Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001).

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m(2) every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m(2), which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.