Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Monotherapy in Patients With Newly-diagnosed FLT3-mutated Acute Myeloid Leukemia.

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT03379727

Collaborator

(none)

303

Enrollment

Locations

Arm

40.8

Actual Duration (Months)

3.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to gather and evaluate additional safety and efficacy data on the combination of midostaurin and standard of care for adult patients with newly diagnosed Fms-like tyrosine kinase receptor (FLT3) mutated Acute Myeloid Leukemia (AML) who are eligible for standard induction and consolidation

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Midostaurin	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

303 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Considering the limited safety impact and the significant clinical benefit of the addition of midostaurin to the standard "7+3" regimen in the RATIFY study (CPKC412A2301), this Phase IIIb study is designed as a single arm study and allows the assessment of variation of the "7+3" regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower dose of cytarabine (100-200 mg/m2/day) and the "5+2" reduced dose regimen). Safety is the primary endpoint. CR/CRi (see Section 7.2.1) in induction, consolidation and maintenance therapy is collected as secondary endpoint. Patients who are newly diagnosed with AML, have a known FLT3 ITD or TKD, mutation and have recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation will be consented and screened for the clinical study. Number of Arms: 1Considering the limited safety impact and the significant clinical benefit of the addition of midostaurin to the standard "7+3" regimen in the RATIFY study (CPKC412A2301), this Phase IIIb study is designed as a single arm study and allows the assessment of variation of the "7+3" regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower dose of cytarabine (100-200 mg/m2/day) and the "5+2" reduced dose regimen). Safety is the primary endpoint. CR/CRi (see Section 7.2.1) in induction, consolidation and maintenance therapy is collected as secondary endpoint. Patients who are newly diagnosed with AML, have a known FLT3 ITD or TKD, mutation and have recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation will be consented and screened for the clinical study.Number of Arms:1

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Multi-Center, Phase IIIb Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Patients 18 Years of Age or Older With Newly-diagnosed FLT3-mutated Acute Myeloid Leukemia Who Are Eligible for "7+3" or "5+2" Chemotherapy

Actual Study Start Date :

Feb 13, 2018

Actual Primary Completion Date :

Jul 9, 2021

Actual Study Completion Date :

Jul 9, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Midostaurin Induction phase - D8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles Maintenance phase - D1 to D28 up to 12 cycles	Drug: Midostaurin Orally administered inhibitor of multiple tyrosine kinases

Arm

Intervention/Treatment

Experimental: Midostaurin

Induction phase - D8 to D28 in combination with standard of care (7+3 or 5+2 chemotherapy) up to 2 cycles Consolidation phase - D8 to D28 in combination with cytarabine up to 4 cycles Maintenance phase - D1 to D28 up to 12 cycles

Drug: Midostaurin

Orally administered inhibitor of multiple tyrosine kinases

Outcome Measures

Primary Outcome Measures

Percentage of patients with AEs, Grade 3&4 AEs, SAEs, AEs leading to discontinuation, and deaths up to 24 months. [Baseline up to approximatly 24 months]
To further assess the safety of midostaurin in induction, consolidation and maintenance therapy, including, the "7+3" regimen, higher dose of Daunorubicin (60-90mg/m2/day), the substitution of Daunorubicin by Idarubicin and lower dose of Cytarabine (100-200 mg/m2/day) and also allowing the "5+2" reduced dose regimen.

Secondary Outcome Measures

Percentage of patients with CR/CRi as per local assessment [Baseline up to approximately 24 months]
CR/CRi rate is defined as the percentage of patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) as per local assessment, in induction, consolidation and maintenance phase. CR/CRi rate will be calculated based on the full analysis set (FAS).

Other Outcome Measures

Health Care Resource Utilization during maintenance [During maintenance up to 12 months]
Collection of health care resource utilization (HCRU) data will focus on hospitalization: reason for the hospitalization, number of hospital days by ward type (e.g. hospital unit, emergency room, intensive care unit), discharge status, and the names of concomitant medications during hospital stay. These measures will be used to quantify the number of hospital day's impact of therapy during the maintenance phase and derive components of the economic impact of midostaurin during maintenance.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

Written informed consent must be obtained prior to any screening procedures.
Patients must be 18 years of age or older at the time of signing informed consent.
Patients must have a documented unequivocal diagnosis of AML according to WHO 2008 classification. A bone marrow or blood blast count of ≥ 20% is required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16) where blast count may be <20%, and, excluding M3 (acute promyelocytic leukemia).
Patients with secondary AML are eligible, e.g. patients with antecedent history of treatment for prior malignancy. AML patients with a history of antecedent treatment for myelodysplasia (MDS), e.g. azacitidine or decitabine, remain eligible for treatment on this study. These agents must have been discontinued for a period of at least 30 days or 5 half-lives of the drug (whichever is greater) before midostaurin can be administered.
Patients must have started "7+3" or "5+2" first induction chemotherapy regimen.
Patients must have a documented FLT3 mutation (ITD or TKD).).
Patients must have an ECOG Performance Status of ≤ 2
Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours prior to the first dose of midostaurin
Patients must have Total Bilirubin ≤ 2.5 x ULN
Patients must have Serum Creatinine ≤ 2.5 x ULN
Patients must be able to communicate well with the investigator to understand and comply with the requirements of the study
Women of child-bearing potential must have a negative pregnancy test before starting use of midostaurin.

Exclusion criteria:

Patients eligible for this study must not meet any of the following criteria:

Prior therapy for AML with the following exceptions:
emergency leukapheresis
emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days
cranial RT for CNS leukostasis (one dose only)
growth factor/cytokine support
Patients with LVEF less than 45% (by echocardiogram or MUGA) or symptomatic congestive heart failure (Class III or IV) according to New York Heart Association (NYHA) classification
Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolved to ≤ Grade 1 within screening timeframe)
Patients with any uncontrolled illness, including, but not limited to, acute or chronic pancreatitis or uncontrolled infection
QTc >470 msec on screening ECG.
History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment.
Participation in a prior investigational interventional (drug) study with administration of the investigational product within 30 days or 5 half-lives of the investigational product, whichever is longer.
Pregnancy statements and contraception requirements:

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 4 months after stopping medication. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should also add a barrier method of contraception, particularly as it is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives.

Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.

Patients enrolled in this study are not permitted to participate in additional parallel study drug or device studies.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Pleven		Bulgaria	5800
2	Novartis Investigative Site	Sofia		Bulgaria	1413
3	Novartis Investigative Site	Sofia		Bulgaria	1756
4	Novartis Investigative Site	Varna		Bulgaria	9000
5	Novartis Investigative Site	Zagreb		Croatia	10000
6	Novartis Investigative Site	Brno		Czechia	625 00
7	Novartis Investigative Site	Praha 10		Czechia	100 34
8	Novartis Investigative Site	Tallinn		Estonia	13419
9	Novartis Investigative Site	Helsinki		Finland	FIN 00290
10	Novartis Investigative Site	Oulu		Finland	FIN-90220
11	Novartis Investigative Site	Tampere		Finland	33521
12	Novartis Investigative Site	Bayonne	Bayonne Cedex	France	64109
13	Novartis Investigative Site	Saint Priest en Jarez	Loire	France	42270
14	Novartis Investigative Site	Besancon cedex		France	25030
15	Novartis Investigative Site	Clamart		France	92141
16	Novartis Investigative Site	Creteil		France	94010
17	Novartis Investigative Site	Dijon		France	21034
18	Novartis Investigative Site	Lille Cedex		France	59037
19	Novartis Investigative Site	Limoges cedex		France	87042
20	Novartis Investigative Site	Lyon Cedex		France	69373
21	Novartis Investigative Site	Metz		France	57085
22	Novartis Investigative Site	Nice Cedex		France	06202
23	Novartis Investigative Site	Paris Cedex 10		France	75475
24	Novartis Investigative Site	Paris		France	75012
25	Novartis Investigative Site	Pierre Benite Cedex		France	69495
26	Novartis Investigative Site	Poitiers		France	86000
27	Novartis Investigative Site	Villejuif Cedex		France	94800
28	Novartis Investigative Site	Budapest		Hungary	1085
29	Novartis Investigative Site	Szeged		Hungary	H 6725
30	Novartis Investigative Site	Ancona	AN	Italy	60126
31	Novartis Investigative Site	Avellino	AV	Italy	83100
32	Novartis Investigative Site	Bergamo	BG	Italy	24127
33	Novartis Investigative Site	Bologna	BO	Italy	40138
34	Novartis Investigative Site	Brescia	BS	Italy	25123
35	Novartis Investigative Site	Cuneo	CN	Italy	12100
36	Novartis Investigative Site	Cosenza	CS	Italy	87100
37	Novartis Investigative Site	San Giovanni Rotondo	FG	Italy	71013
38	Novartis Investigative Site	Firenze	FI	Italy	50134
39	Novartis Investigative Site	Genova	GE	Italy	16132
40	Novartis Investigative Site	Lecce	LE	Italy	73100
41	Novartis Investigative Site	Latina	LT	Italy	04100
42	Novartis Investigative Site	Monza	MB	Italy	20900
43	Novartis Investigative Site	Milano	MI	Italy	20122
44	Novartis Investigative Site	Milano	MI	Italy	20132
45	Novartis Investigative Site	Milano	MI	Italy	20162
46	Novartis Investigative Site	Rozzano	MI	Italy	20089
47	Novartis Investigative Site	Modena	MO	Italy	41124
48	Novartis Investigative Site	Palermo	PA	Italy	90146
49	Novartis Investigative Site	Piacenza	PC	Italy	29100
50	Novartis Investigative Site	Padova	PD	Italy	35128
51	Novartis Investigative Site	Pescara	PE	Italy	65124
52	Novartis Investigative Site	Perugia	PG	Italy	06100
53	Novartis Investigative Site	Parma	PR	Italy	43100
54	Novartis Investigative Site	Reggio Emilia	RE	Italy	42123
55	Novartis Investigative Site	Roma	RM	Italy	00128
56	Novartis Investigative Site	Roma	RM	Italy	00133
57	Novartis Investigative Site	Roma	RM	Italy	00161
58	Novartis Investigative Site	Roma	RM	Italy	00168
59	Novartis Investigative Site	Salerno	SA	Italy	84131
60	Novartis Investigative Site	Siena	SI	Italy	53100
61	Novartis Investigative Site	Torino	TO	Italy	10128
62	Novartis Investigative Site	Venezia	VE	Italy	30174
63	Novartis Investigative Site	Verona	VR	Italy	37126
64	Novartis Investigative Site	Napoli		Italy	80131
65	Novartis Investigative Site	Napoli		Italy	80132
66	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
67	Novartis Investigative Site	Bergen		Norway	5021
68	Novartis Investigative Site	Craiova		Romania	200136
69	Novartis Investigative Site	Iasi		Romania	700483
70	Novartis Investigative Site	Belgrade		Serbia	11000
71	Novartis Investigative Site	Bratislava	Slovak Republic	Slovakia	833 10
72	Novartis Investigative Site	Banska Bystrica		Slovakia	975 17
73	Novartis Investigative Site	Bratislava		Slovakia	85107
74	Novartis Investigative Site	Barcelona	Cataluna	Spain	08026
75	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
76	Novartis Investigative Site	Palma De Mallorca	Islas Baleares	Spain	07120
77	Novartis Investigative Site	Pozuelo de Alarcon	Madrid	Spain	28223
78	Novartis Investigative Site	Gasteiz	País Vasco	Spain	01009
79	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife	Spain	38320
80	Novartis Investigative Site	Las Palmas de Gran Canaria		Spain	35010
81	Novartis Investigative Site	Leon		Spain	24080
82	Novartis Investigative Site	Madrid		Spain	28006
83	Novartis Investigative Site	Madrid		Spain	28046
84	Novartis Investigative Site	Valencia		Spain	46026
85	Novartis Investigative Site	Boras		Sweden	501 82
86	Novartis Investigative Site	Uppsala		Sweden	SE-751 85