臨床研究等提出・公開システム

Phase 1b, open-Label, dose escalation study of quizartinib in combination with induction and consolidation chemotherapy in Japanese patients with newly diagnosed acute myeloid leukemia (AML)

Phase 1b study of quizartinib

7

A total of 7 Japanese subjects with newly diagnosed AML were enrolled (4 subjects for Level 1 [20 mg/day] and 3 subjects for Level 2 [40 mg/day]). Of the 7 enrolled subjects, the mean age (SD) was 57.5 (10.47) years in Level 1 and 53.7 (17.10) years in Level 2. Two male and 2 female subjects were enrolled in Level 1. One male and 2 female subjects were enrolled in Level 2. The mean body weight (SD) was 62.55 (12.273) kg in Level 1 and 55.27 (4.801) kg in Level 2. Three subjects had an ECOG PS of 0 and 1 subject had an ECOG PS of 1 in Level 1. Two subjects had an ECOG PS of 0 and 1 subject had an ECOG PS of 1 in Level 2. Of the 4 subjects in Level 1, 2 subjects had AML with recurrent genetic abnormalities, 1 subject had AML with myelodysplasia related changes, and 1 subject had AML with acute myelomonocytic leukemia in WHO classification. Of the 3 subjects in Level 2, 2 subjects had AML with myelodysplasia related changes and 1 subject had AML with maturation. The FLT3 genotype in 1 subject in Level 2 was positive for the FLT3-ITD mutation, whereas that in 6 subjects (4 subjects in Level 1 and 2 subjects in Level 2) was negative for the FLT3-ITD mutation.

Of the 7 enrolled subjects, all subjects received the study treatment (quizartinib or coadministered drugs [cytarabine and anthracycline drugs]). Three subjects completed the induction phase: 2 subjects in Level 1 and 1 subject in Level 2. And 1 subject in Level 1 completed the consolidation phase. In Level 1, although the planned sample size was 3 subjects unless DLTs occurred, 2 eligible subjects were enrolled at almost the same time after 2 subjects had enrolled. Consequently, there were 4 subjects in Level 1. All 7 subjects were included in the safety analysis set as well as all other analysis sets

The incidence of TEAEs was 100% (7/7 subjects) in the induction phase and 100% (3/3 subjects) in the consolidation phase. Commonly reported TEAEs in the induction phase were febrile neutropenia in 7 subjects (100%), alopecia in 5 subjects (71.4%), and decreased appetite, abdominal pain upper, nausea, and gammaglutamyltransferase increased in 4 subjects (57.1%) each. Commonly reported TEAEs in the consolidation phase were febrile neutropenia in 3 subjects (100%), diarrhoea, platelet count decreased, and white blood cell count decreased in 2 subjects (66.7%) each. Commonly reported TEAEs in the entire period were febrile neutropenia in 7 subjects (100%), diarrhoea, nausea, and alopecia in 5 subjects (71.4%) each, decreased appetite, dysgeusia, abdominal pain upper, stomatitis, and gamma-glutamyltransferase increased in 4 subjects (57.1%) each. The most frequent quizartinib-related TEAEs reported in the induction phase were febrile neutropenia and gamma-glutamyletransferase increased in 3 subjects (42.9%) each. The most common quizartinib-related TEAEs in the consolidation phase were febrile neutropenia in 3 subjects (100%), platelet count decreased and white blood cell count decreased in 2 subjects (66.7%) each. The most common quizartinib-related TEAEs in the entire period were febrile neutropenia in 4 subjects (57.1%). No Grade 5 (death related to AE) TEAEs were reported. All subjects experienced worst Grade 3 or 4 TEAEs in both the induction phase and consolidation phase. In the induction phase, the Grade 3 or 4 TEAEs reported in 2 or more subjects were pneumonia, febrile neutropenia, anaemia, hypokalaemia, platelet count decreased, and white blood cell count decreased. In the consolidation phase, the Grade 3 or 4 TEAEs reported in 2 or more subjects were febrile neutropenia, platelet count decreased, and white blood cell count decreased. Grade 3 or 4 quizartinib-related TEAEs reported in 2 or more subjects were febrile neutropenia, anaemia, platelet count decreased, and white blood cell count decreased in the induction phase, and febrile neutropenia, platelet count decreased, and white blood cell count decreased in the consolidation phase. Grade 4 TEAEs were leukopenia, neutropenia, thrombocytopenia (1 subject in Level 1), platelet count decreased, and white blood cell count decreased (2 subjects: 1 subject in each level) in the induction phase, and platelet count decreased and white blood cell count decreased (2 subjects: 1 subject in each level) in the consolidation phase. All of these TEAEs except neutropenia developed in 1 subject (Level 1) were reported as Grade 4 events prior to the administration of quizartinib. All Grade 4 TEAEs except leukopenia developed in 1 subject (Level 1) were resolved. Grade 4 quizartinib-related TEAEs were leukopenia, neutropenia, thrombocytopenia, platelet count decreased, and white blood cell count decreased in the induction phase and platelet count decreased and white blood cell count decreased in the consolidation phase.

[Safety] No DLTs were reported. Quizartinib 20 mg once daily and 40 mg once daily in combination with standard chemotherapy were confirmed well-tolerated. [Pharmacokinetics] On Day 8 of Cycle 1 in the induction phase, the mean Cmax and AUCtau of quizartinib, AC886, and quizartinib + AC886 increased as dose increased within the dose range tested. The median Tmax of quizartinib was 3.03 h in Level 1 and 2.17 h in Level 2, and that of AC886 was 5.01 h in Level 1 and 6.08 h in Level 2. On Day 21 of Cycle 1 in the induction phase, the mean Cmax and AUCtau of quizartinib, AC886, and quizartinib + AC886 increased as dose increased within the dose range tested. The mean accumulation ratio for Cmax (AR [Cmax]) and AUCtau (AR [AUCtau]) of quizartinib and AC886 were comparable between Level 1 and Level 2, although only 2 evaluable subjects were included in Level 2.

[Efficacy] CRc was observed in 3 of 4 subjects (75.0%) in Level 1 and 2 of 3 subjects (66.7%) in Level 2. The best percentage changes from baseline in bone marrow aspirate blast count in Level 1 ranged from -84.9% to -99.4% and those in Level 2 ranged from -85.5% to -95.7%. In this study, only 1 subject who had FLT3-ITD mutated AML was included. The subject was a 34-year-old female enrolled in Level 2, and on Day 36 (Cycle 1 of the induction phase); this subject discontinued the study treatment due to aggravated primary disease. [Pharmacodynamics] Administration of quizartinib resulted in FLT3 inhibition in plasma, as measured by plasma inhibitory activity (PIA) assay, for all enrolled subjects.

This study demonstrated that doses of quizartinib 20 mg once daily or 40 mg once daily in combination with standard chemotherapy are generally well-tolerated. The Cmax and AUCtau values of quizartinib, AC886, and quizartinib + AC886 increased as dose increased within the dose range tested. The pharmacokinetic profiles of quizartinib and AC886 were similar to those in the previous study which conducted in overseas.

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

Aug. 12, 2016

Interventional

Multi-center, open label study

treatment purpose

1

- No prior treatment for AML (including quizartinib)
- ECOG Performance Status (PS) of 0 to 2

- Diagnosis of acute promyelocytic leukemia
- Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy

Both

Newly diagnosed 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 administered in combination with induction and consolidation chemotherapy will be assessed by CTCAE.
- The maximum tolerated dose of quizartinib, and the recommended dose of quizartinib in combination with induction and consolidation chemotherapy for the following clinical studies will be estimated.

efficacy
other
- 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.

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June. 29, 2016