Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Leukemia, Myeloid, Acute Clinical Trial

Official title:

A Phase 2, Randomized, Open-Label Study of the Safety and Efficacy of Two Doses of Quizartinib (AC220; ASP2689) in Subjects With FLT3-ITD Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01565668
• Other study ID #: 2689-CL-2004
• Secondary ID: 2011-005408-13
• Status: Completed
• Phase: Phase 2
• Start date: April 2012
• Est. completion date: March 2015

Study information

• Verified date: December 2019
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate two doses of Quizartinib in patients with relapsed or refractory acute myeloid leukemia who are also FMS-like tyrosine kinase - internal tandem duplication ( FLT3-ITD) positive. Patient will be randomly assigned in a 1:1 ratio to one of two treatment arms. Both treatment arms will receive Quizartinib but at different doses. The study treatment is taken orally in 28 day cycles until either disease progression occurs or an unacceptable toxicity occurs. In addition to the study assessments to evaluate the disease, blood will be drawn to measure drug levels and biomarkers. Patients will be followed for survival at three month intervals after the end of treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subject has morphologically documented primary acute myeloid leukemia (AML) or AML secondary to myelodysplastic syndrome (MDS) as defined by the World Health Organization (WHO) criteria, as determined by pathology review at the treating institution and has relapsed or is refractory after 1 second line (salvage) regimen or after hematopoietic stem cell transplantation (HSCT)

• Subject is positive for FLT3-ITD activating mutation in bone marrow or peripheral blood (>10% allelic ratio)

• Eastern Cooperative Oncology Group performance status of 0 to 2

• In the absence of rapidly progressing disease clearly documented by the investigator, the interval from prior treatment to time of AC220 administration will be at least 2 weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior noncytotoxic agents, including immunosuppressive therapy post HSCT

• Persistent chronic clinically significant nonhematological toxicities from prior treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, HSCT, or surgery) must be Grade = 1

• Patients - both males and females - with reproductive potential are eligible

Exclusion Criteria:

• Subject received previous treatment with AC220

• Subject has a diagnosis of acute promyelocytic leukemia

• Subject has a diagnosis of chronic myelogenous leukemia (CML) in blast crisis

• Subject has AML or antecedent MDS secondary to prior chemotherapy

• Subject has had HSCT and has either of the following:

• Donor lymphocyte infusion (DLI) is not permitted during the study or < 30 days prior to study entry

• Subject has clinically active central nervous system (CNS) leukemia. A subject is considered eligible if CNS leukemia is controlled and subject is receiving intrathecal (IT) therapy at study entry. Subjects should continue to receive IT therapy (or cranial radiation) as clinically indicated

• Subject has received concurrent chemotherapy, immunotherapy, or radiotherapy within 14 days prior to the first dose of AC220, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug

• Subject requires treatment with concomitant drugs that prolong QT/QTc interval or with strong inhibitors or inducers of cytochrome P450- isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject

• Subject requires treatment with anticoagulant therapy

• Subject has a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen

• Subject had major surgery within 4 weeks prior to first dose of AC220

• Subject has uncontrolled or significant cardiovascular disease, including

• Subject has a pre-existing disorder predisposing the subject to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML)

• Subject has an active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection

• Subject has any of the following laboratory values:

• Subject is a female with a positive pregnancy test, pregnant, or breastfeeding

• Subject has any medical, psychiatric, addictive or other kind of disorder which compromises the ability of the subject to give written informed consent and/or to comply with procedures

Related Conditions & MeSH terms

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

Intervention

Drug:
• AC220
oral

Locations

Country	Name	City	State
France	CHU d'Angers	Angers
France	CHU de Grenoble	Grenoble
France	Hôpital Saint Antoine	Paris
France	Hôpital Haut Lévêque	Pessac
Italy	Universitaria Policlinico S. Orsola Malpighi, Institute of Hemtology "L. & A. Seragnoli"	Bologna
United Kingdom	Nottingham University Hospitals	Nottingham	England
United States	John Hopkins University	Baltimore	Maryland
United States	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland
United States	Tufts University School of Medicine-Tufts Medical Center	Boston	Massachusetts
United States	Medical University of South Carolina, Hollings Cancer Center	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	UT Southwestern Medical Center, Simmons Cancer Center	Dallas	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	MD Anderson	Houston	Texas
United States	UCLA School of Medicine	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University, Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.	Ambit Biosciences Corporation

Countries where clinical trial is conducted

United States,  France,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Achieved Composite Complete Response (CRc) (Intent-to-Treat Population)	CRc is defined as Complete remission (CR) + Complete remission with incomplete platelet recovery (CRp) + Complete remission with incomplete hematological recovery (CRi).; Participants with CR must have normal hematopoietic cells and achieved a morphologic leukemia-free state (<5% bone marrow blasts in bone marrow, no blasts with Auer rods and no persistence of extramedullary disease) and must have had an absolute neutrophil count (ANC) =1 × 10^9/L and platelet count =100 × 10^9/L and were red blood cell (RBC) and platelet transfusion independent. Blasts in the peripheral blood was to be =1% (if blood sample was available).; Participants with CRp must have achieved CR except for incomplete platelet recovery (< 100 ×10^9/L).; Participants with CRi must have fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia <1 × 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required.	At end of Cycle 2 (after two complete 28-day cycles post treatment)
Secondary	Number of Participants Who Achieved Complete Remission (CR) (Intent-to-Treat Population)	Participant must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state (< 5% bone marrow blasts in bone marrow, no blasts with Auer rods and no persistence of extramedullary disease) and must have an absolute neutrophil count (ANC) = 1x10^9/L and platelet count = 100 x 10^9/L and they will be red blood cell (RBC) and platelet transfusion independent (defined as 4 weeks without RBC transfusions and 1 week without platelet transfusion).	At end of treatment visit (approximately 3 years post treatment)
Secondary	Overall Survival (OS) After Approximately 3 Years (Intent-to-Treat Population)	OS was defined as the time from the date of randomization until the date of death from any cause.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Event Free Survival (EFS) After Approximately 3 Years (Intent-to-Treat Population)	EFS was defined as the time from the date of randomization until the date of documented relapse or death.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Leukemia Free Survival (LFS) After Approximately 3 Years (Intent-to-Treat Population)	LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Duration of Remission After Approximately 3 Years (Intent-to-Treat Population)	Duration of remission was defined as the time from first documented remission until documented relapse. CRc was defined as composite complete remission and CRi was defined as complete remission with incomplete hematological recovery.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Time to Composite Complete Remission (CRc) in Participants Who Achieved CRc After Approximately 3 Years (Intent-to-Treat Population)	Time to CRc was defined as the time from the date of randomization until the first disease assessment of CRc. Time to CRc was only evaluated in participants who achieved CRc.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Percentage of Participants Undergoing Hematopoietic Stem Cell Transplantation (HSCT) After Approximately 3 Years (Intent-to-Treat Population)	Transplantation rate was defined as the percentage of participants who underwent HSCT directly after treatment with quizartinib (no other intervening acute myeloid leukemia therapies other than conditioning regimens for the HSCT).	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)
Secondary	Percentage of Participants With Grade 2 or Higher QT Interval Corrected for Heart Rate Using Fridericia's Formula (QTcF) Prolongation After Receiving Quizartinib (Safety Analysis Set)	QT interval corrected for heart rate using Fridericia's formula (QTcF) grading was to be done according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the definition of Grade 2 or higher prolongation is QTcF more than 480 msec.	Evaluated at end of study, up to 6 months (approximately 3 years post treatment)