臨床研究等提出・公開システム

Phase 1, open-label, dose escalation study of DS-3032b, an oral MDM2 inhibitor, to assess safety, tolerability and pharmacokinetics in Japanese patients with relapsed or refractory acute myeloid leukemia

Phase 1 study of DS-3032b in Japanese patients with relapsed or refractory acute myeloid leukemia

14

A total of 14 subjects were enrolled in the study and received DS-3032b. All of the 14 subjects were Japanese. There were 10 males and 4 females. The median age (range) was 72.0 (42 to 76) years, with 11 subjects aged 65 years or older. The median body weight (range) was 56.20 (41.7 to 84.7) kg. All of the 14 subjects had ECOG PS of 0 or 1, in accordance with the inclusion criteria of the study. Four subjects had "AML with recurrent genetic abnormalities" (mutated RUNX1-RUNKS1T1) according to the WHO classification. Eight subjects were classified as "AML, not otherwise categorized, " including AML with maturation (5 subjects), acute myelomonocytic leukemia (2 subjects), and acute monoblastic and monocytic leukemia (1 subject).

Enrolled/Treated: 14 subjects (4 in the 90-mg cohort, 6 in the 120-mg cohort, and 4 in the 160-mg cohort) Discontinued: 14 subjects Safety, PK and PDy (biomarker) analysis sets: 14 subjects (4 in the 90-mg cohort, 6 in the 120-mg cohort, and 4 in the 160-mg cohort) Efficacy analysis set: 12 subjects (4 in the 90-mg cohort, 5 in the 120-mg cohort, and 3 in the 160-mg cohort) MTD analysis set: 11 subjects (4 in the 90-mg cohort, 3 in the 120-mg cohort, and 4 in the 160-mg cohort)

Of the 14 subjects in the safety analysis set, all but one had at least one TEAE. The exception was a subject in the 120-mg cohort who took only 1 dose of the study drug. The most frequently occurring TEAEs were decreased appetite, febrile neutropenia, nausea, and anaemia. Grade 3 or higher TEAEs were reported in 10 of 14 subjects (71.4%). No Grade 5 TEAEs were reported, and Grade 4 TEAEs included platelet count decreased (3 subjects), neutropenia and thrombocytopenia (2 subjects each), and neutrophil count decreased (1 subject). No subject died due to a TEAE in the study. Serious TEAEs occurred in 4 of 14 subjects (28.6%), of which Grade 3 febrile neutropenia in 2 subjects and Grade 2 pneumonia in 1 subject were assessed by the investigator to be drug related. No subjects had TEAEs leading to study treatment discontinuation. One of 14 subjects (7.1%) had a TEAE leading to dose reduction (acute kidney injury). Three of 14 subjects (21.4%) had TEAEs leading to study treatment interruption (febrile neutropenia in 2 subjects and decreased appetite, dysgeusia, diarrhoea, neutrophil count decreased, and platelet count decreased in 1 subject each). No clinically relevant changes from baseline or consistent trends were seen in laboratory parameters (hematology, blood chemistry, or urinalysis), vital signs, or ECG parameters, except for platelet counts. The means of platelet counts were decreased from baseline in all cohorts.

Safety result: Safety analyses were performed on the safety analysis set, whereas DLT was analyzed on the MTD analysis set. All of the 14 enrolled and treated subjects were included in the safety analysis set. The MTD analysis set consisted of 11 subjects. Three subjects in the 120-mg cohort were excluded from the MTD analysis set because study treatment for those subjects was discontinued due to progressive disease before completion of the DLT evaluation period. In the 11 subjects in the MTD analysis set, no DLTs were reported during the DLT evaluation period (Cycle 1). Therefore, the MTD could not be determined in the study (qd 14/28-day schedule).

Pharmacokinetic Results: The PK analyses were performed on the PK analysis set. All of the 14 enrolled and treated subjects were included in the PK analysis set. The plasma concentrations of DS-3032a were listed and summary statistics were calculated for each time point by subtrial/dose level/cycle/study day. On Day 1 of Cycle 1, the mean values of Cmax and AUC (AUC8h, AUC24h, AUClast, and AUCinf) increased with the increasing dose of DS-3032b. The values of Tmax and t1/2 were generally consistent within the tested dose range. On Day 14 of Cycle 1, the mean values of Cmax, Ctrough, and AUC8h increased with the increasing dose of DS-3032b. The value of Tmax was consistent within the tested dose range. Efficacy Results: Efficacy analyses were performed on the efficacy analysis set. A total of 12 subjects were included in the efficacy analysis set. One subject in the 120-mg cohort and 1 subject in the 160-mg cohort were excluded from the efficacy analysis set because of no efficacy data. With regard to the best response, no subjects achieved CR, CRh, CRi, or PR. MLFS and SD were observed in 2 of 12 subjects (16.7%) and 1 of 12 subjects (8.3%), respectively. Both the CRc rate and the overall response rate were 0.0% (95% CI; 0.0%, 26.5%). Four subjects (33.3%) (95% CI; 9.9%, 65.1%) had a reduction of 50% or greater from baseline in blast count in bone marrow aspirate. The individual percent changes ranged widely from -100.0% to 95.5% without a relationship to the dose level of DS-3032b.

DS-3032b was generally safe and well tolerated up to the dose level of 160 mg in the qd 14/28- day schedule in Japanese subjects with relapsed or refractory AML. The MTD in the qd 14/28-day schedule could not be determined because no DLTs were observed. The PK parameters including Cmax and AUC increased dose dependently.

Oct. 19, 2022

https://doi.org/10.1007/s12185-022-03464-z

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/

https://www.clinicaltrials.jp/file/PlFnWBBgd

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Aug. 27, 2018

Interventional

Multi-center, uncontrolled, 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)
- Presence of central nervous system involvement of leukemia or a history of primary central nervous system leukemia

Both

AML

investigational material(s)
Generic name etc : DS-3032b
INN of investigational material : Milademetan
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Oral administration

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

safety
Safety and tolerability
- The safety of DS-3032b will be assessed by CTCAE.
- The maximum tolerated dose of DS-3032b will be estimated.

efficacy
pharmacokinetics
- Assessment of pharmacokinetics for DS-3032a (Free form for DS-3032b)
- Exploratory assessment of tumor response to DS-3032b

- Pharmacokinetics of DS-3032a will be evaluated by following the instruction of the study protocol.
- Tumor response will be assessed by the bone marrow findings, and absolute neutrophil count and platelet count in the peripheral blood.

July. 31, 2018