臨床研究等提出・公開システム

A Phase 1, Open-Label, Dose Escalation Study of Quizartinib, An Oral FLT3 Inhibitor, in Japanese Patients with Relapsed or Refractory Acute Myeloid Leukemia

Phase 1 study of quizartinib

17

Among the 16 patients who received quizartinib, the median (range) age was 68.0 (33-91) years and median (range) body mass index was 19.6 (15.6-28.3) kg/m2. FLT3-ITD mutation was positive in nearly half [7 (43.8%)] of the patients. ECOG PS was 0 or 1 at baseline in 16 patients.

A total of 17 patients were registered, but 1 patient discontinued from the study due to AEs before initiating quizartinib treatment (20 mg/day, dose-escalation part). The remaining 16 patients comprised the dose-escalation (20 mg/day, n = 4; 30 mg/day, n = 3; 60 mg/day, n = 4) and dose-expansion (20 mg/day, n = 5) parts.

Among the 16 patients who received quizartinib, TEAEs of any grade were observed in 15 (93.8%) patients. Grade >= 3 TEAEs were reported in 68.8% (11/16) of the patients (febrile neutropenia in 5 patients; anaemia in 3 patients; and hypophosphataemia, hypokalaemia, disease progression, lipase increased, and white blood cell count decreased in 2 patients each). However, no DLTs were observed at doses up to 60 mg/day quizartinib. A total of 14 (87.5%) patients developed drug-related TEAEs. The only drug-related TEAE leading to treatment discontinuation was bronchopulmonary aspergillosis [1 of 16 patients (6.3%)] in the 20 mg/day dose-escalation part. A total of 6 serious TEAEs were reported, of which 3 (bronchopulmonary aspergillosis, pneumonia, and lung infection) were drug-related. Although TEAEs leading to death were reported in 3 patients (disease progression in 2 patients and haemorrhage intracranial in 1 patient), none of them were drug-related.

No DLTs were observed and quizartinib multiple-dose monotherapy was well tolerated at doses up to 60 mg/day. The most commonly reported (43.8%) TEAE was grade 1 or 2 electrocardiogram QT prolonged. No treatment-related deaths were reported. The mean plasma concentrations of quizartinib and AC886 at day 15 of cycle 1 were similar between pre-dose and 24 h after the quizartinib dose, which means steady state of quizartinib at day 15. At day 15 of cycle 1, the geometric mean Cmax increased dose dependently for quizartinib (81.5, 148, and 283 ng/mL with 20, 30, and 60 mg/day, respectively), AC886 (132, 160, and 231 ng/mL with 20, 30, and 60 mg/day, respectively), and their sum (quizartinib + AC886, 215, 316, and 512 ng/mL with 20, 30, and 60 mg/day, respectively). The geometric mean AUCtau also increased dose dependently (quizartinib, 1280, 2010, and 5080 ng h/mL with 20, 30, and 60 mg/day, respectively; AC886, 2650, 3160, and 4930 ng h/mL with 20, 30, and 60 mg/day, respectively; quizartinib + AC886, 4010, 5520, and 10,200 ng h/mL with 20, 30, and 60 mg/day, respectively.

The CRc rate was 37.5% (95% CI, 18.5-61.4), and the response rate was 56.3% (95% CI, 33.2-76.9). None of the patients achieved CR, but CRp and CRi were achieved in 1 (6.3%) and 5 (31.3%) patients, respectively. In the 20 mg/day (n = 9), 30 mg/day (n = 3), and 60 mg/day (n = 4) cohorts, the CRc rate was 22.2%, 66.7%, and 50.0%, respectively. No clear dose-dependent relationship was observed for CRc rate, response rate, or best response. CRc was reported in 5 out of 7 patients among the FLT3-ITD positive patients in total, 1 out of 3 patients in the 20 mg/day cohort, 2 out of 2 patients in the 30 mg/day cohort, and 2 out of 2 patients in the 60 mg/day cohort.

Quizartinib multiple-dose monotherapy was well tolerated in Japanese relapsed or refractory AML patients at doses up to 60 mg/day, and the MTD was higher than 60 mg/day.

July. 29, 2019

https://link.springer.com/article/10.1007%2Fs12185-019-02709-8

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Mar. 02, 2016

Interventional

Multi-center, open label study

treatment purpose

1

- Relapsed or refractory AML
- AML for which no standard treatment is available
- ECOG Performance Status (PS) of 0 to 2

- Acute Promyelocytic Leukemia
- Chronic myelogenous leukemia in blast crisis (BCR-ABL fusion gene positive)
- History of other malignancies within 3 years prior to enrollment, except curatively treated in-situ carcinoma, AML, or MDS.

Both

Relapsed or refractory AML

investigational material(s)
Generic name etc : AC220
INN of investigational material : Quizartinib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Oral administration once daily

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
pharmacokinetics
Safety, tolerability, and pharmacokinetics
- The safety of quizartinib will be assessed by CTCAE.
- The maximum tolerated dose of quizartinib, and the recommended dose of quizartinib for the following clinical studies will be estimated.

efficacy
exploratory
- Exploratory assessment of quizartinib-related biomarkers
- Exploratory assessment of tumor response to quizartinib

- Biomarker analyses will be conducted using the bone marrow aspirate specimen and blood samples.
- Tumor response will be assessed by the bone marrow findings, and absolute neutrophil count and platelet count in the peripheral blood.

Feb. 16, 2016