Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML)

A Phase 1 Study of Milademetan in Combination With Quizartinib in Subjects With FLT3-ITD Mutant Acute Myeloid Leukemia That Are Relapsed/Refractory, or Newly Diagnosed and Unfit for Intensive Chemotherapy

Participants with AML that have gone into remission and come back (relapsed) or gone into remission with a number of leukemia cells still in their system (refractory) will be recruited for this study. They will also be positive for FLT3-ITD mutation.

Participants will receive a combined dose of quizartinib and milademetan that have not been approved by the US Food and Drug Administration yet (m).

The combination of these drugs will be provided in different amounts on defined days (dosing schedules).

It is expected that the combination of milademetan and quizartinib will be safe and well tolerated. It is expected that the combination may fight the leukemia better than a single drug.

The study will run for approximately 3 years. There may be up to 156 participants.

The study has 2 parts:

• Part 1 will test 24-36 participants in approximately 15 study centers globally. Participants will receive two study drugs (milademetan and quizartinib) in different amounts on specific days. Information will be gathered to see what dosing schedule of the drug combination is best (maximum tolerated/recommended dose).
• Part 2 of the study will confirm the recommended dosing schedule identified in Part 1 is effective. A larger number of participants will receive the recommended dose in approximately 15 additional sites worldwide as necessary, based on the enrollment rate, the population, and the standard of care available to them at the time of enrollment.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Quizartinib; Drug: Milademetan; Drug: Milademetan

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan Medical Center, UCLA
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Rogel Cancer Center, University of Michigan
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Sidney Kimmel Cancer Center, Thomas Jefferson University
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has reached ≥18 years old or the age of the age of majority in their country
• Part 1 (dose escalation): Has FLT3-ITD mutant (≥ 3% FLT3-ITD/total FLT3) AML (primary AML, secondary, or therapy-related AML), and has treatment failure to prior AML therapy or have relapsed after prior AML therapy
• Part 2 (dose expansion): Has FLT3-ITD mutant (≥3% FLT3-ITD/total FLT3) AML (primary, secondary, or therapy-related AML), and has treatment failure to prior AML therapy or have relapsed after prior AML therapy, OR has newly diagnosed AML who are ineligible for intensive induction chemotherapy
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (or 3 for patients with newly diagnosed AML between 18 and 74 years old)
• Has protocol-defined adequate renal, hepatic and cardiac status
• Is not pregnant, and if not postmenopausal or a surgically sterile male or female, is willing to use a highly effective contraceptive method upon enrollment, during the course of the study, and for 6 months following the last dose of investigational drug
• Is able and willing to provide protocol-defined bone marrow biopsies/aspirates

Exclusion Criteria:

• Has central nervous system (CNS) involvement of leukemia - patients with a history of CNS leukemia may be eligible if the CNS leukemia is adequately controlled (defined as no clinical symptoms of CNS disease and at least 2 consecutive lumbar punctures with no evidence of disease prior to study enrollment) after discussion and approval from the Sponsor
• Has acute promyelocytic leukemia (AML subtype M3)
• Has uncontrolled or significant cardiovascular disease or QTc interval >450 ms (average of triplicate determination)
• Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals.
• Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection based on positive tests during Screening
• Has persistent, clinically significant > Grade 1 non-hematologic toxicity from prior AML therapies

• Has any history or medical condition, metastatic condition, drug/medication use or other condition that might, per protocol or in the opinion of the investigator, compromise:

  1. safety or well-being of the participant or offspring
  2. safety of study staff
  3. analysis of results

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: Part 1 - Quizartinib + Milademetan; Participants with relapsed/refractory FLT3-ITD Mutant AML receive quizartinib + milademetan at increasing and/or decreasing doses and schedules	Drug: Quizartinib; 20 or 30 mg tablets for oral administration; Other Names: AC220; Vanflyta; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; Other Names: DS-3032b; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized; Other Names: DS-3032b
Experimental: Part 2 - Cohort 1; Participants with relapsed/refractory FLT3-ITD Mutant AML receive the recommended dose of quizartinib + milademetan determined by Part 1	Drug: Quizartinib; 20 or 30 mg tablets for oral administration; Other Names: AC220; Vanflyta; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; Other Names: DS-3032b; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized; Other Names: DS-3032b
Experimental: Part 2 - Cohort 2; Participants with newly diagnosed FLT3-ITD Mutant AML unfit for chemotherapy receive the recommended dose of quizartinib + milademetan determined by Part 1	Drug: Quizartinib; 20 or 30 mg tablets for oral administration; Other Names: AC220; Vanflyta; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; Other Names: DS-3032b; Drug: Milademetan; 5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized; 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 Combination With Quizartinib	A dose limiting toxicity (DLT) is defined as any non-hematological treatment-emergent adverse event (TEAE) unless incontrovertibly related to disease progression, intercurrent illness, or concomitant medication, that occurs during the DLT evaluation period (28 days) in each dose level cohort, and is Grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, with exceptions specified: Grade 3 or higher aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels, OR elevation in total bilirubin ≥3.0 × upper limit of normal (ULN) that does not return to ≤Grade 2 elevation within 7 days. Absolute neutrophil count (ANC) <0.5 × 10^9/L, platelets <20 × 10^9/L, and marrow cellularity <5% at 6 weeks or later from start of therapy without any evidence of leukemia.	Baseline up to 28 days (Cycle 1) from the start of study drug administration
Number of Participants With Any Treatment-emergent Adverse Events by System Organ Class Following Administration of Milademetan in Combination With Quizartinib	A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) that emerges during the treatment period (from date of first dose up to 35 days after the last dose of the study treatment), having been absent at pretreatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment related to the pretreatment state, when the AE is continuous. AEs collected after 35 days after the last dose of study drug were not considered TEAEs unless they were treatment-related.	Baseline up to 35 days after last dose of study drug, up to approximately 2 years 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Best Overall Response Following Administration of Milademetan in Combination With Quizartinib	Based on European LeukemiaNet criteria, complete remission (CR) was bone marrow (BM) blasts <5%, absence of circulating blasts/blasts with Auer rods, absence of extramedullary disease (EMD), absolute neutrophil count (ANC) ≥1.0×10^9/L, and platelet count ≥100×10^9/L; CR with Incomplete Blood Count Recovery (CRi): all CR criteria except for residual neutropenia or thrombocytopenia; Morphologic Leukemia Free State (MLFS): BM blasts <5%, absence of blasts with Auer rods, absence of EMD, and no hematologic recovery required; Partial Remission (PR): decrease of BM blast percentage by at least 50% (to 5% to 25%) and all criteria of CR; Stable disease: absence of CR, CRi, MLFS, or PR, and criteria for progressive disease (PD) not met; Relapse (after CR/CRi): BM blasts ≥5%, or reappearance of leukemic blasts, or EMD development; and PD: increase in BM blast % and/or increase of absolute blast counts: >50% increase in marrow blasts over baseline, >50% increase in peripheral blasts, or new EMD.	Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months
Overall Response Rate Following Administration of Milademetan in Combination With Quizartinib	Overall response rate was defined as the number of participants with composite Complete Remission (CRc)+Morphological Leukemia Free State (MLFS)+Partial Remission (PR) based on the European LeukemiaNet criteria. Based on the European LeukemiaNet criteria, CRc was defined as complete remission (CR) as bone marrow (BM) blasts <5%, absence of circulating blasts/blasts with Auer rods, absence of extramedullary disease (EMD), absolute neutrophil count (ANC) ≥1.0×10^9/L, and platelet count ≥100×10^9/L; CR with Incomplete Blood Count Recovery (CRi): all CR criteria except for residual neutropenia or thrombocytopenia; Morphologic Leukemia Free State (MLFS): BM blasts <5%, absence of blasts with Auer rods, absence of EMD, and no hematologic recovery required; Partial Remission (PR): decrease of BM blast percentage by at least 50% (to 5% to 25%) and all criteria of CR.	Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2018
• Primary Completion (Actual): April 1, 2021
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: May 17, 2018
• First Submitted That Met QC Criteria: May 29, 2018
• First Posted (Actual): June 11, 2018

Study Record Updates

• Last Update Posted (Actual): May 20, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Newly Diagnosed; Relapsed/Refractory; Unfit for Chemotherapy; Positive for FLT3-ITD Mutation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: DS3032-A-U105

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: Yes
• Studies a U.S. FDA-regulated device product: No