Description:
This is a clinical study for adult patients who have recently been diagnosed with acute
myeloid leukemia or AML. AML is a type of cancer. It is when bone marrow makes white blood
cells that are not normal. These are called leukemia cells. Some patients with AML have a
mutation, or change, in the FLT3 gene. This gene helps leukemia cells make a protein called
FLT3. This protein causes the leukemia cells to grow faster.
For patients with AML who cannot receive standard chemotherapy, azacitidine (also known as
Vidaza®) is a current standard of care treatment option in the United States. This clinical
study is testing an experimental medicine called ASP2215, also known as gilteritinib.
Gilteritinib works by stopping the leukemia cells from making the FLT3 protein. This can help
stop the leukemia cells from growing faster.
This study will compare two different treatments. Patients are assigned to one of these two
groups by chance: a medicine called azacitidine, also known as Vidaza®, or an experimental
medicine gilteritinib in combination with azacitidine. There is a twice as much chance to
receive both medicines combined than azacitidine alone. The clinical study may help show
which treatment helps patients live longer.
Title
- Brief Title: A Study of ASP2215 (Gilteritinib) by Itself, ASP2215 Combined With Azacitidine or Azacitidine by Itself to Treat Adult Patients Who Have Recently Been Diagnosed With Acute Myeloid Leukemia With a FLT3 Gene Mutation and Who Cannot Receive Standard Chemotherapy
- Official Title: A Phase 3 Multicenter, Open-label, Randomized Study of ASP2215 (Gilteritinib), Combination of ASP2215 Plus Azacitidine and Azacitidine Alone in the Treatment of Newly Diagnosed Acute Myeloid Leukemia With FLT3 Mutation in Patients Not Eligible for Intensive Induction Chemotherapy
Clinical Trial IDs
- ORG STUDY ID:
2215-CL-0201
- SECONDARY ID:
2015-001790-41
- NCT ID:
NCT02752035
Conditions
- Acute Myeloid Leukemia (AML)
- Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation
Interventions
Drug | Synonyms | Arms |
---|
gilteritinib | ASP2215 | Arm A: ASP2215 |
azacitidine | | Arm AC: ASP2215 + azacitidine |
Purpose
This is a clinical study for adult patients who have recently been diagnosed with acute
myeloid leukemia or AML. AML is a type of cancer. It is when bone marrow makes white blood
cells that are not normal. These are called leukemia cells. Some patients with AML have a
mutation, or change, in the FLT3 gene. This gene helps leukemia cells make a protein called
FLT3. This protein causes the leukemia cells to grow faster.
For patients with AML who cannot receive standard chemotherapy, azacitidine (also known as
Vidaza®) is a current standard of care treatment option in the United States. This clinical
study is testing an experimental medicine called ASP2215, also known as gilteritinib.
Gilteritinib works by stopping the leukemia cells from making the FLT3 protein. This can help
stop the leukemia cells from growing faster.
This study will compare two different treatments. Patients are assigned to one of these two
groups by chance: a medicine called azacitidine, also known as Vidaza®, or an experimental
medicine gilteritinib in combination with azacitidine. There is a twice as much chance to
receive both medicines combined than azacitidine alone. The clinical study may help show
which treatment helps patients live longer.
Detailed Description
Patients considered an adult according to local regulation at the time of obtaining informed
consent may participate in the study.
Safety Cohort Prior to initiation of the randomized trial, 8 to 12 patients will be enrolled
to evaluate the safety and tolerability of ASP2215 given with azacitidine therapy in the
study population.
Randomized Trial Approximately 250 patients will be randomized in a 2:1 ratio to receive
ASP2215 plus azacitidine (Arm AC) or azacitidine only (Arm C). Patients will enter the
screening period up to 14 days prior to the start of treatment. Patients will be administered
treatment over 28-day cycles.
Earlier protocol versions included a 1:1:1 randomization ratio to receive Arm A: ASP2215, Arm
AC: ASP2215 + azacitidine or Arm C: azacitidine. Patients previously randomized to Arm A
should continue following treatment and assessments as outlined in the protocol.
Trial Arms
Name | Type | Description | Interventions |
---|
Dose escalation of ASP2215 given with azacitidine | Experimental | Subjects will be treated with ASP2215 daily (days 1-28) and azacitidine daily for 7 days (days 1-7). | |
Arm A: ASP2215 | Experimental | Subjects will be treated daily each 28-day cycle. | |
Arm AC: ASP2215 + azacitidine | Experimental | Subjects will be treated with ASP2215 daily and azacitidine daily for 7 days (days 1-7) each 28-day cycle. | |
Arm C: azacitidine | Active Comparator | Subjects will be treated with azacitidine for 7 days (days 1-7) each 28-day cycle. | |
Eligibility Criteria
Inclusion Criteria:
- Subject is considered an adult according to local regulation at the time of obtaining
informed consent.
- Subject has a diagnosis of previously-untreated AML according to World Health
Organization (WHO) classification [Swerdlow et al, 2008] as determined by pathology
review at the treating institution.
- Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine
kinase domain [TKD] [D835/I836] mutation) (or for Korea only: ITD alone or ITD with
concurrent TKD activating mutation) in bone marrow or whole blood as determined by
central laboratory. Note: Only requirement of FLT3 mutation assessment by central
laboratory is only applicable to the randomization portion of the study.
- Subject is ineligible for intensive induction chemotherapy by meeting at least 1 of
the following criteria:
- Subject is ≥ 65 years of age and ineligible for intensive induction chemotherapy.
- Subject is ≥ 18 to 64 years of age and has any of the following comorbidities:
[Ex-US Only]: Congestive heart failure (New York Heart Association {NYHA} class ≤
3) or ejection fraction (Ef) ≤ 50%; [US Only]: Severe cardiac disorder e.g.
congestive heart failure (New York Heart Association [NYHA] class ≤ 3) requiring
treatment, ejection fraction ≤ 50%, or chronic stable angina; [Ex-US Only]:
Creatinine > 2 mg/dL (177 µmol/L), dialysis or prior renal transplant; [US Only]:
Creatinine clearance < 45 mL/min; ECOG performance status ≥ 2;
- [Ex-US Only]: Known pulmonary disease with decreased diffusion capacity of lung
for carbon monoxide (DLCO) and/or requiring oxygen ≤ 2 liters per minute; [US
Only] Severe pulmonary disorder (e.g., diffusion capacity of lung for carbon
monoxide [DLCO] ≤ 65% or forced expiratory volume in the first second [FEV1] ≤
65%); Prior or current malignancy that does not require concurrent treatment;
Subject has received a cumulative anthracycline dose above 400 mg/m2 of
doxorubicin (or cumulative maximum dose of another anthracycline). Any other
comorbidity incompatible with intensive chemotherapy must be reviewed and
approved by the Medical Monitor during screening and before randomization.
- Subject must meet the following criteria as indicated on the clinical laboratory
tests:
- Serum AST and ALT ≤ 3.0 x Institutional upper limit of normal (ULN)
- Serum total bilirubin ≤ 1.5 x Institutional ULN
- Serum potassium ≥ Institutional lower limit of normal (LLN)
- Serum magnesium ≥ Institutional LLN Repletion of potassium and magnesium levels
during the screening period is allowed.
- Subject is suitable for oral administration of study drug.
- Female subject is eligible to participate if female subject is not pregnant and at
least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP); OR
- WOCBP agrees to follow the contraceptive guidance starting at screening and
continue throughout the study period, and for at least 180 days after the final
study drug administration.
- Female subject must agree not to breastfeed starting at screening and throughout the
study period, and for 60 days after the final study drug administration.
- Female subject must not donate ova starting at screening and throughout the study
period, and for 180 days after the final study drug administration.
- Male subject with female partners of childbearing potential must agree to use
contraception as detailed in Contraception Requirements, starting at screening and
continue throughout the study period, and for 120 days after the final study drug
administration.
- Male subject must not donate sperm starting at screening and throughout the study
period and for 120 days after the final study drug administration.
- Subject agrees not to participate in another interventional study while on treatment.
Exclusion Criteria:
- Subject was diagnosed as acute promyelocytic leukemia (APL).
- Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
- Subject has received previous therapy for AML, with the exception of the following:
- Emergency leukapheresis
- Hydroxyurea
- Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days
- Growth factor or cytokine support
- Steroids
- Subject has clinically active central nervous system leukemia.
- Subject has been diagnosed with another malignancy that requires concurrent treatment
(with the exception of hormone therapy limited to those therapies that prevent
recurrence and/or spread of cancer) or hepatic malignancy regardless of need for
treatment.
- Subject requires treatment with concomitant drugs that are strong inducers of
cytochrome P450 CYP3A/P-glycoprotein (P-gp).
- Subject requires treatment with concomitant drugs that are strong inhibitors or
inducers of P-gp with the exception of drugs that are considered absolutely essential
for the care of the subject.
- Subject requires treatment with concomitant drugs that target serotonin
5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the
exception of drugs that are considered absolutely essential for the care of the
subject.
- Subject has congestive heart failure classified as New York Heart Association Class
IV.
- Subject with mean Fridericia-corrected QT interval (QTcF) > 480 ms at screening based
on central reading.
- Subject with a history of Long QT Syndrome at screening.
- [Ex-US Only]: Subject has known pulmonary function tests with diffusion capacity of
lung for carbon monoxide (DLCO) ≤ 50%, forced expiratory volume in the first second
(FEV1) ≤ 60%, dyspnea at rest or requiring oxygen or any pleural neoplasm (Transient
use of supplemental oxygen is allowed.)
- Subject has active hepatitis B or C or other active hepatic disorder.
- Subjects with positive hepatitis B surface antigen (HBsAg) or detectable
hepatitis B DNA are not eligible.
- Subjects with negative HBsAg, positive hepatitis B core antibody and negative
hepatitis B surface antibody will be eligible if hepatitis B DNA is undetectable.
- Subjects with antibodies to hepatitis C virus will be eligible if hepatitis C RNA
is undetectable
- Subject has any condition which makes the subject unsuitable for study participation,
including any contraindications of azacitidine.
- Subject has a known or suspected hypersensitivity to ASP2215, azacitidine or any
components of the formulations used.
- [US Only]: Subject is ≥ 65 to 74 years of age, suitable for and willing to receive
intensive induction chemotherapy.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Overall survival (OS) |
Time Frame: | Up to 77 months |
Safety Issue: | |
Description: | OS is defined as the time from the date of randomization until the date of death from any cause. |
Secondary Outcome Measures
Measure: | Event free survival (EFS) |
Time Frame: | Up to 77 months |
Safety Issue: | |
Description: | EFS is defined as the time from the date of randomization until the date of documented relapse from complete remission (CR), treatment failure or death from any cause, whichever occurs first. |
Measure: | Best response |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | Best response is defined as the best measured response (in the order of CR, CRp, Cri or treatment failure defined by lack of composite complete remission (CRc)) from all post-baseline visits. |
Measure: | Complete remission (CR) rate |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | Complete remission rate is defined as the number of patients with all complete CRs. |
Measure: | Composite complete remission (CRc) rate |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | CRc rate is defined as the number of patients with all complete and incomplete CRs (i.e., CR + Complete remission with incomplete platelet recovery (CRp) + Complete remission with incomplete hematologic recovery (Cri)). |
Measure: | Complete remission with partial hematologic recovery (CRh) rate |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | CRh rate is defined as the number of patients who achieve CRh at any of the post-baseline visits and do not have best response of CR divided by the number of patients in the analysis population. |
Measure: | Complete remission and complete remission with partial hematological recovery (CR/CRh) rate |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | CR/CRh rate is defined as the number of patients who achieve either CR or CRh at any of the post-baseline visits divided by the number of patients in the analysis population. |
Measure: | Transfusion conversion rate |
Time Frame: | Up to 49 months |
Safety Issue: | |
Description: | Transfusion conversion rate is defined as the number of patients who were transfusion dependent at the baseline period but become transfusion independent at the post-baseline period divided by the total number of patients who were transfusion dependent at baseline period. |
Measure: | Transfusion maintenance rate |
Time Frame: | Up to 49 months |
Safety Issue: | |
Description: | Transfusion maintenance rate is defined as the number of patients who were transfusion independent at the baseline period and still maintain transfusion independence at the post-baseline period divided by the number of patients who were transfusion independent at baseline period. |
Measure: | Leukemia free survival (LFS) |
Time Frame: | Up to 77 months |
Safety Issue: | |
Description: | LFS is defined as the time from the date of first composite complete remission (CRc) until the date of documented relapse or death for subjects who achieve CRc. |
Measure: | Duration of remission |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | Duration of remission includes duration of CRc, CR, Cri, CRp and response (CRc + partial response [PR]). Duration of CRc is defined as the time from the date of first CRc until the date of documented relapse for subjects who achieve CRc. Duration of remission is similarly defined for CR, Cri and CRp. |
Measure: | Participant reported fatigue from Brief Fatigue Inventory (BFI) |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | The BFI was developed to assess the severity of fatigue and the impact of fatigue on daily functioning in subjects with fatigue due to cancer and cancer treatment The BFI inventory has 9 items and a 24-hour recall. A global fatigue score is computed by averaging the 9 items. |
Measure: | Safety assessed by adverse events (AEs) |
Time Frame: | Up to 49 months |
Safety Issue: | |
Description: | |
Measure: | Number of participants with abnormal laboratory values and/or adverse events related to treatment |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | |
Measure: | Number of participants with abnormal vital signs and/or adverse events related to treatment |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | |
Measure: | Number of participants with Physical Exam abnormalities and/or adverse events |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | Number of participants with potentially clinically significant physical exam values. |
Measure: | Safety assessed by electrocardiograms (ECGs) |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | The 12-lead ECGs will be recorded in triplicate (3 separate ECGs) and transmitted electronically for central reading. The mean of the triplicate ECG from central read will be used for all final treatment decisions and adverse event reporting. |
Measure: | Eastern Cooperative Oncology Group (ECOG) performance status score |
Time Frame: | Up to 48 months |
Safety Issue: | |
Description: | ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead. 0=Best status; 5=Worst status. |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Astellas Pharma Global Development, Inc. |
Trial Keywords
- AML
- ASP2215
- Newly Diagnosed AML
- gilteritinib
- Acute Myeloid Leukemia (AML)
- FLT3
Last Updated
June 24, 2021