Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial

Kyriakos P Papadopoulos, Eytan Ben-Ami, Amita Patnaik, Denise Trone, Jianke Li, George D Demetri, Kyriakos P Papadopoulos, Eytan Ben-Ami, Amita Patnaik, Denise Trone, Jianke Li, George D Demetri

Abstract

Background: Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy.

Methods: This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib.

Results: Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease.

Conclusion: The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors.

Trial registration: Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.

Keywords: FLT3; PDGFR; Quizartinib; Receptor tyrosine kinase inhibitor.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the ethics committee of Southern Texas Accelerated Research Therapeutics (San Antonio, TX) and Dana-Farber Cancer Institute (Boston, MA), and patients provided written informed consent and indicated availability for periodic follow-up at the study site.

Consent for publication

Not applicable.

Competing interests

Kyriakos P. Papadopoulos: Support to START from Ambit Biosciences for the conduct of clinical trials.

Eytan Ben-Ami: The author(s) declare(s) that they have no competing interests.

Amita Patnaik: Institutional funding from Daiichi Sankyo Pharma during the conduct of the study.

Denise Trone: Employment: Daiichi Sankyo Pharma Development during the conduct of the study; Ambit Biosciences.

Jianke Li: Employment: Daiichi Sankyo Inc. during the conduct of the study.

George D. Demetri: Received grant/personal fees from Bayer, Daiichi Sankyo, Novartis, Pfizer; holds a patent at Dana-Farber licensed for imatinib use in GIST; holds minor equity as a member of the Board of Directors for Blueprint Medicines; is a member of the Scientific Advisory Board for Daiichi-Sankyo.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Tumor response with quizartinib monotherapy in a patient with GIST. Computed tomography scans of a patient with GIST demonstrated a 27% reduction in tumor burden with quizartinib monotherapy at the end of Cycle 1. Panels on the left represent baseline scans; panels on the right are from end of Cycle 1. GIST gastrointestinal stromal tumor

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