Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Compound AC220

• Registration Number: NCT00989261
• Lead Sponsor: Daiichi Sankyo

Brief Summary

AC220 will be administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-10-01
• Study First Submitted QC: 2009-10-01
• Study First Posted: 2009-10-05
• Study Start: 2009-11
• Primary Completion: 2012-09-28
• Study Completion: 2014-12-31
• Disposition First Submitted: 2016-09-30
• Disposition First Submitted QC: 2016-09-30
• Disposition First Posted: 2016-10-03
• Results First Submitted: 2019-09-25
• Results First Submitted QC: 2019-11-11
• Results First Posted: 2019-11-29
• Status Verified: 2019-12
• Last Update Submitted: 2019-12-03
• Last Update Posted: 2019-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 333

Inclusion Criteria

1. Males and females age ≥18 years in second relapse or refractory.
2. Males and females age ≥60 years in first relapse or refractory.
3. Must have baseline bone marrow sample taken.
4. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS with ≥20% bone marrow or peripheral blasts), as defined by the World Health Organization (WHO) criteria, confirmed by pathology review at treating institution.
5. Able to swallow the liquid study drug.
6. Eastern Cooperative Oncology Group performance status of 0 to 2
7. In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic agents other than hydroxyurea is not permitted during the study with the possible exception of intrathecal (IT) therapy at the discretion of the Investigator and with the agreement of the Sponsor.
8. Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade 1.
9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.
10. Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min
11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.
12. Total serum bilirubin ≤1.5 × ULN
13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN
14. Females of childbearing potential must have a negative pregnancy test (urine β-hCG).
15. Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.
16. Written informed consent must be provided.

Exclusion Criteria

1. Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.
2. Diagnosis of acute promyelocytic leukemia
3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis
4. AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment
5. AML or antecedent MDS secondary to prior chemotherapy
6. Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy
7. Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity related to the transplant
8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.
9. Patients who have previously received AC220
10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
11. Major surgery within 4 weeks prior to enrollment in the study
12. Radiation therapy within 4 weeks prior to, or concurrent with study
13. Use of concomitant drugs that prolong the time between the start of the Q wave and the end of the T wave (QT)/corrected interval between the Q wave and T wave (QTc) interval and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
14. Uncontrolled or significant cardiovascular disease
15. Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential
16. Men who are unwilling to use contraception if their partners are of childbearing potential
17. Active, uncontrolled infection
18. Human immunodeficiency virus positivity
19. Active hepatitis B or C or other active liver disease
20. History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1; ≥60 years of age	Compound AC220	Participants ≥60 years of age who were relapsed after one first-line chemotherapy regimen (with or without consolidation) and after first complete remission \<12 months or are primary refractory to first-line chemotherapy received a starting dose of 200 mg/day quizartinib. Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-) After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.
Cohort 2; ≥18 years of age	Compound AC220	Participants ≥18 years of age (including participants ≥60 years of age) who were relapsed or refractory after one second-line (salvage) regimen or after hematopoietic stem cell transplant (HSCT) received a starting dose of 200 mg/day quizartinib. Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-) After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.

Primary Outcome Measures

Name	Time	Method
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)	Within the first 3 cycles of treatment (84 days)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD\[+\] Participants); Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.
Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)	Within the first 3 cycles of treatment (84 days)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD\[-\] Participants); Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.
Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status	within 28 months	CRc is defined as composite complete remission (CR+CRp+CRi) - CR = complete remission; CRp = complete remission with incomplete platelet recovery; CRi = complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia \<1 x 10\^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = all criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion.

Secondary Outcome Measures

Name	Time	Method
Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).
Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population).; The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of \>1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.
Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population).; The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of \>1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.
Duration of Any Response in FLT3-ITD (+) Participants	From the time of any response until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).
Duration of Any Response in FLT3-ITD (-) Participants	From the time of any response until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).
Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).
Median Duration of Overall Survival in FLT3-ITD (+) Participants	Time from first dose to death from any cause, up to 3 years post treatment	Kaplan-Meier analysis of overall survival (Safety Population)
Median Duration of Overall Survival in FLT3-ITD (-) Participants	Time from first dose to death from any cause, up to approximately 3 years post treatment	Kaplan-Meier analysis of overall survival (Safety Population)
Early Treatment-related Death	Within first 3 cycles of treatment (84 days)	Early treatment-related deaths included all treatment-related deaths prior to the end of Cycle 3 with a 3-day window (Cycle 3 end date + 3 days), unless the death was following a CRc response assessed by the Investigator.

Trial Locations

Locations (85)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

University of Maryland; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

University of Michigan Medical Center; 🇺🇸 Ann Arbor, Michigan, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

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