A phase I dose escalation trial of pulsatile high dose gefitinib and docetaxel in patients with an advanced solid tumor

Abstract

3132 Background: Gefitinib has known anti-tumor activity with partial response, durable stable disease and symptom improvement in NSCLC. Concurrent gefitinib and other EGFR-TKI with chemotherapy failed to demonstrate an advantage over chemotherapy alone in phase 3 studies. We have shown that pulsatile administration of gefitinib and taxane therapy in mice xenograft studies allowed for gefitinib dose-escalation and was significantly more effective than continuous therapy. Methods: We initiated a phase 1 study in patients with a solid tumor to study gefitinib preceding docetaxel to determine the MTD and toxicity of pulsatile gefitinib (days 1 and 2) + docetaxel (75 mg/m2 day 3). The starting dose of gefitinib is 1000 mg/day with 6 dose escalation levels planned: 50%→50%→33%→33%→25%. Gefitinib PK was obtained Cycles 1 and 2 of each dose level. Results: We have completed the first two dose levels (n=9 patients). Patient characteristics: 2 F, 7 M; KPS median 80% (70–90%); age median 62 years; prior chemotherapy median 1 regimen (0–2); 4 patients with NSCLC, 3 patients with H/N, 1 patient with NPC, and 1 patient with thyroid cancer. Median cycles = 4 (2–7). No DLTs were observed for the 1st dose level of 1000 mg/day of gefitinib. Toxicities during cycle 1 at dose level 1 (n=3): G1–2 rash (n=3), G3 neutropenia (n=1), G1 diarrhea (n=1). At the 2nd level, 1 patient experienced neutropenic fever and grade 3 hyperbilirubinemia. The dose level was expanded to 6 patients and no further DLT was observed. Toxicities during cycle 1 of dose level 2 (1500 mg/day) (n=6): G1–2 rash (n=3), G1–2 fatigue (n=2), G2 neutropenia (n=1), G4 neutropenia (n=1), G3 hyperbilirubinemia (n=1), G1 diarrhea (n=2). 1 patient with anaplastic thyroid carcinoma with dermal metastases experienced a partial response. 2/3 pretreated H/N patients had symptom improvement and disease stabilization (>7 cycles). Conclusions: Preliminary results suggest that pulsatile high dose gefitinib preceding docetaxel is well tolerated without dose limiting diarrhea or rash to date. We are currently accruing to dose level 3 (gefitinib 2250 mg/day). Supported in part by AstraZeneca. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca