臨床研究等提出・公開システム

A phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral MDM2 Inhibitor, in Japanese Subjects with Advanced Solid Tumors or Lymphomas

Phase 1 study of DS-3032b

18

All of the 18 subjects were Japanese. There were 10 males and 8 females. The median age (range) was 49.0 (31 to 74) years, with 2 subjects aged 65 years or older. The median body weight (range) was 59.45 (44.1 to 80.0) kg. All of the 18 subjects had ECOG PS of 0 or 1 in accordance with the inclusion criteria of the study. The most common cancer type other than "other" (9 subjects) was sarcoma (5 subjects), followed by unknown primary (2 subjects), and breast and stomach (1 subject each). There were no subjects with lymphoma. Wild-type and mutant TP53 were detected in tumors from 11 and 6 subjects, respectively.

Enrolled/Treated: 18 subjects (3 in Cohort 1 [60 mg], 11 in Cohort 2 [90 mg], and 4 in Cohort 3 [120 mg]) Discontinued: 18 subjects Safety, PK and PDy (biomarker) analysis sets: 18 subjects (3 in Cohort 1, 11 in Cohort 2, and 4 in Cohort 3) Efficacy analysis set: 17 subjects (3 in Cohort 1, 11 in Cohort 2, and 3 in Cohort 3) MTD analysis set: 17 subjects (3 in Cohort 1, 10 in Cohort 2, and 4 in Cohort 3)

All of the 18 subjects in the safety analysis set had at least 1 TEAE. The TEAEs that occurred frequently were nausea, decreased appetite, platelet count decreased, anaemia, fatigue, and white blood cell count decreased. Grade 3 or higher TEAEs were reported in 8 of 18 subjects (44.4%), including Grade 5 (ie, fatal) disease progression (1 subject in Cohort 3) and Grade 4 events of anaemia and platelet count decreased (1 subject each in Cohort 2), and sepsis, platelet count decreased, and lymphocyte count decreased (1 subject each in Cohort 3). As a TEAE leading to death, disease progression was reported in 1 subject (Cohort 3). The event was not considered to be related to the study drug. Serious TEAEs occurred in 6 of 18 subjects (33.3%). Grade 4 platelet count decreased was the only drug-related serious TEAE, which was reported in the subject who experienced the above-mentioned fatal TEAE. Three of 18 subjects (16.7%) reported TEAEs leading to drug withdrawn: 1 in Cohort 2 (jaundice cholestatic) and 2 in Cohort 3 (platelet count decreased and nausea). No subjects reported TEAEs leading to dose reduction. Ten of 18 subjects (55.6%) reported TEAEs leading to dose interruption. No clinically relevant changes from baseline or consistent trends were seen in laboratory parameters (hematology, blood chemistry, coagulation, or urinalysis), vital signs, or ECG parameters, except platelet counts. The means of platelet counts were decreased from baseline, with greater changes in Cohorts 2 and 3 than those in Cohort 1.

Safety Results: Safety analyses were performed on the safety analysis set except that DLT was evaluated on the MTD analysis set. Of the 17 subjects in the MTD analysis set, 4 subjects in Cohort 3 experienced DLTs. The final MTD or tentative RP2D was decided to be 90 mg in the qd 21/28-day schedule. Pharmacokinetic Results: PK analyses were performed on the PK analysis set. Based on the plasma concentrations of DS-3032a, PK parameters were calculated using non-compartmental analysis. On Day 1 of Cycle 1, the mean values of Cmax and AUC (AUC8h, AUCtau, AUClast, and AUCinf) increased with the increasing dose of DS-3032b. The values of other PK parameters were generally consistent within the tested dose range. On Day 21 of Cycle 1, the number of subjects included in the summary was even smaller than that on Day 1. The mean values of Cmax, Ctrough, and AUC (AUC8h, AUCtau, and AUClast) increased with the increasing dose of DS-3032b. The values of other PK parameters were generally consistent within the tested dose range. The means of accumulation rates ranged from 1.18 (Cohort 3) to 3.11 (Cohort 1).

Pharmacodynamic (Biomarker) Results: The PDy and biomarker analyses were performed on the PDy (biomarker) analysis set. The means of serum MIC-1 levels in all cohorts were increased from baseline at all time points after study drug administration. Although it was difficult to interpret the data because of the limited number of subjects, the means of serum MIC-1 levels in Cohorts 2 and 3 were higher than those in Cohort 1 at all time points. Scatter plots of the percent change in serum MIC-1 levels from baseline and plasma DS-3032a concentrations suggested that the change in serum MIC-1 levels from baseline became greater at all time points with the increasing concentration of or exposure to DS-3032a. Efficacy Results: Efficacy analyses were performed on the efficacy analysis set. With regard to the best overall response, no subjects achieved CR or PR. SD was observed in 7 of 16 subjects (43.8%). The DCR was 43.8% (95% CI; 19.8%, 70.1%). Three of the 7 subjects with SD experienced PD. The median (minimum, maximum) duration of SD was 55.43 (7.3+, 202.1+) weeks. Eight of 17 subjects had a PFS event. The median (minimum, maximum) PFS was 15.29 (0.1+, 202.1+) weeks. The mean (standard deviation) best (minimum) percent change from baseline in target lesions for 16 subjects was 6.82% (25.272%). The individual percent changes ranged widely from -15.1% to 95.0% without a relationship to the dose level of DS-3032b. All of the subjects who experienced SD had tumors with wild-type TP53. Subjects with wild-type TP53 generally had better results in the efficacy evaluation compared with those with mutant TP53, although the interpretation of the data was limited by the small sample size.

DS-3032b was generally safe and well tolerated up to the dose level of 90 mg in the qd 21/28-day schedule. The PK parameters including Cmax and AUC indicated a dose-dependent increase in DS-3032a exposure. The MTD in the qd 21/28-day schedule was determined to be 90 mg in Japanese patients with solid tumors.

Mar. 09, 2021

https://onlinelibrary.wiley.com/doi/10.1111/cas.14875

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

DAIICHISANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Jan. 14, 2015

Interventional

Multicenter, open-label

treatment purpose

1

- Advanced solid tumors or lymphomas that are refractory to standard therapy or for which no standard therapy is available.
- An Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

- Previously had or currently has any of the following diseases:
Cardiac failure (NYHA Functional Classification ≥ Class III), myocardial infarction, cerebral infarction, unstable angina, arrhythmia requiring treatment, coronary/peripheral bypass surgery, pulmonary thrombosis, uncontrolled deep vein thrombosis, clinically severe thromboembolic event, or autoimmune disease requiring treatment.
- Previously had or currently has clinically severe pulmonary disease (eg, interstitial pneumonia, pneumonitis, pulmonary fibrosis, radiation pneumonia).
- Severe or uncontrolled concomitant disease.
- Clinically active brain metastases, which are symptomatic or requiring treatment.
- Has a second concurrent primary malignancy such as solid tumor or lymphoma.

Both

Advanced solid tumors or lymphomas that are refractory to standard therapy or for which no standard therapy is available.

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
pharmacokinetics
Safety, tolerability, and pharmacokinetics
-The safety of DS-3032b will be assessed by CTCAE.
-The maximum tolerated dose of DS-3032b, and the recommended dose of DS-3032b for the following clinical studies will be estimated.
-Pharmacokinetics of DS-3032b will be evaluated by following the instruction of the study protocol.

pharmacodynamics
-Pharmacodynamic effect of DS-3032b.
-Exploratory assessment of tumor or hematologic response.
-Exploratory assessment of the relationship between tumor response to DS-3032b and predictive biomarkers.
-Pharmacodynamic effect of DS-3032b and exploratory assessment of DS-3032b-related biomarkers will be assessed by analysis of samples collected from subjects based on the study protocol schedule.
-Tumor response will be assessed by RECIST ver 1.1 or revised IWG criteria.

Nov. 20, 2014