PMID- 30081867 OWN - NLM STAT- MEDLINE DCOM- 20190107 LR - 20190107 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 18 IP - 1 DP - 2018 Aug 6 TI - Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial. PG - 790 LID - 10.1186/s12885-018-4692-z [doi] LID - 790 AB - 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. FAU - Papadopoulos, Kyriakos P AU - Papadopoulos KP AD - South Texas Accelerated Research Therapeutics, 4383 Medical Dr, Suite 4021, San Antonio, TX, 78229, USA. FAU - Ben-Ami, Eytan AU - Ben-Ami E AD - Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. FAU - Patnaik, Amita AU - Patnaik A AD - South Texas Accelerated Research Therapeutics, 4383 Medical Dr, Suite 4021, San Antonio, TX, 78229, USA. FAU - Trone, Denise AU - Trone D AD - Formerly Daiichi Sankyo Pharma Development, 3172 Mount Acmar Court, San Diego, CA, 92111, USA. FAU - Li, Jianke AU - Li J AD - Daiichi Sankyo Pharma Development, 10201 Wateridge Circle, Suite 240, San Diego, CA, 92121, USA. FAU - Demetri, George D AU - Demetri GD AD - Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. gdemetri@dfci.harvard.edu. AD - Ludwig Center at Harvard, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA. gdemetri@dfci.harvard.edu. LA - eng SI - ClinicalTrials.gov/NCT01049893 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20180806 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Antineoplastic Agents) RN - 0 (Benzothiazoles) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 7LA4O6Q0D3 (quizartinib) RN - EC 2.7.10.1 (FLT3 protein, human) RN - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Benzothiazoles/*administration & dosage/adverse effects/pharmacokinetics MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/diagnostic imaging/*drug therapy/enzymology/pathology MH - Phenylurea Compounds/*administration & dosage/adverse effects/pharmacokinetics MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/pharmacokinetics MH - Signal Transduction/drug effects MH - Tomography, X-Ray Computed MH - Treatment Outcome MH - United States MH - fms-Like Tyrosine Kinase 3/*antagonists & inhibitors/metabolism PMC - PMC6080548 OTO - NOTNLM OT - FLT3 OT - PDGFR OT - Quizartinib OT - Receptor tyrosine kinase inhibitor COIS- 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. EDAT- 2018/08/08 06:00 MHDA- 2019/01/08 06:00 PMCR- 2018/08/06 CRDT- 2018/08/08 06:00 PHST- 2018/02/08 00:00 [received] PHST- 2018/07/24 00:00 [accepted] PHST- 2018/08/08 06:00 [entrez] PHST- 2018/08/08 06:00 [pubmed] PHST- 2019/01/08 06:00 [medline] PHST- 2018/08/06 00:00 [pmc-release] AID - 10.1186/s12885-018-4692-z [pii] AID - 4692 [pii] AID - 10.1186/s12885-018-4692-z [doi] PST - epublish SO - BMC Cancer. 2018 Aug 6;18(1):790. doi: 10.1186/s12885-018-4692-z.