Trial Outcomes & Findings for Study of Milademetan in Japanese Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) (NCT NCT03671564)

Last Updated: 2023-11-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

14 participants

Primary outcome timeframe

First 28 Days of Cycle 1

Results posted on

2023-11-07

Participant Flow

A total of 14 participants who met all the inclusion criteria and no exclusion criteria were enrolled in study sites in Japan.

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	4	6	4
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	4	6	4

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Progressive Disease	3	5	3
Overall Study Confirmed TP53 Genotyping Mutation	0	0	1
Overall Study Withdrawal by Subject	1	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Total n=14 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Age, Continuous	74.5 years n=5 Participants	70.0 years n=7 Participants	71.5 years n=5 Participants	72.0 years n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	10 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	14 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment Japan	4 participants n=5 Participants	6 participants n=7 Participants	4 participants n=5 Participants	14 participants n=4 Participants

PRIMARY outcome

Timeframe: First 28 Days of Cycle 1

Population: Dose-limiting toxicities were assessed in the DLT Evaluable Set. 3 participants in the 120-mg cohort were excluded from analysis because study treatment was discontinued before completion of the DLT evaluation period.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=3 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From date of signing of informed consent form up to 30 days after last dose of study drug, up to 1 year

Population: Treatment-emergent adverse events were assessed in the Safety Analysis Set.

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.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	4 Participants	5 Participants	4 Participants

SECONDARY outcome

Timeframe: Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)

Population: Pharmacokinetic parameter was assessed in the Pharmacokinetic Analysis Set.

Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Maximum Plasma Concentration (Cmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1, Day 14	1090 ng/mL Standard Deviation 327	1680 ng/mL Standard Deviation 657	2710 ng/mL Standard Deviation 540
Maximum Plasma Concentration (Cmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1, Day 1	653 ng/mL Standard Deviation 196	1010 ng/mL Standard Deviation 444	1380 ng/mL Standard Deviation 540

SECONDARY outcome

Timeframe: Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)

Population: Pharmacokinetic parameter was assessed in the Pharmacokinetic Analysis Set.

Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Time to Reach Maximum Plasma Concentration (Tmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1, Day 1	4.45 hours Interval 2.97 to 5.88	3.13 hours Interval 1.92 to 5.92	2.54 hours Interval 2.0 to 8.0
Time to Reach Maximum Plasma Concentration (Tmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1, Day 14	3.02 hours Interval 2.97 to 3.08	2.98 hours Interval 2.08 to 5.92	3.03 hours Interval 1.87 to 3.17

SECONDARY outcome

Timeframe: Days 1 & 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)

Population: Pharmacokinetic parameter was assessed in the Pharmacokinetic Analysis Set. 2 participants from the Milademetan 90 mg/day and 160 mg/day cohorts for AUC 24 and AUCinf were excluded from the summary as AUC data was not evaluable. 1 participant from Milademetan 120 mg/day cohort for AUC 24 and AUCinf was excluded from the summary as AUC data was not evaluable.

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.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1 Day 1: AUC24h	8640 ng*h/mL Standard Deviation 2210	12100 ng*h/mL Standard Deviation 4080	15000 ng*h/mL Standard Deviation 1380
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1 Day 1: AUCinf	13700 ng*h/mL Standard Deviation 4100	18600 ng*h/mL Standard Deviation 8600	22700 ng*h/mL Standard Deviation 5080
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1 Day 1: AUC8h	3170 ng*h/mL Standard Deviation 905	4940 ng*h/mL Standard Deviation 1590	6560 ng*h/mL Standard Deviation 3200
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1 Day 14: AUC8h	6220 ng*h/mL Standard Deviation 1480	10000 ng*h/mL Standard Deviation 4750	15300 ng*h/mL Standard Deviation 3320
Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Cycle 1 Day 1: AUClast	8060 ng*h/mL Standard Deviation 1400	11300 ng*h/mL Standard Deviation 3450	14900 ng*h/mL Standard Deviation 4400

SECONDARY outcome

Timeframe: Day 1 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)

Population: Pharmacokinetic parameter was assessed in the Pharmacokinetic Analysis Set. 2 participants from the Milademetan 90 mg/day and 160 mg/day cohorts were excluded from the summary as data was not evaluable. 1 participant from Milademetan 120 mg/day cohort was excluded from the summary as data was not evaluable.

Terminal elimination half-life (T1/2) was assessed using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=2 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=5 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=2 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Terminal Elimination Half-Life (T1/2) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	15.9 hours Standard Deviation 1.35	14.1 hours Standard Deviation 4.27	14.6 hours Standard Deviation 4.36

SECONDARY outcome

Timeframe: Day 14 of Cycle 1: Pre-dose and 1, 2, 3, 6, and 8 hours post-dose (each cycle is 28 days)

Population: Pharmacokinetic parameter was assessed in the Pharmacokinetic Analysis Set.

Trough plasma concentration (Ctrough) was assessed using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=5 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Trough Plasma Concentration (Ctrough) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia	422 ng/mL Standard Deviation 147	635 ng/mL Standard Deviation 533	769 ng/mL Standard Deviation 221

SECONDARY outcome

Timeframe: From the start of study treatment to the end of study treatment, up to 1 year

Population: Best Response was assessed on the Efficacy Analysis Set.

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).

Outcome measures

Outcome measures
Measure	Milademetan (90 mg/Day) n=4 Participants Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=5 Participants Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=3 Participants Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Complete remission (CR)	0 Participants	0 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia CR with incomplete hematological recovery (CRi)	0 Participants	0 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Partial remission (PR)	0 Participants	0 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Morphologic leukemia-free state (MLFS)	0 Participants	1 Participants	1 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Progressive disease (PD)	1 Participants	1 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia CR with partial hematological recovery (CRh)	0 Participants	0 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Stable disease (SD)	1 Participants	0 Participants	0 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Not applicable (NA)	2 Participants	3 Participants	2 Participants
Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia Not Evaluable (NE)	0 Participants	0 Participants	0 Participants

Adverse Events

Milademetan (90 mg/Day)

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Milademetan (120 mg/Day)

Serious events: 2 serious events

Other events: 5 other events

Deaths: 0 deaths

Milademetan (160 mg/Day)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Milademetan (90 mg/Day) n=4 participants at risk Participants who received milademetan 90 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (120 mg/Day) n=6 participants at risk Participants who received milademetan 120 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.	Milademetan (160 mg/Day) n=4 participants at risk Participants who received milademetan 160 mg daily (QD) Day 1 - 14 followed by 14-day rest in a 28-day cycle.
Infections and infestations Pneumonia	50.0% 2/4 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.	16.7% 1/6 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.	0.00% 0/4 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.
Blood and lymphatic system disorders Febrile neutropenia	25.0% 1/4 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.	16.7% 1/6 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.	0.00% 0/4 • Adverse events (AE) were collected from the date of signing the informed consent form up to 30 days after last dose of the study drug, up to 1 year. 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.

Other adverse events

Additional Information

Clinical Director

Daiichi Sankyo, Inc.

Phone: 908-992-6400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place