were enrolled into a phase I dose-escalation clinical trial. After completion of eligibility and informed consent, BIBW 2992 was administered orally, once daily, for 21 days followed by a 7-day rest. Three patients were accrued in each cohort using a traditional dose escalation 3+3 trial design. After reaching DLT, the MTD dose group was expanded to 18 patients. PK sampling and skin biopsies were performed at baseline and day 21. Tumor biopsies in appropriate patients were obtained pre- and post-treatment in the final cohort to analyze inhibition of the EGFR pathway. Results: Forty-three patients were enrolled. Dose levels ranged from 10 to 65 mg daily. Tumor types included colon (10), breast (8), pancreas and ovarian (4), thyroid and esophageal (3), prostate and NSCLC (2), gastric, cholangiocarcinoma, basal cell, parotid, NPC, HCC, and mesothelioma (1 ). An interim PK analysis showed that BIBW 2992 exposure and peak plasma concentrations increased with increasing dose on day 1 and at steady state. Steady state was reached at day 8. Adverse events were diarrhea, skin rash, pruritus, mucositis, nausea, and vomiting. Doses were escalated to 65 mg/day, with two DLTs noted (skin rash and mucositis). The 40-mg dose was chosen as the recommended phase II dose based on acceptable toxicity when administered chronically. No objective responses have been observed; however, 15 of 35 evaluable patients (43%) experienced stable disease and have been on treatment for > 3 mos. Four patients have continued in an extension study. Two of these patients are still active and one has been taking BIBW 2992 for approximately 1 year. Conclusion: BIBW 2992 is well tolerated at 40 mg per day using a 21-day, 7-day off-treatment schedule. The adverse events observed were typical of receptor tyrosine kinases, including skin rash, pruritis, mucositis and GI disturbance. [Table: see text]