Clinical trial NCT02927262: A Study of ASP2215 (Gilteritinib), Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FMS-like Tyrosine Kinase 3 (FLT3/ITD) Acute Myeloid Leukemia (AML) in First Complete Remission
Official title: A Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the FLT3 Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FLT3/ITD AML in First Complete Remission
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) / Internal Tandem Duplication (ITD) Mutation
Keywords: Acute myeloid leukemia
First Complete Remission
gilteritinib
FLT3/ITD
AML
ASP2215
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-10-07
Enrollment: 98
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: The purpose of this study was to compare relapse-free survival (RFS) between participants with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who were randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Detailed description: Participants in CR1 were approached for this study after induction/consolidation therapy was complete and a decision not to proceed with transplantation was made or a suitable donor could not be identified. Participants were randomized in a 2:1 ratio to receive gilteritinib or placebo. Participants entered the screening period up to 14 days prior to the start of treatment. Participants were administered treatment over continuous 28-day cycles. Gilteritinib or placebo was given daily for up to 2 years. After treatment discontinuation, participants had a 30-day follow-up visit for safety, after which the participants entered the long-term follow up period for collection of subsequent AML treatment, remission status, and survival (cause of death and date of death). Final database lock will occur when last subject last follow-up visit is reached, per protocol. Study drug was not provided during the follow-up period.

Eligibility criteria: Inclusion Criteria:

* Subject is considered an adult according to local regulation at the time of obtaining consent form (ICF).
* Subject consents to allow access to subject's diagnostic bone marrow aspirate or peripheral blood sample and/or the DNA derived from that sample, if available, that may be used to validate a companion diagnostic test for gilteritinib.
* Subject has confirmed morphologically documented AML, excluding acute promyelocytic leukemia (APL), in CR1 (including CRp and CRi). For the purposes of enrollment, CR will be defined as \< 5% blasts in the bone marrow with no morphologic characteristics of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma.
* Subject will not proceed with transplantation as either a decision not to proceed with transplantation has been made either on the recommendation of the treating physician or by the patient or a suitable donor could not be identified.
* Subject is \< 2 months from the start of the last cycle of consolidation and should have completed the recommended number of consolidations per local practice.
* Subject has had no use of investigational agents, with the exception of FLT3 inhibiting agents during induction and/or consolidation therapy, within the prior 4 weeks.
* Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral blood as determined by the local institution at diagnosis.
* Subject has an ECOG performance status 0 to 2.
* Subject must meet the following criteria as indicated on the clinical laboratory tests:

  * Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) \> 40 mL/min/1.73m\^2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation.
  * Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's syndrome.
  * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN.
  * Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).
  * Absolute neutrophil count (ANC) ≥ 500/μl and platelets ≥ 20000/μl (unsupported by transfusions).
* Subject is suitable for oral administration of study drug.
* Female subject must either:

  * Be of nonchildbearing potential:
  * Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
  * Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
  * Or, if of childbearing potential,
  * Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
  * And have a negative urine or serum pregnancy test at screening
  * And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards (in addition to a barrier method) starting at screening and throughout the study period and for 6 months after the final study drug administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
* Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
* Male subject and subject's female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards (in addition to a barrier method) starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
* Male subject must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
* Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

* Subject has had prior allogeneic transplant.
* Subject has QTcF interval \> 450 msec (average of triplicate determinations based on central reading).
* Subject with Long QT Syndrome.
* Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN).
* Subject has clinically active central nervous system leukemia.
* Subject is known to have human immunodeficiency virus infection.
* Subject has active hepatitis B or C.
* Subject has an uncontrolled infection. If a bacterial or viral infection is present, the subject must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to randomization. If a fungal infection is present, the subject must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization.
* Subject has progressing infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
* Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
* Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
* Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (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 1 (5HT1R) or 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 a serious medical or psychiatric illness likely to interfere with participation in this clinical study.
* Subject has prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent \< 5 years previously will not be allowed.
* Subject has any condition which makes the subject unsuitable for study participation.

Primary outcomes:
measure: Relapse-free Survival (RFS) Per Independent Review Committee (IRC) Adjudication
timeFrame: From the date of randomization until the date of documented relapse, or death; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization until the date of death from any cause; (Median time on study drug was 427 days for gilteritinib group and 212 days for placebo group)
measure: Event-Free Survival (EFS)
timeFrame: From date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause; (Median time on study drug was 427 days for gilteritinib and 212 days for Placebo)
measure: Change From Baseline in Quantitative Minimal Residual Disease Measured as Log10-transformed Overall FLT3/ITD Mutation Ratio at Months 3, 6, 12, 24/End of Treatment (EoT)
timeFrame: Baseline and months 3, 6, 12, 24/EoT
measure: Number of Participants With Adverse Events (AE)
timeFrame: From first dose date up to 30 days after last dose or data cut-off date 25-May 2021 (Maximum treatment duration was 744 days)
measure: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score
timeFrame: Months 1, 2, 3, 4, 5, 6, 8, 10. 12, 14, 16, 18, 20, 22 and 24/EoT
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: Site US10017
state: Florida
city: Jacksonville
country: United States
facility: Site US10030
state: Florida
city: Chicago
country: United States
facility: Site US10012
state: Illinois
city: Syracuse
country: United States
facility: Site US10025
state: New York
city: Portland
country: United States
facility: Site US10007
state: Oregon
city: Greenville
country: United States
facility: Site US10029
state: South Carolina
city: Goiania
country: Brazil
facility: Site BR55002
state: Goias
city: Halifax
country: Canada
facility: Site CA15001
state: Nova Scotia
city: Toronto
country: Canada
facility: Site CA15003
state: Ontario
city: Ostrava-Poruba
country: Czechia
facility: Site CZ42001
city: Arhus
country: Denmark
facility: Site DK45002
state: Region Midtjylland
city: Brest
country: France
facility: Site FR33004
state: Finistere
city: Tours cedex 01
country: France
facility: Site FR33002
state: Indre-et-Loire
city: Vandoeuvre les Nancy
country: France
facility: Site FR33014
state: Meurthe-et-Moselle
city: Pierre-Benite
country: France
facility: Site FR33007
state: Rhone
city: Bayonne
country: France
facility: Site FR33001
city: Mulhouse
country: France
facility: Site FR33009
city: Nice Cedex 2
country: France
facility: Site FR33008
city: Duisburg
country: Germany
facility: Site DE49001
state: Nordrhein-Westfalen
city: Stuttgart
country: Germany
facility: Site DE49008
city: Athens
country: Greece
facility: Site GR30010
state: Attiki
city: Thessaloniki
country: Greece
facility: Site GR30004
state: Kentriki Makedonia
city: Athens
country: Greece
facility: Site GR30009
city: Larissa
country: Greece
facility: Site GR30007
city: Nyiregyhaza
country: Hungary
facility: Site HU36003
state: Szabolcs-Szatmar-Bereg
city: Jerusalem
country: Israel
facility: Site IL97205
state: Yerushalayim
city: Milano
country: Italy
facility: Site IT39011
state: Lombardia
city: Castelfranco Veneto (TV)
country: Italy
facility: Site IT39004
state: Treviso
city: Bergamo
country: Italy
facility: Site IT39008
city: Parma
country: Italy
facility: Site IT39005
city: Reggio Emilia
country: Italy
facility: Site IT39010
city: Roma
country: Italy
facility: Site IT39002
city: Nagoya
country: Japan
facility: Site JP81018
state: Aichi
city: Matsuyama
country: Japan
facility: Site JP81025
state: Ehime
city: Yoshida-gun
country: Japan
facility: Site JP81002
state: Fukui
city: Sapporo
country: Japan
facility: Site JP81024
state: Hokkaido
city: Kobe
country: Japan
facility: Site JP81012
state: Hyogo
city: Kanazawa
country: Japan
facility: Site JP81004
state: Ishikawa
city: Yokohama
country: Japan
facility: Site JP81009
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81014
state: Miyagi
city: Shimotsuke
country: Japan
facility: Site JP81023
state: Tochigi
city: Tachikawa
country: Japan
facility: Site JP81011
state: Tokyo
city: Aomori
country: Japan
facility: Site JP81010
city: Okayama
country: Japan
facility: Site JP81017
city: Suwon-si
country: Korea, Republic of
facility: Site KR82005
state: Gyeonggi-do
city: Bucheon-Si
country: Korea, Republic of
facility: Site KR82014
state: Gyeonggido
city: Goyang
country: Korea, Republic of
facility: Site KR82013
state: Gyeonggido
city: Namdong
country: Korea, Republic of
facility: Site KR82008
state: Incheon Gwang'yeogsiv
city: Hwasungun
country: Korea, Republic of
facility: Site KR82003
state: Jeonranamdo
city: Seoul
country: Korea, Republic of
facility: Site KR82012
state: Seoul Teugbyeolsi
city: Busan
country: Korea, Republic of
facility: Site KR82006
city: Seoul
country: Korea, Republic of
facility: Site KR82009
city: Olsztyn
country: Poland
facility: Site PL48001
state: Warmińsko-mazurskie
city: Bydgoszcz
country: Poland
facility: Site PL48002
city: Poznan
country: Poland
facility: Site PL48007
city: Coimbra
country: Portugal
facility: Site PT35106
city: Porto
country: Portugal
facility: Site PT35101
city: București
country: Romania
facility: Site RO40005
city: Belgrade
country: Serbia
facility: Site RS38102
city: Vitoria
country: Spain
facility: Site ES34009
state: Alava
city: Stockholm
country: Sweden
facility: Site SE46003
state: Stockholms Lan
city: Lund
country: Sweden
facility: Site SE46002
city: Kaohsiung
country: Taiwan
facility: Site TW88605
city: Kaohsiung
country: Taiwan
facility: Site TW88604
city: Taipei
country: Taiwan
facility: Site TW88603
city: Exeter
country: United Kingdom
facility: Site GB44007
state: Devon
city: Plymouth
country: United Kingdom
facility: Site GB44019
state: Devon
city: Cottingham
country: United Kingdom
facility: Site GB44006
state: East Riding Of Yorkshire
city: London
country: United Kingdom
facility: Site GB44018
state: London, City Of
city: Birmingham
country: United Kingdom
facility: Site GB44002
city: Cardiff
country: United Kingdom
facility: Site GB44015
city: Leeds
country: United Kingdom
facility: Site GB44020
city: Nottingham
country: United Kingdom
facility: Site GB44004
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References: