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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03671564
• Other study ID #: DS3032-A-J104
• Secondary ID: 184054
• Status: Completed
• Phase: Phase 1
• Start date: August 23, 2018
• Est. completion date: September 11, 2019

Study information

• Verified date: January 2023
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: September 11, 2019
• Est. primary completion date: September 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Milademetan
Milademetan was administered orally once daily on Days 1 to 14 in a 28-day cycle.

Locations

Country	Name	City	State
Japan	Japanese Red Cross Narita Hospital	Chiba
Japan	Kyusyu University Hospital	Fukuoka
Japan	Gifu Municipal Hospital	Gifu
Japan	Chugoku Central Hospital	Hiroshima
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto
Japan	Tenri Hospital	Nara
Japan	National Hospital Organization Disaster Medical Center	Tokyo
Japan	NTT Medical Center Tokyo	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo Co., Ltd.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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