Clinical trial NCT03552029: Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: Relapsed/Refractory
Newly Diagnosed
Unfit for Chemotherapy
Positive for FLT3-ITD Mutation
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2018-06-11
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 Single Group 1 Arm, Part 2 Parallel, 2 Cohorts
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Combination With Quizartinib
timeFrame: Baseline up to 28 days (Cycle 1) from the start of study drug administration
measure: Number of Participants With Any Treatment-emergent Adverse Events by System Organ Class Following Administration of Milademetan in Combination With Quizartinib
timeFrame: Baseline up to 35 days after last dose of study drug, up to approximately 2 years 3 months
Secondary outcomes:
measure: Number of Participants With Best Overall Response Following Administration of Milademetan in Combination With Quizartinib
timeFrame: Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months
measure: Overall Response Rate Following Administration of Milademetan in Combination With Quizartinib
timeFrame: Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan Medical Center, UCLA
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Fairway
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Ann Arbor
country: United States
facility: Rogel Cancer Center, University of Michigan
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center, Thomas Jefferson University
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Daiichi Sankyo
name: Clinical Team Leader
role: STUDY_DIRECTOR
References: