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

Sponsor

Astellas Pharma Global Development, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02752035

Collaborator

(none)

183

Enrollment

111

Locations

Arms

Anticipated Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation	Drug: gilteritinib Drug: azacitidine	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

183 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 1, 2016

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Aug 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose escalation of ASP2215 given with azacitidine Subjects will be treated with ASP2215 daily (days 1-28) and azacitidine daily for 7 days (days 1-7).	Drug: gilteritinib Tablet, oral Other Names: ASP2215 Drug: azacitidine Subcutaneous injection or intravenous infusion
Experimental: Arm A: ASP2215 Subjects will be treated daily each 28-day cycle.	Drug: gilteritinib Tablet, oral Other Names: ASP2215
Experimental: Arm AC: ASP2215 + azacitidine Subjects will be treated with ASP2215 daily and azacitidine daily for 7 days (days 1-7) each 28-day cycle.	Drug: gilteritinib Tablet, oral Other Names: ASP2215 Drug: azacitidine Subcutaneous injection or intravenous infusion
Active Comparator: Arm C: azacitidine Subjects will be treated with azacitidine for 7 days (days 1-7) each 28-day cycle.	Drug: azacitidine Subcutaneous injection or intravenous infusion

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [Up to 77 months]
OS is defined as the time from the date of randomization until the date of death from any cause.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 class ≤

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA David Geffen School of Medicine	Los Angeles	California	United States	90095
2	University of California, Irvine Medical Center	Orange	California	United States	92868
3	Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611-5975
4	Rush University Medical Center	Chicago	Illinois	United States	60612
5	St. Louis University Cancer Center - Hematology/Oncology	Saint Louis	Missouri	United States	63110
6	Hackensack University Medical Center - John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
7	Hematology-Oncology Associates of Northern NJ	Morristown	New Jersey	United States	07962
8	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
9	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
10	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York	United States	10021
11	GHS Cancer Institute	Greenville	South Carolina	United States	26615
12	LDS Hospital	Salt Lake City	Utah	United States	84143
13	Site AU61004	Liverpool	New South Wales	Australia	2170
14	Site AU61008	Adelaide	South Australia	Australia	SA 5000
15	Site AU61007	Geelong	Victoria	Australia	3220
16	Site BE32003	Bruxelles	Bruxelles-Capitale, Region De	Belgium	1200
17	Site BE32007	Brussel	Bruxelles	Belgium	1090
18	Site BE32006	Gent		Belgium	9000
19	Site CA15009	Edmonton	Alberta	Canada	T6G 2B7
20	Site CA15011	Toronto	Ontario	Canada	M4N 3M5
21	Site CA15002	Toronto	Ontario	Canada	M5G 2M9
22	Site CA15006	Montreal	Quebec	Canada	H4A 3J1
23	Site FR33003	Nimes Cedex 09	Gard	France	30029
24	Site FR33002	Pessac	Gironde	France	33604
25	Site FR33015	Rouen	Haute-Normandie	France	76038
26	Site FR33019	Montpellier Cedex 5	Herault	France	34295
27	Site FR33018	Rennes	Ille-et-Vilaine	France	35033
28	Site FR33001	Nantes cedex 01	Loire-Atlantique	France	44093
29	Site FR33023	Valenciennes	Nord	France	59322
30	Site FR33013	Pierre-Benite	Rhone	France	69310
31	Site FR33017	Le Mans	Sarthe	France	72037
32	Site FR33012	Poitiers	Vienne	France	86000
33	Site FR33009	Angers		France	49033
34	Site FR33020	Bayonne		France
35	Site FR33004	Lille cedex		France	59020
36	Site FR33006	Lille		France	59037
37	Site DE49002	Tuebingen	Baden-Wurttemberg	Germany	72076
38	Site DE49007	Munchen	Bayern	Germany	81737
39	Site DE49005	Frankfurt	Hessen	Germany	60590
40	Site DE49015	Rostock	Mecklenburg-Vorpommern	Germany	18057
41	Site DE49012	Braunschweig	Niedersachsen	Germany	38118
42	Site DE49004	Hannover	Niedersachsen	Germany	30625
43	Site DE49009	Halle (Saale)	Sachsen-Anhalt	Germany	06120
44	Site DE49003	Berlin		Germany	13353
45	Site DE49011	Stuttgart		Germany	70376
46	Site IT39009	Ancona		Italy	60126
47	Site IT39015	Bologna		Italy	40138
48	Site IT39012	Firenze		Italy
49	Site IT39004	Milano		Italy	20162
50	Site IT39007	Monza		Italy
51	Site IT39001	Napoli		Italy	80131
52	Site IT39014	Novara		Italy
53	Site IT39006	Palermo		Italy	90146
54	Site IT39005	Pavia		Italy
55	Site IT39011	San Giovanni Rotondo		Italy	71013
56	Site JP81018	Anjo	Aichi	Japan
57	Site JP81007	Nagoya	Aichi	Japan
58	Site JP81027	Matsuyama	Ehime	Japan
59	Site JP81021	Fukuyama	Hiroshima	Japan
60	Site JP81031	Sapporo	Hokkaido	Japan
61	Site JP81033	Sapporo	Hokkaido	Japan
62	Site JP81015	Kobe	Hyogo	Japan
63	Site JP81034	Hitachi	Ibaraki	Japan
64	Site JP81023	Kanazawa	Ishikawa	Japan
65	Site JP81001	Isehara	Kanagawa	Japan
66	Site JP81032	Yokohama	Kanagawa	Japan
67	Site JP81012	Sendai	Miyagi	Japan
68	Site JP81011	Kurashiki	Okayama	Japan
69	Site JP81029	Shibuya-ku	Tokyo	Japan
70	Site JP81014	Shinagawa-ku	Tokyo	Japan
71	Site JP81035	Chiba		Japan
72	Site JP81008	Fukuoka		Japan
73	Site JP81024	Gifu		Japan
74	Site JP81005	Kumamoto		Japan
75	Site JP81016	Kyoto		Japan
76	Site JP81004	Nagasaki		Japan
77	Site JP81017	Nagasaki		Japan
78	Site JP81030	Osaka		Japan
79	Site JP81036	Osaka		Japan
80	Site JP81026	Tokushima		Japan
81	Site JP81019	Toyama		Japan
82	Site KR82003	Namdong	Incheon Gwang'yeogsiv	Korea, Republic of	405 760
83	Site KR82013	Seoul	Seoul Teugbyeolsi	Korea, Republic of	05505
84	Site KR82006	Seoul	Seoul Teugbyeolsi	Korea, Republic of	110-744
85	Site KR82002	Seoul	Seoul Teugbyeolsi	Korea, Republic of	137-701
86	Site KR82001	Ulsan	Ulsan Gwang'yeogsi	Korea, Republic of	682-714
87	Site KR82014	Busan		Korea, Republic of	49241
88	Site KR82010	Hwasun-gun		Korea, Republic of
89	Site KR82015	Seongnam-si		Korea, Republic of
90	Site KR82012	Seoul		Korea, Republic of	156-707
91	Site PL48003	Lublin	Lubelskie	Poland	20-081
92	Site PL48004	Warszawa	Mazowieckie	Poland	02-776
93	Site PL48002	Opole	Opolskie	Poland	45-061
94	Site PL48001	Olsztyn	Warmińsko-mazurskie	Poland	10-228
95	Site ES34003	Oviedo	Asturias	Spain	33011
96	Site ES34007	Palma de Mallorca	Baleares	Spain	07010
97	Site ES34008	Barcelona		Spain	08003
98	Site ES34004	Barcelona		Spain	08035
99	Site ES34010	Barcelona		Spain	08036
100	Site ES34009	Barcelona		Spain	8041
101	Site ES34002	Caceres		Spain	10003
102	Site ES34013	Madrid		Spain
103	Site ES34005	Valencia		Spain	46026
104	Site TW88604	Kaohsiung		Taiwan	83301
105	Site TW88605	Kwei Shan Hsiang		Taiwan
106	Site TW88602	Tainan		Taiwan	704
107	Site TW88609	Tainan		Taiwan	736
108	Site TW88601	Taipei		Taiwan	10002
109	Site TW88608	Taipei		Taiwan	10449
110	Site TW88610	Taipei		Taiwan	11217
111	Site GB44007	Sheffield		United Kingdom	S10 2JF