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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03552029
• Other study ID #: DS3032-A-U105
• Status: Terminated
• Phase: Phase 1
• Start date: December 12, 2018
• Est. completion date: April 1, 2021

Study information

• Verified date: March 2022
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: April 1, 2021
• Est. primary completion date: April 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Quizartinib
20 or 30 mg tablets for oral administration
• Milademetan
5, 20, 80 or 200 mg capsules for oral administration
• Milademetan
5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized

Locations

Country	Name	City	State
United States	Rogel Cancer Center, University of Michigan	Ann Arbor	Michigan
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Duke University Cancer Center	Durham	North Carolina
United States	University of Kansas Cancer Center	Fairway	Kansas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Ronald Reagan Medical Center, UCLA	Los Angeles	California
United States	Yale Cancer Center	New Haven	Connecticut
United States	Sidney Kimmel Cancer Center, Thomas Jefferson University	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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