Study of Milademetan in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Phase 1, Open-label, Dose Escalation Study of Milademetan, an Oral MDM2 Inhibitor, to Assess Safety, Tolerability and Pharmacokinetics in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia

This is a Phase 1, multicenter, open-label study to evaluate safety, tolerability and pharmacokinetics of milademetan in Japanese patients with relapsed or refractory acute myeloid leukemia. The milademetan initial dose will be Level 1: 90 mg. No increase in the milademetan dose will be made in the same participant. Dose-limiting toxicity associated with milademetan occurring at each level will be assessed, and the maximum tolerated dose (MTD) will be decided using a modified continuous reassessment method (mCRM).

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Milademetan

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 286-0041
    • Japanese Red Cross Narita Hospital
  • Fukuoka, Japan, 812-8582
    • Kyusyu University Hospital
  • Gifu, Japan, 500-8513
    • Gifu Municipal Hospital
  • Hiroshima, Japan, 720-0001
    • Chugoku Central Hospital
  • Kumamoto, Japan, 860-0008
    • National Hospital Organization Kumamoto Medical Center
  • Nara, Japan, 632-8552
    • Tenri Hospital
  • Tokyo, Japan, 141-8625
    • Ntt Medical Center Tokyo
  • Tokyo, Japan, 190-0014
    • National Hospital Organization Disaster Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Relapsed or refractory AML
• AML for which no standard treatment is available
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milademetan (90 mg/Day); Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Drug: Milademetan; Milademetan was administered orally once daily on Days 1 to 14 in a 28-day cycle.; Other Names: DS-3032b
Experimental: Milademetan (120 mg/Day); Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Drug: Milademetan; Milademetan was administered orally once daily on Days 1 to 14 in a 28-day cycle.; Other Names: DS-3032b
Experimental: Milademetan (160 mg/Day); Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Drug: Milademetan; Milademetan was administered orally once daily on Days 1 to 14 in a 28-day cycle.; Other Names: DS-3032b

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	A dose limiting toxicities (DLTs) is defined as any Grade 3 or higher non-hematological adverse event unless related to the primary disease, course of the primary disease, complications, or concomitant medications, that occurs during the DLT evaluation period (28 days of Cycle 1). The following events will be assessed as DLTs: Grade 4 aspartate aminotransferase (AST)/alanine aminotransferase (ALT), Grade 3 AST/ALT lasting ≥3 days, Grade 3 AST/ALT with Grade ≥2 total bilirubin, and unable to complete at least 75% of the prescribed doses of milademetan in Cycle1 (28 days) as a result of Grade ≥2 events.	First 28 Days of Cycle 1
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Treatment-emergent adverse event (TEAE) is defined as an adverse event that occurs after the first administration, or that worsens relative to the pre-treatment state. An AE is any untoward or unintended sign, symptom, or disease noted in participants who received the study drug, whether it is considered to be related to the study drug or not.	From date of signing of informed consent form up to 30 days after last dose of study drug, up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.	Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)
Time to Reach Maximum Plasma Concentration (Tmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.	Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	AUC during 8 hours (AUC8h), AUC during 24 hours (AUC24h), AUC up to the last quantifiable concentration (AUClast), and AUC up to infinity (AUCinf) are presented for Day 1 of Cycle 1 and were assessed using non-compartmental analysis. AUC8h for Day 14 of Cycle 1 is also presented.	Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)
Terminal Elimination Half-Life (T1/2) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Terminal elimination half-life (T1/2) was assessed using non-compartmental analysis.	Day 1 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)
Trough Plasma Concentration (Ctrough) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Trough plasma concentration (Ctrough) was assessed using non-compartmental analysis.	Day 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	Best response was defined as the best measured response over all response assessments (complete remission [CR], CR with incomplete hematological recovery [CRi], CR with partial hematological recovery [CRh], partial remission [PR], morphologic leukemia-free state [MLFS], stable disease [SD], or progressive disease [PD]) at all time points after the start of study treatment. The best response will be SD if the response is assessed as SD three or more times consecutively in the protocol-specified evaluation of the antitumor effect. If the response is not assessed as SD three or more times consecutively, the best response will be Not Applicable (unconfirmed SD).	From the start of study treatment to the end of study treatment, up to 1 year

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Co., Ltd.
• Investigators: Study Director: Clinical Study Leader, Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2018
• Primary Completion (Actual): September 11, 2019
• Study Completion (Actual): September 11, 2019

Study Registration Dates

• First Submitted: September 4, 2018
• First Submitted That Met QC Criteria: September 12, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Oncology; MDM2; Escalation with overdose control (EWOC)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: DS3032-A-J104; 184054 (Registry Identifier: JAPIC CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No