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

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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

Time frame: 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.

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).

Time frame: 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.

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

Time frame: 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.

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

Time frame: 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.

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

Time frame: 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.