Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in patients with solid tumors
3557 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB inhibitor of the tyrosine kinase receptors, erbB-1,-2 and -4. In this phase 1 study, a combination dose of neratinib plus paclitaxel that is tolerable was determined in patients (pts) with solid tumors, and safety and preliminary efficacy were assessed in pts with erbB-2+ metastatic breast cancer. Methods: In this open label, 2-part study, ascending multiple daily oral doses of neratinib (160 mg, 240 mg) were administered in combination with IV paclitaxel 80 mg/m2, if tolerable, or 70 mg/m2 on days 1, 8 and 15. Pts with solid tumors and pts with only metastatic erbB-2+ breast cancer are enrolled in part 1 and 2, respectively. Tumor measurements were made at screening and at every 8 weeks (2 cycles) by modified RECIST criteria. Timed blood samples were collected for neratinib and paclitaxel plasma concentration determination, and PK analyses were performed using a noncompartmental method. Results: Data for 54 pts as of 30 Oct 2008 are presented (median age [range] of 51.5 [20–74] yrs; 91% female; 26 % with prior trastuzumab treatment of median duration [range] 32.5 [10–52] wks; 15% with prior lapatinib treatment). Tumor types in part 1 included breast, endometrial, cervical, colorectal and esophageal cancer. There were no dose-limiting toxicities (DLTs) at the 240 mg neratinib-80 mg/m2 paclitaxel dose, and as standard doses of neratinib and paclitaxel were reached, there was no reason for further escalation. Neratinib-related AEs, any grade in ≥10% of pts included diarrhea (50%), neutropenia (17%), rash (13%), nausea (11%) and vomiting (11%). Neratinib- related AEs, grade ≥3 in ≥2% of pts were diarrhea (20%), neutropenia (9%) and dehydration (4%). Only 2 pts (at the 240 mg neratinib-80 mg/m2 paclitaxel dose) had dose reductions due to diarrhea. In 35 efficacy evaluable pts, 5 had confirmed partial response (PR). Confirmed clinical benefit (PR and prolonged disease stabilization) was seen in 2 pts in part 1, 1 pt with endometrial cancer and 1 pt with cervical cancer. Conclusions: This combination of 240 mg neratinib and 80 mg/m2 paclitaxel was tolerable with a toxicity profile similar to that observed for neratinib, and had promising antitumor activity in pts with solid tumors and erbB-2 + breast cancer. [Table: see text]