People with acute myeloid leukemia (AML) are usually treated with chemotherapy. Some people with AML have a changed FLT3 gene which causes leukemia cells to grow faster. Therefore, chemotherapy is less suitable to treat AML in people with the changed FLT3 gene. Gilteritinib, given with venetoclax and azacitidine, is a potential new treatment for people with AML with the changed FLT3 gene. They cannot have chemotherapy due to old age or other conditions. Before these combined 3 medicines are available as a treatment, the researchers need to understand how they are processed by and act upon the body when given together. In this study, they do this to find a suitable dose for venetoclax and to check for potential medical problems from the treatment. In this study, people newly diagnosed with AML who have the changed FLT3 gene and cannot have chemotherapy can take part. The main aims of this study are: to find suitable doses of gilteritinib, venetoclax and azacitidine as a combined treatment; to learn how they are processed by and act upon the body; to learn the remission rate; to check for medical problems during this treatment. In the study, people will visit the study clinic many times. The first visit is to check if they can take part. People will be asked about their medical history, have a medical examination, and have their vital signs checked. Also, they will have an ECG to check their heart rhythm and have some blood and urine samples taken for laboratory tests. They will have a chest X-ray and a bone marrow sample will be taken. The changed FLT3 gene will be confirmed, either by the bone marrow or a blood sample. This study will be in 2 phases. In Phase 1, different small groups of people will take venetoclax tablets containing lower to higher doses in the combined treatment. The doses of gilteritinib and azacytidine will be unchanged. This is done to find a suitable dose of venetoclax to use in phase 2 of the study. People will take tablets of gilteritinib and venetoclax once a day on a 28-day cycle. They will be given azacytidine as an infusion or an injection just under the skin. This will be for 7 days at the beginning of each 28-day cycle. They will continue cycles of treatment throughout this phase of the study. In Phase 2, more people newly diagnosed with AML with the changed FLT3 gene will take part. They will be treated with the suitable doses of the combined treatment worked out from Phase 1. Treatment will be on a 28-day cycle. People will continue on cycles of treatment throughout this phase of the study. Researchers will work out the remission rate from this phase of the study. In each phase of the study, people can continue with up to 12 cycles of treatment if they can manage any medical problems. People will visit the study clinic many times during their first treatment cycle, and less often during the next cycles. During these visits, medical problems will be recorded and some blood samples will be taken for laboratory tests. On some visits, people will also have their vital signs checked. Bone marrow samples will be taken during cycle 1, and at the beginning of cycle 3. More samples will be taken during the study from people who are not in remission. When people have finished treatment, those who have responded well to treatment and are in remission will be invited to continue with up to 24 more cycles of gilteritinib plus azacitidine. All people taking part in the study will visit the study clinic for an end-of-treatment visit. During this visit, medical problems will be recorded and some blood samples will be taken for laboratory tests. People will have a medical examination, an ECG, and will have their vital signs checked. Also, a bone marrow sample will be taken. There will be a follow-up visit 30 days later to check for medical problems. Then people will visit the clinic or get a phone call every 3 months for up to 3 years. This is to give an update on their current treatment for AML. Some people can have a stem cell transplant during the study if they meet certain study rules. They will pause their study treatment during the stem cell transplant process and continue study treatment afterwards.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
70
City of Hope Nat'l Medical Center
Duarte, California, United States
Univ. of California - Irvine
Irvine, California, United States
UCLA Medical Center
Los Angeles, California, United States
Sarah Cannon Research Institute
Denver, Colorado, United States
Memorial Cancer Institute
Pembroke Pines, Florida, United States
University of Chicago
Chicago, Illinois, United States
Robert H. Lurie Comprehensive Cancer Center
Chicago, Illinois, United States
University of Maryland
Baltimore, Maryland, United States
Johns Hopkins University
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
...and 10 more locations
Number of Participants with Dose Limiting Toxicities (DLTs)
A DLT is defined as any of the events meeting DLT criteria that occur with the first dose on Cycle 1 Day 1 (C1D1) and that is considered to be possibly or probably related to the study treatment regimen.
Time frame: Up to 42 Days
Number of Participants with Adverse Events (AEs)
An AE is any untoward medical occurrence in a patient or clinical study participant temporally associated with the use of study investigational product (IP), whether or not considered related to the study IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study IP. This includes events related to the comparator and events related to the (study) procedures.
Time frame: Up to 49 months
Number of Participants with Serious AEs (SAEs)
An SAE is defined as any untoward medical occurrence that, at any dose: * results in death * is life threatening * requires inpatient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other situations where medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above. These events should usually be considered serious.
Time frame: Up to 49 months
Number of Participants with laboratory value abnormalities and/or AEs
Number of participants with potentially clinically significant laboratory values.
Time frame: Up to 48 months
Number or Participants with electrocardiogram (ECG) abnormalities and/or AEs
Number of participants with potentially clinically significant ECG values.
Time frame: Up to 48 months
Number of Participants with vital sign abnormalities and/or AEs
Number of participants with potentially clinically significant vital sign values.
Time frame: Up to 48 months
Number of Participants with physical exam abnormalities and/or AEs
Number of participants with potentially clinically significant physical exam values.
Time frame: Up to 48 months
Number of Participants at each grade of the Eastern Cooperative Oncology Group (ECOG) performance status scores
The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.
Time frame: Up to 48 months
Percentage of Participants with Complete Remission (CR)
CR rate is defined as the number of participants who achieve the best response of CR divided by the number of participants in the analysis population. CR is defined as participants having bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have bone marrow blasts \< 5% by morphological examination, absolute neutrophil count (ANC) \> 1 x 10\^9/L, platelet count \> 100 x 10\^9/L, and an absence of leukemic blasts in the peripheral blood by morphological examination. There should be no evidence of extramedullary disease. Other participants who do not relapse on study are considered nonevents and censored at the last
Time frame: Up to 24 months
Pharmacological activity by Plasma Inhibitory Activity Assay (PIA)
Inhibition of FLT3 phosphorylation after drug treatment will be determined relative to pretreatment phosphorylated FLT3 levels in participants to assess the relationship with gilteritinib dose. Phosphorylated FLT3 will be measured by plasma inhibitory activity (PIA) assay.
Time frame: Up to 2 months
Pharmacokinetics (PK) of ASP2215 in plasma: concentration
Concentration will be recorded from the PK plasma samples collected.
Time frame: Up to 6 months
Percentage of Participants with Complete Remission and Complete Remission with Partial Hematological Recovery (CR/CRh) rate
The CR/CRh rate is defined as the number of participants who achieved either CR or CRh at any of the post baseline visits divided by the number of participants in the analysis population.
Time frame: Up to 24 months
Percentage of Participants with Composite Complete Remission (CRc)
CRc rate is defined as the number of participants who achieve the best response of CRc divided by the number of participants in the analysis population.
Time frame: Up to 24 months
Duration of Remission (DOR)
Duration of remission includes duration of CRc, CR, CR/CRh, CRh, complete remission with incomplete hematologic recovery (CRi), complete remission with incomplete platelet recovery (CRp). Duration of CRc is defined as the time from the date of first CRc until the date of confirmed relapse or death due to any cause for participants who achieve CRc. Participants without confirmed relapse or death will be censored at their last relapse-free disease assessment date. The duration of CR, CR/CRh, CRh, CRp or CRi is defined similarly as duration of CRc.
Time frame: Up to 24 months
Duration of Overall Survival (OS)
OS is defined as the time from the date of enrollment until the date of death from any cause. For a participant who is not known to have died by the end of study follow-up, OS is censored at the date of last contact.
Time frame: Up to 24 months
Duration of Event free survival (EFS)
EFS is defined as the number of days from the date of enrollment to the date of earliest evidence of relapse, treatment failure, or death.
Time frame: Up to 24 months
Pharmacokinetics (PK) of ASP2215 in plasma: area under the plasma concentration-time curve during a dosage interval (AUCtau)
AUCtau will be recorded from the PK plasma samples collected.
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Time frame: Up to 6 months
PK of ASP2215 in plasma: maximum observed concentration (Cmax)
Cmax will be recorded from PK plasma samples collected.
Time frame: Up to 6 months
PK of ASP2215 in plasma: pre-dose trough concentration (Ctrough)
Ctrough will be recorded from PK plasma samples collected.
Time frame: Up to 6 months
PK of ASP2215 in plasma: area under the curve from time 0 to the time of the last measurable concentration (AUClast)
AUClast will be recorded from PK plasma samples collected.
Time frame: Up to 6 months
PK of ASP2215 in plasma: time to Cmax (tmax)
tmax will be recorded from PK plasma samples collected.
Time frame: Up to 6 months
Number of participants with negative minimal residual disease (MRD) status
MRD testing will be performed on left over bone marrow samples taken at different time points during the study, and at end of treatment.
Time frame: Up to 48 months
Transplantation rate
Transplantation rate is defined as the percentage of participants undergoing hematopoietic stem cell transplantation (HSCT) during the study treatment period.
Time frame: 24 months