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

• ClinicalTrials.gov Identifier: NCT03552029
• Recruitment Status: Terminated
• First Posted: June 11, 2018
• Results First Posted: May 20, 2022
• Last Update Posted: May 20, 2022
• Sponsor: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): Daiichi Sankyo, Inc.

Tracking Information

• First Submitted Date: May 17, 2018
• First Posted Date: June 11, 2018
• Results First Submitted Date: December 13, 2021
• Results First Posted Date: May 20, 2022
• Last Update Posted Date: May 20, 2022
• Actual Study Start Date: December 12, 2018
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2022)

• Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Combination With Quizartinib [ Time Frame: Baseline up to 28 days (Cycle 1) from the start of study drug administration ]
  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.
• Number of Participants With Any Treatment-emergent Adverse Events by System Organ Class Following Administration of Milademetan in Combination With Quizartinib [ Time Frame: Baseline up to 35 days after last dose of study drug, up to approximately 2 years 3 months ]
  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.

Original Primary Outcome Measures (submitted: May 29, 2018)

• Number of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: approximately 28 days after start of treatment ]
• Number of Participants with Adverse Events (AEs) During the Study [ Time Frame: within approximately 3 years ]
  Adverse events are collected for the entire duration of study participation plus 30 days after the last dose

Current Secondary Outcome Measures (submitted: March 14, 2022)

• Number of Participants With Best Overall Response Following Administration of Milademetan in Combination With Quizartinib [ Time Frame: Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months ]
  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.
• Overall Response Rate Following Administration of Milademetan in Combination With Quizartinib [ Time Frame: Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months ]
  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.

Original Secondary Outcome Measures (submitted: May 29, 2018)

• Maximum Concentration (Cmax) of Study Drug in Plasma [ Time Frame: within approximately 3 years ]
  Categories: Quizartinib, Metabolite AC886, Milademetan
• Area Under the Time-Drug Concentration Curve (AUC) in 24 hours (AUC0-24) [ Time Frame: within approximately 3 years ]
  Categories: Quizartinib, Metabolite AC886, Milademetan
• Number of Participants with Response to Treatment [ Time Frame: within approximately 3 years ]
• Composite Complete Remission Rate [ Time Frame: within approximately 3 years ]
  Composite complete remission rate is defined as the percentage of participants who achieve CR+CRi+CRh
• Partial Remission Rate [ Time Frame: within approximately 3 years ]
  Partial remission rate is defined as the percentage of participants who achieve partial remission (PR)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Part 1 Single Group 1 Arm, Part 2 Parallel, 2 Cohorts

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Acute Myeloid Leukemia

Intervention

• 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 Name: 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 Name: DS-3032b

Study Arms

• Experimental: Part 1 - Quizartinib + Milademetan
  Participants with relapsed/refractory FLT3-ITD Mutant AML receive quizartinib + milademetan at increasing and/or decreasing doses and schedules
  Interventions:

  • Drug: Quizartinib
  • Drug: Milademetan
• Experimental: Part 2 - Cohort 1
  Participants with relapsed/refractory FLT3-ITD Mutant AML receive the recommended dose of quizartinib + milademetan determined by Part 1
  Interventions:

  • Drug: Quizartinib
  • Drug: Milademetan
• 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
  Interventions:

  • Drug: Quizartinib
  • Drug: Milademetan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 14, 2021): 10
• Original Estimated Enrollment (submitted: May 29, 2018): 156
• Actual Study Completion Date: April 1, 2021
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03552029
• Other Study ID Numbers: DS3032-A-U105
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (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.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Daiichi Sankyo, Inc.
• Verification Date: March 2022