An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors

Hajime Asahina, Yosuke Tamura, Hiroshi Nokihara, Noboru Yamamoto, Yoshitaka Seki, Takashi Shibata, Yasushi Goto, Maki Tanioka, Yasuhide Yamada, Andrew Coates, Yi-Lin Chiu, Xiaohui Li, Rajendra Pradhan, Peter J Ansell, Evelyn M McKeegan, Mark D McKee, Dawn M Carlson, Tomohide Tamura, Hajime Asahina, Yosuke Tamura, Hiroshi Nokihara, Noboru Yamamoto, Yoshitaka Seki, Takashi Shibata, Yasushi Goto, Maki Tanioka, Yasuhide Yamada, Andrew Coates, Yi-Lin Chiu, Xiaohui Li, Rajendra Pradhan, Peter J Ansell, Evelyn M McKeegan, Mark D McKee, Dawn M Carlson, Tomohide Tamura

Abstract

Purpose: This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors.

Methods: Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors.

Results: Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks).

Conclusion: Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.

Trial registration: ClinicalTrials.gov NCT00718380.

Figures

Fig. 1
Fig. 1
CT images for two patients with confirmed partial responses following linifanib treatment. a A 39-year-old female patient with lung cancer who received prior chemotherapy had lesions in the lung, pleura, and lymph nodes. This patient had a confirmed PR in C4, following linifanib treatment at 0.25 mg/kg. Arrows indicate tumor location at screening and at C5D1. b A 42-year-old female patient with breast cancer who received prior chemotherapy had target lesions in the mediastinal lymph nodes. This patient had a confirmed PR in C2, following linifanib treatment at 0.20 mg/kg. Arrows indicate tumor location at screening and at C6D21. Abbreviations: CT computerized tomography; PR partial response; C cycle; D day
Fig. 2
Fig. 2
Best percentage change from baseline in tumor size in patients treated with linifanib. Data for 17 of 18 patients are shown. Of the 18 patients in this study, one patient had no measurable lesions at baseline. This patient was not evaluable due to incomplete data
Fig. 3
Fig. 3
Baseline subtracted day 15 placental growth factor (PlGF). a Average PlGF increase from baseline by dose cohort. b PlGF increase from baseline to C1D15 in patients who required a dose interruption during the first 30 days of therapy compared with patients who did not. Avg average; C cycle; D day

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