A Phase 1/2, Multicenter, Open-Label, Randomized Dose Ranging and Expansion Study of the Combination of Gilteritinib, Venetoclax and Azacitidine in Patients With Newly Diagnosed FLT3 Mutated Acute Myeloid Leukemia (AML) Not Eligible for Intensive Induction Chemotherapy
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Enrollment
- 70
- Locations
- 39
- Primary Endpoint
- Number or Participants with electrocardiogram (ECG) abnormalities and/or AEs
Overview
Brief Summary
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participant has a diagnosis of previously untreated Acute Myeloid Leukemia (AML) according to World Health Organization classification as determined by pathology review at the treating institution.
- •Participant is positive for FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication \[ITD\] and/or tyrosine kinase domain \[TKD\] \[D835/I836\] mutation) in bone marrow or whole blood as determined by the central laboratory. A participant with rapidly proliferative disease and unable to wait for the central laboratory results can be enrolled from a local test result.
- •Participant is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
- •Participant is \>= 75 years of age with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or
- •Participant is \>= 18 to 75 years of age and has any of the following comorbidities: ECOG performance status 2 or 3, cardiac history of congestive heart failure requiring treatment or ejection fraction \<= 50% or chronic stable angina, known history of diffusion capacity of lung for carbon monoxide (DLCO) \<= 65% or forced expiratory volume in the first second (FEVI) \<= 65%, creatinine clearance \> 30 mL/min to 45 mL/min, calculated by the Cockcroft Gault formula, moderate hepatic impairment with total bilirubin \> 1.5 to \< 3.0 x upper limit of normal (ULN), any other comorbidity incompatible with intensive chemotherapy during screening and before enrollment.
- •Participant must have a projected life expectancy of at least 12 weeks.
- •Participant must have adequate organ and bone marrow function prior to enrollment, as specified per protocol's laboratory parameters.
- •Participant is suitable for oral administration of study drug (gilteritinib and venetoclax) and is willing/able to swallow oral tablets/capsules.
- •Participant with a known history of human immunodeficiency virus (HIV) on effective antiretroviral therapy must have a viral load undetectable for 6 months prior to Cycle 1 Day 1 (C1D1).
- •Female participant is eligible to participate if she is not pregnant and at least one of the following conditions apply:
Exclusion Criteria
- •Participant with the following conditions:
- •Acute promyelocytic leukemia (APL)
- •Active, symptomatic central nervous system (CNS) involvement with AML
- •History of myeloproliferative neoplasm (MPN), including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation or AML with BCR-ABL1 translocation
- •Participant previously treated with CAR-T cell therapy for AML or MDS. Exceptions for prior treatment of AML are (i.e., the following treatments are allowed):
- •Hydroxyurea for increased blast count (No washout period required. It can be continued throughout the first cycle of therapy).
- •Leukapheresis for leukocytosis (No washout period required. It can be continued during the study).
- •Preemptive treatment with retinoic acid prior to exclusion of APL \< 7 days.
- •Participant who is receiving treatment with any other investigational agents.
- •Participant requires treatment with concomitant drugs that are strong or moderate inducers of cytochrome P450 (CYP)3A or P glycoprotein (P-gp) during study treatment.
Arms & Interventions
Dose Ranging Cohort (Phase 1)
Participants will receive daily dose of gilteritinib and venetoclax for 28 days, and azacitidine for 7 days in each 28-day cycle.
Intervention: Gilteritinib (Drug)
Dose Ranging Cohort (Phase 1)
Participants will receive daily dose of gilteritinib and venetoclax for 28 days, and azacitidine for 7 days in each 28-day cycle.
Intervention: Venetoclax (Drug)
Dose Ranging Cohort (Phase 1)
Participants will receive daily dose of gilteritinib and venetoclax for 28 days, and azacitidine for 7 days in each 28-day cycle.
Intervention: Azacitidine (Drug)
Dose Expansion Cohort (Phase 2)
Participants will receive daily dose of gilteritinib, venetoclax, and azacitidine at an optimized dose established from dose ranging cohort (Phase 1)
Intervention: Gilteritinib (Drug)
Dose Expansion Cohort (Phase 2)
Participants will receive daily dose of gilteritinib, venetoclax, and azacitidine at an optimized dose established from dose ranging cohort (Phase 1)
Intervention: Venetoclax (Drug)
Dose Expansion Cohort (Phase 2)
Participants will receive daily dose of gilteritinib, venetoclax, and azacitidine at an optimized dose established from dose ranging cohort (Phase 1)
Intervention: Azacitidine (Drug)
Outcomes
Primary Outcomes
Number or Participants with electrocardiogram (ECG) abnormalities and/or AEs
Time Frame: Up to 48 months
Number of participants with potentially clinically significant ECG values.
Number of Participants with vital sign abnormalities and/or AEs
Time Frame: Up to 48 months
Number of participants with potentially clinically significant vital sign values.
Number of Participants with physical exam abnormalities and/or AEs
Time Frame: Up to 48 months
Number of participants with potentially clinically significant physical exam values.
Number of Participants with Dose Limiting Toxicities (DLTs)
Time Frame: Up to 42 Days
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.
Number of Participants with Adverse Events (AEs)
Time Frame: Up to 49 months
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.
Number of Participants with Serious AEs (SAEs)
Time Frame: Up to 49 months
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.
Number of Participants with laboratory value abnormalities and/or AEs
Time Frame: Up to 48 months
Number of participants with potentially clinically significant laboratory values.
Number of Participants at each grade of the Eastern Cooperative Oncology Group (ECOG) performance status scores
Time Frame: Up to 48 months
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.
Percentage of Participants with Complete Remission (CR)
Time Frame: Up to 24 months
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
Pharmacological activity by Plasma Inhibitory Activity Assay (PIA)
Time Frame: Up to 2 months
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.
Pharmacokinetics (PK) of ASP2215 in plasma: concentration
Time Frame: Up to 6 months
Concentration will be recorded from the PK plasma samples collected.
Secondary Outcomes
- PK of ASP2215 in plasma: pre-dose trough concentration (Ctrough)(Up to 6 months)
- Percentage of Participants with Composite Complete Remission (CRc)(Up to 24 months)
- Duration of Event free survival (EFS)(Up to 24 months)
- Pharmacokinetics (PK) of ASP2215 in plasma: area under the plasma concentration-time curve during a dosage interval (AUCtau)(Up to 6 months)
- PK of ASP2215 in plasma: maximum observed concentration (Cmax)(Up to 6 months)
- Percentage of Participants with Complete Remission and Complete Remission with Partial Hematological Recovery (CR/CRh) rate(Up to 24 months)
- Duration of Remission (DOR)(Up to 24 months)
- Duration of Overall Survival (OS)(Up to 24 months)
- PK of ASP2215 in plasma: time to Cmax (tmax)(Up to 6 months)
- Transplantation rate(24 months)
- PK of ASP2215 in plasma: area under the curve from time 0 to the time of the last measurable concentration (AUClast)(Up to 6 months)
- Number of participants with negative minimal residual disease (MRD) status(Up to 48 months)