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Completed

NCT Number: NCT03671564

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

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).

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Key information

Conditions

Acute Myeloid Leukemia Hematologic Diseases Hemic and Lymphatic Diseases Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms Neoplasms by Histologic Type

Age range

20 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Japanese Red Cross Narita Hospital, Chiba, Japan

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Milademetan

Drug

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

Other names: DS-3032b

Primary outcomes

  1. Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

    Time frame: First 28 Days of Cycle 1

    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.

  2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

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

    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.

Secondary outcomes

  1. Maximum Plasma Concentration (Cmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

    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)

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

  2. Time to Reach Maximum Plasma Concentration (Tmax) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

    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)

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

  3. Area Under the Plasma Concentration-Time Curve (AUC) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

    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)

    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.

  4. Terminal Elimination Half-Life (T1/2) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

    Time frame: Day 1 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) was assessed using non-compartmental analysis.

  5. Trough Plasma Concentration (Ctrough) of Milademetan Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

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

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

  6. Number of Participants With Best Response Following Administration of Milademetan in Participants With Relapsed or Refractory Acute Myeloid Leukemia

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

    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).

Sponsors and collaborators

Lead sponsor

Daiichi Sankyo Co., Ltd.

Industry

Registry information

Official study 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

Important dates

Study start
2018
Primary completion
2019
Study completion
2019
First posted
Sep 14, 2018
Registry last updated
Nov 7, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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