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

Acute Myeloid Leukemia (AML) Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02752035
• Other study ID #: 2215-CL-0201
• Secondary ID: 2015-001790-41
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 1, 2016
• Est. completion date: June 30, 2024

Study information

• Verified date: June 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 183
• Est. completion date: June 30, 2024
• Est. primary completion date: March 10, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• gilteritinib
Tablet, oral
• azacitidine
Subcutaneous injection or intravenous infusion

Locations

Country	Name	City	State
Australia	Site AU61008	Adelaide	South Australia
Australia	Site AU61007	Geelong	Victoria
Australia	Site AU61004	Liverpool	New South Wales
Belgium	Site BE32007	Brussel	Bruxelles
Belgium	Site BE32003	Bruxelles	Bruxelles-Capitale, Region De
Belgium	Site BE32006	Gent
Canada	Site CA15009	Edmonton	Alberta
Canada	Site CA15006	Montreal	Quebec
Canada	Site CA15002	Toronto	Ontario
Canada	Site CA15011	Toronto	Ontario
France	Site FR33009	Angers
France	Site FR33020	Bayonne
France	Site FR33017	Le Mans	Sarthe
France	Site FR33006	Lille
France	Site FR33004	Lille cedex
France	Site FR33019	Montpellier Cedex 5	Herault
France	Site FR33001	Nantes cedex 01	Loire-Atlantique
France	Site FR33003	Nimes Cedex 09	Gard
France	Site FR33002	Pessac	Gironde
France	Site FR33013	Pierre-Benite	Rhone
France	Site FR33012	Poitiers	Vienne
France	Site FR33018	Rennes	Ille-et-Vilaine
France	Site FR33015	Rouen	Haute-Normandie
France	Site FR33023	Valenciennes	Nord
Germany	Site DE49003	Berlin
Germany	Site DE49012	Braunschweig	Niedersachsen
Germany	Site DE49005	Frankfurt	Hessen
Germany	Site DE49009	Halle (Saale)	Sachsen-Anhalt
Germany	Site DE49004	Hannover	Niedersachsen
Germany	Site DE49007	Munchen	Bayern
Germany	Site DE49015	Rostock	Mecklenburg-Vorpommern
Germany	Site DE49011	Stuttgart
Germany	Site DE49002	Tuebingen	Baden-Wurttemberg
Italy	Site IT39009	Ancona
Italy	Site IT39015	Bologna
Italy	Site IT39012	Firenze
Italy	Site IT39004	Milano
Italy	Site IT39007	Monza
Italy	Site IT39001	Napoli
Italy	Site IT39014	Novara
Italy	Site IT39006	Palermo
Italy	Site IT39005	Pavia
Italy	Site IT39011	San Giovanni Rotondo
Japan	Site JP81018	Anjo	Aichi
Japan	Site JP81035	Chiba
Japan	Site JP81008	Fukuoka
Japan	Site JP81021	Fukuyama	Hiroshima
Japan	Site JP81024	Gifu
Japan	Site JP81034	Hitachi	Ibaraki
Japan	Site JP81001	Isehara	Kanagawa
Japan	Site JP81023	Kanazawa	Ishikawa
Japan	Site JP81015	Kobe	Hyogo
Japan	Site JP81005	Kumamoto
Japan	Site JP81011	Kurashiki	Okayama
Japan	Site JP81016	Kyoto
Japan	Site JP81027	Matsuyama	Ehime
Japan	Site JP81004	Nagasaki
Japan	Site JP81017	Nagasaki
Japan	Site JP81007	Nagoya	Aichi
Japan	Site JP81030	Osaka
Japan	Site JP81036	Osaka
Japan	Site JP81031	Sapporo	Hokkaido
Japan	Site JP81033	Sapporo	Hokkaido
Japan	Site JP81012	Sendai	Miyagi
Japan	Site JP81029	Shibuya-ku	Tokyo
Japan	Site JP81014	Shinagawa-ku	Tokyo
Japan	Site JP81026	Tokushima
Japan	Site JP81019	Toyama
Japan	Site JP81032	Yokohama	Kanagawa
Korea, Republic of	Site KR82014	Busan
Korea, Republic of	Site KR82010	Hwasun-gun
Korea, Republic of	Site KR82003	Namdong	Incheon Gwang'yeogsiv
Korea, Republic of	Site KR82015	Seongnam-si
Korea, Republic of	Site KR82002	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Site KR82006	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Site KR82012	Seoul
Korea, Republic of	Site KR82013	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Site KR82001	Ulsan	Ulsan Gwang'yeogsi
Poland	Site PL48003	Lublin	Lubelskie
Poland	Site PL48001	Olsztyn	Warminsko-mazurskie
Poland	Site PL48002	Opole	Opolskie
Poland	Site PL48004	Warszawa	Mazowieckie
Spain	Site ES34004	Barcelona
Spain	Site ES34008	Barcelona
Spain	Site ES34009	Barcelona
Spain	Site ES34010	Barcelona
Spain	Site ES34002	Caceres
Spain	Site ES34013	Madrid
Spain	Site ES34003	Oviedo	Asturias
Spain	Site ES34007	Palma de Mallorca	Baleares
Spain	Site ES34005	Valencia
Taiwan	Site TW88604	Kaohsiung
Taiwan	Site TW88605	Kwei Shan Hsiang
Taiwan	Site TW88602	Tainan
Taiwan	Site TW88609	Tainan
Taiwan	Site TW88601	Taipei
Taiwan	Site TW88608	Taipei
Taiwan	Site TW88610	Taipei
United Kingdom	Site GB44007	Sheffield
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	GHS Cancer Institute	Greenville	South Carolina
United States	Hackensack University Medical Center - John Theurer Cancer Center	Hackensack	New Jersey
United States	UCLA David Geffen School of Medicine	Los Angeles	California
United States	Hematology-Oncology Associates of Northern NJ	Morristown	New Jersey
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York
United States	University of California, Irvine Medical Center	Orange	California
United States	St. Louis University Cancer Center - Hematology/Oncology	Saint Louis	Missouri
United States	LDS Hospital	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)	OS is defined as the time from the date of randomization until the date of death from any cause.	Up to 77 months
Secondary	Event free survival (EFS)	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.	Up to 77 months
Secondary	Best response	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.	Up to 48 months
Secondary	Complete remission (CR) rate	Complete remission rate is defined as the number of patients with all complete CRs.	Up to 48 months
Secondary	Composite complete remission (CRc) rate	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)).	Up to 48 months
Secondary	Complete remission with partial hematologic recovery (CRh) rate	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.	Up to 48 months
Secondary	Complete remission and complete remission with partial hematological recovery (CR/CRh) rate	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.	Up to 48 months
Secondary	Transfusion conversion rate	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.	Up to 49 months
Secondary	Transfusion maintenance rate	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.	Up to 49 months
Secondary	Leukemia free survival (LFS)	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.	Up to 77 months
Secondary	Duration of remission	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.	Up to 48 months
Secondary	Participant reported fatigue from Brief Fatigue Inventory (BFI)	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.	Up to 48 months
Secondary	Safety assessed by adverse events (AEs)		Up to 49 months
Secondary	Number of participants with abnormal laboratory values and/or adverse events related to treatment		Up to 48 months
Secondary	Number of participants with abnormal vital signs and/or adverse events related to treatment		Up to 48 months
Secondary	Number of participants with Physical Exam abnormalities and/or adverse events	Number of participants with potentially clinically significant physical exam values.	Up to 48 months
Secondary	Safety assessed by electrocardiograms (ECGs)	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.	Up to 48 months
Secondary	Eastern Cooperative Oncology Group (ECOG) performance status score	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.	Up to 48 months