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

NCT03552029 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: DS3032-A-U105
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Keywords

Relapsed/Refractory; Newly Diagnosed; Unfit for Chemotherapy; Positive for FLT3-ITD Mutation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Number of Participants With Best Overall Response Following Administration of Milademetan in Combination With Quizartinib

  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

  Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months

Study Arms (3)

Part 1 - Quizartinib + Milademetan

EXPERIMENTAL

Participants with relapsed/refractory FLT3-ITD Mutant AML receive quizartinib + milademetan at increasing and/or decreasing doses and schedules

Drug: Quizartinib; Drug: Milademetan

Part 2 - Cohort 1

EXPERIMENTAL

Participants with relapsed/refractory FLT3-ITD Mutant AML receive the recommended dose of quizartinib + milademetan determined by Part 1

Drug: Quizartinib; Drug: Milademetan

Part 2 - Cohort 2

EXPERIMENTAL

Participants with newly diagnosed FLT3-ITD Mutant AML unfit for chemotherapy receive the recommended dose of quizartinib + milademetan determined by Part 1

Drug: Quizartinib; Drug: Milademetan

Interventions

Quizartinib DRUG

20 or 30 mg tablets for oral administration

Also known as: AC220, Vanflyta

Part 1 - Quizartinib + Milademetan; Part 2 - Cohort 1; Part 2 - Cohort 2

Milademetan DRUG

5, 20, 80 or 200 mg capsules for oral administration

Also known as: DS-3032b

Part 1 - Quizartinib + Milademetan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• safety or well-being of the participant or offspring
• safety of study staff
• analysis of results

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (8)

Ronald Reagan Medical Center, UCLA

Los Angeles, California, 90095, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

University of Kansas Cancer Center

Fairway, Kansas, 66205, United States

Location

Rogel Cancer Center, University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

Location

Duke University Cancer Center

Durham, North Carolina, 27710, United States

Location

Sidney Kimmel Cancer Center, Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Zhang W, Li L, Muftuoglu M, Basyal M, Togashi N, Iwanaga K, Tanzawa F, Numata M, Bixby DL, Erba HP, Podoltsev N, Schiller GJ, Kumar P, Lesegretain A, Isoyama T, Seki T, Daver N, Andreeff M. Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition with Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild-type Acute Myeloid Leukemias. Clin Cancer Res. 2025 Jul 15;31(14):3033-3047. doi: 10.1158/1078-0432.CCR-24-2764.

  PMID: 40327322 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

quizartinib; milademetan

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

This study was terminated based on a business decision by the Sponsor and was not due to a safety concern.

Results Point of Contact

• Title: Contact for Clinical Trial Disclosure Information
• Organization: Daiichi Sankyo

CTRinfo@dsi.com

908-992-6400

Study Officials

• Clinical Team Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 Single Group 1 Arm, Part 2 Parallel, 2 Cohorts

Study Record Dates

• First Submitted: May 17, 2018
• First Posted: June 11, 2018
• Study Start: December 12, 2018
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: May 20, 2022
• Results First Posted: May 20, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

US (8)