Clinical trial NCT02752035: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation
Keywords: AML
ASP2215
Newly Diagnosed AML
gilteritinib
Acute Myeloid Leukemia (AML)
FLT3
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-04-26
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 77 months
Secondary outcomes:
measure: Event free survival (EFS)
timeFrame: Up to 77 months
measure: Best response
timeFrame: Up to 48 months
measure: Complete remission (CR) rate
timeFrame: Up to 48 months
measure: Composite complete remission (CRc) rate
timeFrame: Up to 48 months
measure: Complete remission with partial hematologic recovery (CRh) rate
timeFrame: Up to 48 months
measure: Complete remission and complete remission with partial hematological recovery (CR/CRh) rate
timeFrame: Up to 48 months
measure: Transfusion conversion rate
timeFrame: Up to 49 months
measure: Transfusion maintenance rate
timeFrame: Up to 49 months
measure: Leukemia free survival (LFS)
timeFrame: Up to 77 months
measure: Duration of remission
timeFrame: Up to 48 months
measure: Participant reported fatigue from Brief Fatigue Inventory (BFI)
timeFrame: Up to 48 months
measure: Safety assessed by adverse events (AEs)
timeFrame: Up to 49 months
measure: Number of participants with abnormal laboratory values and/or adverse events related to treatment
timeFrame: Up to 48 months
measure: Number of participants with abnormal vital signs and/or adverse events related to treatment
timeFrame: Up to 48 months
measure: Number of participants with Physical Exam abnormalities and/or adverse events
timeFrame: Up to 48 months
measure: Safety assessed by electrocardiograms (ECGs)
timeFrame: Up to 48 months
measure: Eastern Cooperative Oncology Group (ECOG) performance status score
timeFrame: Up to 48 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA David Geffen School of Medicine
state: California
city: Orange
country: United States
facility: University of California, Irvine Medical Center
state: California
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Saint Louis
country: United States
facility: St. Louis University Cancer Center - Hematology/Oncology
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center - John Theurer Cancer Center
state: New Jersey
city: Morristown
country: United States
facility: Hematology-Oncology Associates of Northern NJ
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College-New York Presbyterian Hospital
state: New York
city: Greenville
country: United States
facility: GHS Cancer Institute
state: South Carolina
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Liverpool
country: Australia
facility: Site AU61004
state: New South Wales
city: Adelaide
country: Australia
facility: Site AU61008
state: South Australia
city: Geelong
country: Australia
facility: Site AU61007
state: Victoria
city: Bruxelles
country: Belgium
facility: Site BE32003
state: Bruxelles-Capitale, Region De
city: Brussel
country: Belgium
facility: Site BE32007
state: Bruxelles
city: Gent
country: Belgium
facility: Site BE32006
city: Edmonton
country: Canada
facility: Site CA15009
state: Alberta
city: Toronto
country: Canada
facility: Site CA15011
state: Ontario
city: Toronto
country: Canada
facility: Site CA15002
state: Ontario
city: Montreal
country: Canada
facility: Site CA15006
state: Quebec
city: Nimes Cedex 09
country: France
facility: Site FR33003
state: Gard
city: Pessac
country: France
facility: Site FR33002
state: Gironde
city: Rouen
country: France
facility: Site FR33015
state: Haute-Normandie
city: Montpellier Cedex 5
country: France
facility: Site FR33019
state: Herault
city: Rennes
country: France
facility: Site FR33018
state: Ille-et-Vilaine
city: Nantes cedex 01
country: France
facility: Site FR33001
state: Loire-Atlantique
city: Valenciennes
country: France
facility: Site FR33023
state: Nord
city: Pierre-Benite
country: France
facility: Site FR33013
state: Rhone
city: Le Mans
country: France
facility: Site FR33017
state: Sarthe
city: Poitiers
country: France
facility: Site FR33012
state: Vienne
city: Angers
country: France
facility: Site FR33009
city: Bayonne
country: France
facility: Site FR33020
city: Lille cedex
country: France
facility: Site FR33004
city: Lille
country: France
facility: Site FR33006
city: Tuebingen
country: Germany
facility: Site DE49002
state: Baden-Wurttemberg
city: Munchen
country: Germany
facility: Site DE49007
state: Bayern
city: Frankfurt
country: Germany
facility: Site DE49005
state: Hessen
city: Rostock
country: Germany
facility: Site DE49015
state: Mecklenburg-Vorpommern
city: Braunschweig
country: Germany
facility: Site DE49012
state: Niedersachsen
city: Hannover
country: Germany
facility: Site DE49004
state: Niedersachsen
city: Halle (Saale)
country: Germany
facility: Site DE49009
state: Sachsen-Anhalt
city: Berlin
country: Germany
facility: Site DE49003
city: Stuttgart
country: Germany
facility: Site DE49011
city: Ancona
country: Italy
facility: Site IT39009
city: Bologna
country: Italy
facility: Site IT39015
city: Firenze
country: Italy
facility: Site IT39012
city: Milano
country: Italy
facility: Site IT39004
city: Monza
country: Italy
facility: Site IT39007
city: Napoli
country: Italy
facility: Site IT39001
city: Novara
country: Italy
facility: Site IT39014
city: Palermo
country: Italy
facility: Site IT39006
city: Pavia
country: Italy
facility: Site IT39005
city: San Giovanni Rotondo
country: Italy
facility: Site IT39011
city: Anjo
country: Japan
facility: Site JP81018
state: Aichi
city: Nagoya
country: Japan
facility: Site JP81007
state: Aichi
city: Matsuyama
country: Japan
facility: Site JP81027
state: Ehime
city: Fukuyama
country: Japan
facility: Site JP81021
state: Hiroshima
city: Sapporo
country: Japan
facility: Site JP81031
state: Hokkaido
city: Sapporo
country: Japan
facility: Site JP81033
state: Hokkaido
city: Kobe
country: Japan
facility: Site JP81015
state: Hyogo
city: Hitachi
country: Japan
facility: Site JP81034
state: Ibaraki
city: Kanazawa
country: Japan
facility: Site JP81023
state: Ishikawa
city: Isehara
country: Japan
facility: Site JP81001
state: Kanagawa
city: Yokohama
country: Japan
facility: Site JP81032
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81012
state: Miyagi
city: Kurashiki
country: Japan
facility: Site JP81011
state: Okayama
city: Shibuya-ku
country: Japan
facility: Site JP81029
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Site JP81014
state: Tokyo
city: Chiba
country: Japan
facility: Site JP81035
city: Fukuoka
country: Japan
facility: Site JP81008
city: Gifu
country: Japan
facility: Site JP81024
city: Kumamoto
country: Japan
facility: Site JP81005
city: Kyoto
country: Japan
facility: Site JP81016
city: Nagasaki
country: Japan
facility: Site JP81004
city: Nagasaki
country: Japan
facility: Site JP81017
city: Osaka
country: Japan
facility: Site JP81030
city: Osaka
country: Japan
facility: Site JP81036
city: Tokushima
country: Japan
facility: Site JP81026
city: Toyama
country: Japan
facility: Site JP81019
city: Namdong
country: Korea, Republic of
facility: Site KR82003
state: Incheon Gwang'yeogsiv
city: Seoul
country: Korea, Republic of
facility: Site KR82013
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Site KR82006
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Site KR82002
state: Seoul Teugbyeolsi
city: Ulsan
country: Korea, Republic of
facility: Site KR82001
state: Ulsan Gwang'yeogsi
city: Busan
country: Korea, Republic of
facility: Site KR82014
city: Hwasun-gun
country: Korea, Republic of
facility: Site KR82010
city: Seongnam-si
country: Korea, Republic of
facility: Site KR82015
city: Seoul
country: Korea, Republic of
facility: Site KR82012
city: Lublin
country: Poland
facility: Site PL48003
state: Lubelskie
city: Warszawa
country: Poland
facility: Site PL48004
state: Mazowieckie
city: Opole
country: Poland
facility: Site PL48002
state: Opolskie
city: Olsztyn
country: Poland
facility: Site PL48001
state: Warmińsko-mazurskie
city: Oviedo
country: Spain
facility: Site ES34003
state: Asturias
city: Palma de Mallorca
country: Spain
facility: Site ES34007
state: Baleares
city: Barcelona
country: Spain
facility: Site ES34008
city: Barcelona
country: Spain
facility: Site ES34004
city: Barcelona
country: Spain
facility: Site ES34010
city: Barcelona
country: Spain
facility: Site ES34009
city: Caceres
country: Spain
facility: Site ES34002
city: Madrid
country: Spain
facility: Site ES34013
city: Valencia
country: Spain
facility: Site ES34005
city: Kaohsiung
country: Taiwan
facility: Site TW88604
city: Kwei Shan Hsiang
country: Taiwan
facility: Site TW88605
city: Tainan
country: Taiwan
facility: Site TW88602
city: Tainan
country: Taiwan
facility: Site TW88609
city: Taipei
country: Taiwan
facility: Site TW88601
city: Taipei
country: Taiwan
facility: Site TW88608
city: Taipei
country: Taiwan
facility: Site TW88610
city: Sheffield
country: United Kingdom
facility: Site GB44007
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Wang ES, Montesinos P, Minden MD, Lee JH, Heuser M, Naoe T, Chou WC, Laribi K, Esteve J, Altman JK, Havelange V, Watson AM, Gambacorti-Passerini C, Patkowska E, Liu S, Wu R, Philipose N, Hill JE, Gill SC, Rich ES, Tiu RV. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022 Oct 27;140(17):1845-1857. doi: 10.1182/blood.2021014586.