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

Study Overview
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Brief Summary
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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).

Official Title
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Phase 2 Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With and Without FLT3-ITD Activating Mutations

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Compound AC220


Participation Criteria
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Eligibility Criteria
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Current enrollment is open only to FLT3-ITD positive, Cohort 1. Inclusion Criteria: Males and females age ≥18 years in second relapse or refractory. Males and females age ≥60 years in first relapse or refractory. Must have baseline bone marrow sample taken. 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. Able to swallow the liquid study drug. Eastern Cooperative Oncology Group performance status of 0 to 2 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. Persistent chronic clinically significant non-hematological toxicities from prior treatment must be ≤Grade 1. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220. Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits. Total serum bilirubin ≤1.5 × ULN Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN Females of childbearing potential must have a negative pregnancy test (urine β-hCG). Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study. Written informed consent must be provided. Exclusion Criteria: Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor. Diagnosis of acute promyelocytic leukemia Diagnosis of chronic myelogenous leukemia (CML) in blast crisis AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment AML or antecedent MDS secondary to prior chemotherapy Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy 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 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. Patients who have previously received AC220 Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment) Major surgery within 4 weeks prior to enrollment in the study Radiation therapy within 4 weeks prior to, or concurrent with study 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. Uncontrolled or significant cardiovascular disease Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential Men who are unwilling to use contraception if their partners are of childbearing potential Active, uncontrolled infection Human immunodeficiency virus positivity Active hepatitis B or C or other active liver disease History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1; ≥60 years of age<br>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. | Drug: Compound AC220<br>* Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.<br>* Other names: AC010220 × 2HCl, oral powder for reconstitution;|
| Experimental: Cohort 2; ≥18 years of age<br>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. | Drug: Compound AC220<br>* Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.<br>* Other names: AC010220 × 2HCl, oral powder for reconstitution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants) | 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. | Within the first 3 cycles of treatment (84 days) | 
| Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants) | 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. | Within the first 3 cycles of treatment (84 days) | 
| Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status | 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. | within 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data | 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. | From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment | 
| Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data | 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. | From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment | 
| Duration of Any Response in FLT3-ITD (+) Participants | 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). | From the time of any response until disease progression or death, up to approximately 3 years post treatment | 
| Duration of Any Response in FLT3-ITD (-) Participants | 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). | From the time of any response until disease progression or death, up to approximately 3 years post treatment | 
| Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants | 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). | From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment | 
| Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants | 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). | From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment | 
| Median Duration of Overall Survival in FLT3-ITD (+) Participants | Kaplan-Meier analysis of overall survival (Safety Population) | Time from first dose to death from any cause, up to 3 years post treatment | 
| Median Duration of Overall Survival in FLT3-ITD (-) Participants | Kaplan-Meier analysis of overall survival (Safety Population) | Time from first dose to death from any cause, up to approximately 3 years post treatment | 
| Early Treatment-related Death | 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. | Within first 3 cycles of treatment (84 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, AC220, acute, FLT3, inhibitor, kinase, leukemia, leukaemia, myeloid, relapsed, refractory