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

Primary Purpose

Acute Myeloid Leukemia

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Quizartinib
Milademetan
Milademetan
Sponsored by
Daiichi Sankyo, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Relapsed/Refractory, Newly Diagnosed, Unfit for Chemotherapy, Positive for FLT3-ITD Mutation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ronald Reagan Medical Center, UCLA
  • Yale Cancer Center
  • University of Kansas Cancer Center
  • Rogel Cancer Center, University of Michigan
  • Roswell Park Comprehensive Cancer Center
  • Duke University Cancer Center
  • Sidney Kimmel Cancer Center, Thomas Jefferson University
  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Part 1 - Quizartinib + Milademetan

Part 2 - Cohort 1

Part 2 - Cohort 2

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
May 17, 2018
Last Updated
March 14, 2022
Sponsor
Daiichi Sankyo, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03552029
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
This study was terminated based on a business decision by the Sponsor.
Study Start Date
December 12, 2018 (Actual)
Primary Completion Date
April 1, 2021 (Actual)
Study Completion Date
April 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Daiichi Sankyo, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
Relapsed/Refractory, Newly Diagnosed, Unfit for Chemotherapy, Positive for FLT3-ITD Mutation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
Part 1 Single Group 1 Arm, Part 2 Parallel, 2 Cohorts
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1 - Quizartinib + Milademetan
Arm Type
Experimental
Arm Description
Participants with relapsed/refractory FLT3-ITD Mutant AML receive quizartinib + milademetan at increasing and/or decreasing doses and schedules
Arm Title
Part 2 - Cohort 1
Arm Type
Experimental
Arm Description
Participants with relapsed/refractory FLT3-ITD Mutant AML receive the recommended dose of quizartinib + milademetan determined by Part 1
Arm Title
Part 2 - Cohort 2
Arm Type
Experimental
Arm Description
Participants with newly diagnosed FLT3-ITD Mutant AML unfit for chemotherapy receive the recommended dose of quizartinib + milademetan determined by Part 1
Intervention Type
Drug
Intervention Name(s)
Quizartinib
Other Intervention Name(s)
AC220, Vanflyta
Intervention Description
20 or 30 mg tablets for oral administration
Intervention Type
Drug
Intervention Name(s)
Milademetan
Other Intervention Name(s)
DS-3032b
Intervention Description
5, 20, 80 or 200 mg capsules for oral administration
Intervention Type
Drug
Intervention Name(s)
Milademetan
Other Intervention Name(s)
DS-3032b
Intervention Description
5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized
Primary Outcome Measure Information:
Title
Number of Participants With Dose Limiting Toxicities (DLTs) Following Administration of Milademetan in Combination With Quizartinib
Description
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.
Time Frame
Baseline up to 28 days (Cycle 1) from the start of study drug administration
Title
Number of Participants With Any Treatment-emergent Adverse Events by System Organ Class Following Administration of Milademetan in Combination With Quizartinib
Description
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.
Time Frame
Baseline up to 35 days after last dose of study drug, up to approximately 2 years 3 months
Secondary Outcome Measure Information:
Title
Number of Participants With Best Overall Response Following Administration of Milademetan in Combination With Quizartinib
Description
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.
Time Frame
Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months
Title
Overall Response Rate Following Administration of Milademetan in Combination With Quizartinib
Description
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.
Time Frame
Baseline up to first documented response, disease progression, withdrawal, or death (whichever occurs first), up to approximately 2 years 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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: safety or well-being of the participant or offspring safety of study staff analysis of results
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Team Leader
Organizational Affiliation
Daiichi Sankyo, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Ronald Reagan Medical Center, UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Yale Cancer Center
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
University of Kansas Cancer Center
City
Fairway
State/Province
Kansas
ZIP/Postal Code
66205
Country
United States
Facility Name
Rogel Cancer Center, University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Roswell Park Comprehensive Cancer Center
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Duke University Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Sidney Kimmel Cancer Center, Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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 URL
https://vivli.org/ourmember/daiichi-sankyo/

Learn more about this trial

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

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