Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors

Toshiaki Takahashi, Narikazu Boku, Haruyasu Murakami, Tateaki Naito, Asuka Tsuya, Yukiko Nakamura, Akira Ono, Nozomu Machida, Kentaro Yamazaki, Junichiro Watanabe, Ana Ruiz-Garcia, Keiji Imai, Emiko Ohki, Nobuyuki Yamamoto, Toshiaki Takahashi, Narikazu Boku, Haruyasu Murakami, Tateaki Naito, Asuka Tsuya, Yukiko Nakamura, Akira Ono, Nozomu Machida, Kentaro Yamazaki, Junichiro Watanabe, Ana Ruiz-Garcia, Keiji Imai, Emiko Ohki, Nobuyuki Yamamoto

Abstract

Background: Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases.

Methods: This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity.

Results: Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease.

Conclusions: Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.

Figures

Fig. 1
Fig. 1
Mean (SD) plasma concentration–time profiles of dacomitinib following single (panel a; D-9) and multiple (panel b; C1D14) dosing
Fig. 2
Fig. 2
Pre- and post-treatment computed tomography: a 70-year-old patient with NSCLC (Table 4, patient No. 1) (a) receiving dacomitinib at 15 mg QD; and a 66-year-old patient with NSCLC (Table 4, patient No. 4) (b) receiving dacomitinib at 30 mg QD
Fig. 3
Fig. 3
Observed tumor size versus population and individual predictions
Fig. 4
Fig. 4
Individual variability in parameter estimates (ETA) for SR and TPR versus gender, ECOG status, dose group, and EGFR mutation status for the final model with EGFR on SR as covariate (left) and base model with no covariates added (right)

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