AML
Conditions
Keywords
Acute Myeloid Leukemia, AML, FMS-like tyrosine kinase 3, FLT3-ITD, Quizartinib, Leukemia, Tablets
Brief summary
The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.
Interventions
DRUGQuizartinib
20 or 30 mg quizartinib tablets administered orally once daily
Low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA) administered during 28-day cycles
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of written informed consent approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) with privacy language in accordance with national regulations (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] authorization for United States \[US\] sites) prior to any study related procedures, including withdrawal of prohibited medications if applicable. 2. Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of Informed consent. 3. Morphologically documented primary Acute Myeloid Leukemia (AML) or AML secondary to Myelodysplastic Syndrome (MDS), as defined by World Health Organization (WHO) criteria, as determined by pathology review at the study site. 4. In first relapse (with duration of remission of 6 months or less) or refractory after prior therapy, with or without HSCT. Induction therapy must have included at least 1 cycle of an anthracycline/mitoxantrone-containing induction block at a standard dose. 5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of ≥3% FLT3-ITD/total FLT3). If a specimen has been sent for FLT3-ITD testing at the central laboratory but the subject requires treatment for AML before the central FLT3-ITD test result is available, a local test result may be acceptable for randomization after consultation with the Medical Monitor. 6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator's assessment. 7. Eastern Cooperative Oncology Group (ECOG) performance score 0-2. 8. Discontinuation of prior AML treatment before the start of study treatment (except hydroxyurea or other treatment to control leukocytosis) for at least 2 weeks for cytotoxic agents, or for at least 5 half-lives for non cytotoxic agents. 9. Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate \>25 mL/min, as calculated with the Cockcroft-Gault formula. 10. Serum potassium, magnesium, and calcium (serum calcium corrected for hypoalbuminemia) within institutional normal limits. Subjects with electrolytes outside the normal range will be eligible if these values are corrected upon retesting following any necessary supplementation. 11. Total serum bilirubin ≤1.5×ULN. 12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN.
Exclusion criteria
1. Acute Promyelocytic Leukemia (AML subtype M3). 2. AML secondary to prior chemotherapy for other neoplasms, except AML secondary to prior Myelodysplastic Syndrome (MDS). 3. History of another malignancy, unless the candidate has been disease-free for at least 5 years. 4. Persistent, clinically significant \> Grade 1 non-hematologic toxicity from prior AML therapy. 5. Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or \> Grade 1 persistent or clinically significant non hematologic toxicity related to HSCT. 6. History of or current, central nervous system involvement with AML. 7. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation. 8. Prior treatment with quizartinib or participated in a prior quizartinib study. 9. Prior treatment with a FLT3 targeted therapy including sorafenib or investigational FLT3 inhibitors (not including the multi-kinase inhibitor, midostaurin). 10. Major surgery within 4 weeks prior to screening. 11. Radiation therapy within 4 weeks prior to screening. 12. Uncontrolled or significant cardiovascular disease 13. Active infection not well controlled by antibacterial or antiviral therapy. 14. Known infection with human immunodeficiency virus, or active hepatitis B or C, or other active clinically relevant liver disease. 15. Unwillingness to receive infusion of blood products according to the protocol. 16. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use a highly effective contraceptive method for the entire study treatment period for at least 3 months after study completion. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and 105 days after the final study drug administration. 17. In a heterosexually active woman of childbearing potential, unwillingness or inability to use a highly effective contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion. Additionally, for women randomized to chemotherapy, unwillingness to adhere to the restrictions in the respective locally established guidelines and local approved label (prescribing information, Summary of Product Characteristics, or US product insert) from the manufacturer and the Patient Information Leaflet (package insert) as instructed by the Investigator. 18. Pregnancy. 19. Female Subjects must agree to not breastfeed from the time of Screening and throughout the study period, and for 25 days after the final study drug administration. 20. Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives. 21. For subjects in the United Kingdom only: Refusal of permission to allow the subject's General Practitioner to be notified of their participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | At approximately 3 years 9 months | Overall Survival is defined as the time (in weeks) from the date of randomization to the date of death due to any cause. Median and quartiles are calculated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | At approximately 3 years 9 months | Event-free survival is defined as the time (in weeks) from randomization until documented refractory disease, relapse after complete composite remission (CRc), or death from any cause, whichever is observed first. |
Countries
Australia, Belgium, Canada, Croatia, Czechia, France, Germany, Hong Kong, Hungary, Italy, Netherlands, Poland, Serbia, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 367 participants who met the inclusion and none of the exclusion criteria were randomized (intent-to-treat population); 335 received study drug (safety analysis set).
Pre-assignment details
Prior to randomization, the investigator was required to pre-select 1 of the 3 salvage chemotherapy regimens for each participant. Randomization was stratified by response to prior therapy (relapsed in ≤6 months \[with or without HSCT\] or refractory) and pre-selected salvage chemotherapy (high or low intensity chemotherapy) for all participants.
Participants by arm
| Arm | Count |
|---|---|
| Quizartinib Participants who were randomized to receive 20 or 30 mg Quizartinib tablets administered orally once daily. | 245 |
| Salvage Chemotherapy Participants who were randomized to receive salvage chemotherapy, such as low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA), were administered during 28-day cycles. | 122 |
| Total | 367 |
Baseline characteristics
| Characteristic | Salvage Chemotherapy | Total | Quizartinib |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 98 Participants | 65 Participants |
| Age, Categorical Between 18 and 65 years | 89 Participants | 269 Participants | 180 Participants |
| Age, Continuous | 57.5 years | 56.0 years | 55.0 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 40 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 12 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 37 Participants | 27 Participants |
| Race (NIH/OMB) White | 93 Participants | 277 Participants | 184 Participants |
| Region of Enrollment Australia | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Canada | 5 participants | 23 participants | 18 participants |
| Region of Enrollment Czechia | 0 participants | 2 participants | 2 participants |
| Region of Enrollment France | 7 participants | 27 participants | 20 participants |
| Region of Enrollment Germany | 18 participants | 43 participants | 25 participants |
| Region of Enrollment Hong Kong | 3 participants | 8 participants | 5 participants |
| Region of Enrollment Hungary | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 19 participants | 53 participants | 34 participants |
| Region of Enrollment Netherlands | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Poland | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Serbia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Singapore | 2 participants | 2 participants | 0 participants |
| Region of Enrollment South Korea | 7 participants | 18 participants | 11 participants |
| Region of Enrollment Spain | 6 participants | 21 participants | 15 participants |
| Region of Enrollment Taiwan | 1 participants | 3 participants | 2 participants |
| Region of Enrollment United Kingdom | 14 participants | 35 participants | 21 participants |
| Region of Enrollment United States | 36 participants | 118 participants | 82 participants |
| Sex: Female, Male Female | 58 Participants | 190 Participants | 132 Participants |
| Sex: Female, Male Male | 64 Participants | 177 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 80 / 241 | 16 / 94 |
| other Total, other adverse events | 238 / 241 | 91 / 94 |
| serious Total, serious adverse events | 168 / 241 | 37 / 94 |
Outcome results
Primary
Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy
Overall Survival is defined as the time (in weeks) from the date of randomization to the date of death due to any cause. Median and quartiles are calculated using the Kaplan-Meier method.
Time frame: At approximately 3 years 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Quizartinib | Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | 27.0 weeks |
| Salvage Chemotherapy | Overall Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | 20.4 weeks |
Comparison: Stratified analysis - stratification factors include prior therapy and response (Relapsed in ≤6 months (not post-HSCT), Refractory, or relapsed in ≤6 months post allogeneic HSCT), and pre-selected chemotherapy (High intensity chemotherapy \[MEC or FLAG-IDA\], or low intensity chemotherapy \[LoDAC\]).p-value: 0.018595% CI: [0.584, 0.983]P-value for HR=1 (1-sided)
Secondary
Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy
Event-free survival is defined as the time (in weeks) from randomization until documented refractory disease, relapse after complete composite remission (CRc), or death from any cause, whichever is observed first.
Time frame: At approximately 3 years 9 months
Population: Event-free survival was assessed in the intent-to-treat (ITT) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Quizartinib | Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | 6.0 weeks |
| Salvage Chemotherapy | Event-free Survival in Participants That Received Quizartinib Versus Salvage Chemotherapy | 3.7 weeks |
Comparison: Stratified analysis - stratification factors include prior therapy and response (Relapsed in ≤6 months (not post-HSCT), Refractory, or relapsed in ≤6 months post allogeneic HSCT), and pre-selected chemotherapy (High intensity chemotherapy \[MEC or FLAG-IDA\], or low intensity chemotherapy \[LoDAC\]).p-value: 0.203495% CI: [0.697, 1.157]P value for HR=1 (1-sided)