A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03512197
• Collaborator: (none)
• Enrollment: 511
• Locations: 133
• Arms: 2
• Actual Duration (Months): 30.8
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off).

This study will evaluate the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR<0.05) AML.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML)	Drug: Midostaurin; Drug: Midostaurin Placebo; Drug: Chemotherapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 511 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-blind Study of Chemotherapy With Daunorubicin or Idarubicin and Cytarabine for Induction and Intermediate Dose Cytarabine for Consolidation Plus Midostaurin (PKC412) or Chemotherapy Plus Placebo in Newly Diagnosed Patients With FLT-3 Mutation Negative Acute Myeloid Leukemia (AML)
• Actual Study Start Date: Jul 20, 2018
• Actual Primary Completion Date: Feb 12, 2021
• Actual Study Completion Date: Feb 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Midostaurin + chemotherapy Participants will receive Midostaurin 50mg twice a day until not achieving CR nor CRi without adequate hematologic recovery for continuation of treatment, intolerable toxicity, relapse or consent withdrawal plus chemotherapy whichever occurs first during induction and consolidation followed by midostaurin monotherapy for 12 cycles of 28 days cycle duration.Chemotherapy consists of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.	Drug: Midostaurin; After randomization, patients will receive midostaurin twice daily until not achieving CR nor CRi, relapse after CR or CRi, intolerable toxicity, or consent withdrawal; Other Names: PKC412 ; Drug: Chemotherapy; Along with the study drug/placebo, chemotherapy will be give as welll: either Daunorubicin or Idarubicin and Cytarabine al take by i.v.
Placebo Comparator: Midostaurin Placebo + chemotherapy Participants will receive matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consists of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation	Drug: Midostaurin Placebo; After randomization, patients will receive midostaurin placebo twice daily until not achieving CR nor CRi, relapse after CR or CRi, intolerable toxicity, or consent withdrawal; Drug: Chemotherapy; Along with the study drug/placebo, chemotherapy will be give as welll: either Daunorubicin or Idarubicin and Cytarabine al take by i.v.

Outcome Measures

Primary Outcome Measures

1. Event Free Survival (EFS) [From date of Randomization up to 5 years of follow-up]

   EFS is defined as the time from randomization to failure to obtain a Complete Remission (CR) or Morphologic Complete Remission without hematopoietic recovery (CRi) with adequate blood count recovery(adequate for treatment continuation) in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurs first as assessed by the investigator

Secondary Outcome Measures

1. Overall survival (OS) [Between randomization to date of death up to 5 years of follow-up of last patients]

   OS is defined as the time from randomization to date of death due to any cause. Patients will enter the survival follow-up phase once they complete the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or have relapse during post-treatment follow-up. Patients will then be contacted by telephone every 3 months +/- 2 weeks or have a visit to follow up on their survival status

2. Complete Remission (CR) with adequate blood count recovery rate [Between randomization to date of death up to 5 years of follow-up of last patients]

   Assessment will be based on the IWG criteria for AML as per investigator assessment

3. Percentage of patients with Minimal Residual Disease (MRD) negative status [Between start and three months after end of treatment]

   Comparisons of the MRD levels between the end of the consolidation phase during the post-consolidation phase. The time to MRD negative status is defined as the time from randomization to first occurrence of MRD negativity

4. Disease-free survival (DFS) [From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up]

   DFS is defined as the time from CR or CRi with adequate blood count recovery to relapse or death due to any cause. Patient who did not relapse nor die will be censored at the last adequate response assessment. Assessment will be based on the IWG criteria for AML as per investigator assessment

5. Number of days from the first day of a chemotherapy cycle to first day neutrophils ≥0.5 x 10^9/L [At maximum 93 days from induction therapy start]

   The time to neutrophil recovery will be assessed for the following criteria: number of days from start of treatment to the first day neutrophils ≥0.5 x 10^9/L, Number of days from start of treatment to the first day neutrophils ≥1.0 x 10^9/L

6. Number of days from the first day of a chemotherapy cycle to first day platelets ≥50 x 10^9/L [At maximum 93 days from induction therapy start]

   Time to platelet recovery will be assessed for the following criteria: Number of days from start of treatment to the first day platelets ≥50 x 10^9/L, Number of days from start of treatment to the first day platelets ≥100 x 10^9/L

7. Plasma concentrations for midostaurin and its metabolites: CGP52421 and CGP62221 [From date of Randomization up to 1.5 years of follow-up]

8. Cumulative incidence of relapse (CIR) [From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up]

   CIR is defined for patients with CR or CRi with adequate blood count recovery and is time from achieving CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Patients without relapse are censored at the last adequate response assessment. Patients who died without relapse are counted as a competing cause of failure. Assessment will be based on the IWG criteria for AML as per investigator assessment

9. Cumulative incidence of death (CID) [From date of CR or CRi with adequate blood count recovery up to 5 years of follow-up]

   CID is defined for all patients achieving CR or CRi with adequate blood count recovery measured from the date of achievement of CR or CRi until the date of death due to any reason. Patients not known to have died are censored on the last contact date. Patients who experienced relapse are counted as a competing cause of failure. Assessment will be based on the IWG criteria for AML as per investigator assessment

10. Number of days from date of randomization to first documented CR or CRi with adequate blood count recovery [At maximum 93 days from induction therapy start]

    Time to CR or CRi with adequate blood count recovery is defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurs first

11. Percentage of patients with MRD negative status during post-consolidation phase [between start and three months after end of treatment]

12. Morphologic complete remission without hematopoietic recovery (CRi) with adequate blood count recovery rate [At maximum 93 days from induction therapy start]

    Assessment will be based on the IWG criteria for AML as per investigator assessment

13. Number of days from day 1 of commencing induction therapy to first day neutrophils ≥1.0 x 10^9/L [At maximum 93 days from induction therapy start]

14. Number of days from day 1 of commencing induction therapy to first day platelets ≥100 x 10^9/L [From date of Randomization up to 5 years of follow-up]

15. Number of days from date of randomization to first documented MRD negativity [From date of Randomization up to 5 years of follow-up]

16. AUC0-t: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [From date of Randomization up to 1.5 years of follow-up]

    The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time is at 12 h, AUC0-12h will be determined after the first dose

17. AUClast: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [From date of Randomization up to 1.5 years of follow-up]

    The AUC from time zero to the last measurable concentration sampling time after the first dose

18. Cmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [From date of Randomization up to 1.5 years of follow-up]

    The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after the first dose administration

19. Tmax: Pharmacokinetic (PK) parameter for midostaurin and its metabolites: CGP52421 and CGP62221 [From date of Randomization up to 1.5 years of follow-up]

    The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration

20. Change from baseline score for each time point for the FACT-Leu [From date of Randomization up to 5 years of follow-up]

    The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better HRQoL. Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.

21. Change from baseline score for each time point for the EQ5D-5L (a visual analogue scale (VAS)) [From date of Randomization up to 5 years of follow-up]

    The EQ5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient is asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a Visual Analogue Scale (VAS), where the patient is asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible.

2. Suitability for intensive induction chemotherapy in the judgment of the investigator

3. Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type signal ratio

4. Age ≥18 years

5. Laboratory values that indicate adequate organ function assessed locally at the screening visit

Exclusion Criteria:

1. Central nervous system (CNS) leukemia

2. Therapy-related secondary AML

3. Isolated extramedullary leukemia

4. Prior therapy for leukemia or myelodysplasia

5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)

6. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center	Chicago	Illinois	United States	60637
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Oregon Health and Science University	Portland	Oregon	United States	97239
4	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1118AAT
5	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
6	Novartis Investigative Site	Woolloongabba	Queensland	Australia	4102
7	Novartis Investigative Site	Prahran	Victoria	Australia	3181
8	Novartis Investigative Site	Murdoch	Western Australia	Australia	6150
9	Novartis Investigative Site	Linz		Austria	A-4010
10	Novartis Investigative Site	Vienna		Austria	1140
11	Novartis Investigative Site	Wien		Austria	1090
12	Novartis Investigative Site	Antwerpen		Belgium	2060
13	Novartis Investigative Site	Brugge		Belgium	8000
14	Novartis Investigative Site	Roeselare		Belgium	8800
15	Novartis Investigative Site	Porto Alegre	RS	Brazil	90035-003
16	Novartis Investigative Site	Sao Paulo	SP	Brazil	03102-002
17	Novartis Investigative Site	Sao Paulo		Brazil	01221 900
18	Novartis Investigative Site	Sofia		Bulgaria	1756
19	Novartis Investigative Site	Brno - Bohunice		Czechia	639 01
20	Novartis Investigative Site	Plzen-Bory		Czechia	30599
21	Novartis Investigative Site	Bayonne	Bayonne Cedex	France	64109
22	Novartis Investigative Site	Angers Cedex 1		France	49033
23	Novartis Investigative Site	Avignon		France	84000
24	Novartis Investigative Site	Dijon		France	21034
25	Novartis Investigative Site	Lille Cedex		France	59037
26	Novartis Investigative Site	Nantes Cedex 1		France	44093
27	Novartis Investigative Site	Paris		France	75012
28	Novartis Investigative Site	Pierre Benite Cedex		France	69495
29	Novartis Investigative Site	Toulouse		France	31059
30	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
31	Novartis Investigative Site	Schwerin	Brandenburg	Germany	19049
32	Novartis Investigative Site	Bad Saarow		Germany	15526
33	Novartis Investigative Site	Berlin		Germany	10967
34	Novartis Investigative Site	Berlin		Germany	12351
35	Novartis Investigative Site	Berlin		Germany	13125
36	Novartis Investigative Site	Berlin		Germany	13353
37	Novartis Investigative Site	Bochum		Germany	44892
38	Novartis Investigative Site	Bonn		Germany	53105
39	Novartis Investigative Site	Braunschweig		Germany	38114
40	Novartis Investigative Site	Darmstadt		Germany	64283
41	Novartis Investigative Site	Duesseldorf		Germany	40225
42	Novartis Investigative Site	Duisburg		Germany	47166
43	Novartis Investigative Site	Eschweiler		Germany	52249
44	Novartis Investigative Site	Essen Werden		Germany	45239
45	Novartis Investigative Site	Flensburg		Germany	24939
46	Novartis Investigative Site	Giessen		Germany	35392
47	Novartis Investigative Site	Gottingen		Germany	37075
48	Novartis Investigative Site	Hamburg		Germany	20099
49	Novartis Investigative Site	Hamburg		Germany	20246
50	Novartis Investigative Site	Hannover		Germany	30625
51	Novartis Investigative Site	Homburg		Germany	66421
52	Novartis Investigative Site	Karlsruhe		Germany	76133
53	Novartis Investigative Site	Kiel		Germany	24116
54	Novartis Investigative Site	Leipzig		Germany	04103
55	Novartis Investigative Site	Luebeck		Germany	23538
56	Novartis Investigative Site	Magdeburg		Germany	39120
57	Novartis Investigative Site	Mainz		Germany	55131
58	Novartis Investigative Site	Muenchen		Germany	80377
59	Novartis Investigative Site	Osnabrueck		Germany	49076
60	Novartis Investigative Site	Paderborn		Germany	33098
61	Novartis Investigative Site	Rostock		Germany	18057
62	Novartis Investigative Site	Siegen		Germany	57072
63	Novartis Investigative Site	Stuttgart		Germany	70176
64	Novartis Investigative Site	Stuttgart		Germany	70376
65	Novartis Investigative Site	Ulm		Germany	89081
66	Novartis Investigative Site	Wuerzburg		Germany	97080
67	Novartis Investigative Site	Zwickau		Germany	08060
68	Novartis Investigative Site	Haifa		Israel	3109601
69	Novartis Investigative Site	Petach Tikva		Israel	4910002
70	Novartis Investigative Site	Tel Aviv		Israel	6423906
71	Novartis Investigative Site	Alessandria	AL	Italy	15100
72	Novartis Investigative Site	Ancona	AN	Italy	60126
73	Novartis Investigative Site	Bergamo	BG	Italy	24127
74	Novartis Investigative Site	Brescia	BS	Italy	25123
75	Novartis Investigative Site	Catania	CT	Italy	95123
76	Novartis Investigative Site	Roma	Lazio	Italy	00168
77	Novartis Investigative Site	Milano	MI	Italy	20162
78	Novartis Investigative Site	Modena	MO	Italy	41124
79	Novartis Investigative Site	Palermo	PA	Italy	90146
80	Novartis Investigative Site	Piacenza	PC	Italy	29100
81	Novartis Investigative Site	Pescara	PE	Italy	65124
82	Novartis Investigative Site	Reggio Calabria	RC	Italy	89124
83	Novartis Investigative Site	Roma	RM	Italy	00133
84	Novartis Investigative Site	Roma	RM	Italy	00161
85	Novartis Investigative Site	Taranto	TA	Italy	74100
86	Novartis Investigative Site	Torino	TO	Italy	10126
87	Novartis Investigative Site	Vicenza	VI	Italy	36100
88	Novartis Investigative Site	Perugia		Italy	06129
89	Novartis Investigative Site	Nagoya-city	Aichi	Japan	466-8650
90	Novartis Investigative Site	Matsuyama-city	Ehime	Japan	790-8524
91	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
92	Novartis Investigative Site	Fukushima city	Fukushima	Japan	960 1295
93	Novartis Investigative Site	Gifu shi	Gifu	Japan	500 8513
94	Novartis Investigative Site	Fukuyama	Hiroshima	Japan	720-0001
95	Novartis Investigative Site	Tsukuba city	Ibaraki	Japan	305-8576
96	Novartis Investigative Site	Isehara	Kanagawa	Japan	259-1193
97	Novartis Investigative Site	Nagasaki-city	Nagasaki	Japan	852-8501
98	Novartis Investigative Site	Okayama city	Okayama	Japan	701-1192
99	Novartis Investigative Site	Hirakata-city	Osaka	Japan	573-1191
100	Novartis Investigative Site	Osaka Sayama	Osaka	Japan	589 8511
101	Novartis Investigative Site	Hamamatsu	Shizuoka	Japan	432-8580
102	Novartis Investigative Site	Shimotsuke	Tochigi	Japan	329-0498
103	Novartis Investigative Site	Bunkyo ku	Tokyo	Japan	113-8677
104	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8603
105	Novartis Investigative Site	Aomori		Japan	030 8553
106	Novartis Investigative Site	Kyoto		Japan	606 8507
107	Novartis Investigative Site	Osaka		Japan	534-0021
108	Novartis Investigative Site	Yamagata		Japan	990 9585
109	Novartis Investigative Site	Bergen		Norway	NO-5021
110	Novartis Investigative Site	Oslo		Norway	0424
111	Novartis Investigative Site	Gdansk		Poland	80 952
112	Novartis Investigative Site	Lisboa		Portugal	1099 023
113	Novartis Investigative Site	Porto		Portugal	4200-072
114	Novartis Investigative Site	Cordoba	Andalucia	Spain	14004
115	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
116	Novartis Investigative Site	Salamanca	Castilla Y Leon	Spain	37007
117	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
118	Novartis Investigative Site	Caceres	Extremadura	Spain	10003
119	Novartis Investigative Site	Barakaldo	Pais Vasco	Spain	48903
120	Novartis Investigative Site	Barcelona		Spain	08041
121	Novartis Investigative Site	Madrid		Spain	28034
122	Novartis Investigative Site	Madrid		Spain	28041
123	Novartis Investigative Site	Valencia		Spain	46026
124	Novartis Investigative Site	Zaragoza		Spain	50009
125	Novartis Investigative Site	Bern		Switzerland	3010
126	Novartis Investigative Site	Zurich		Switzerland	8091
127	Novartis Investigative Site	Putzu City	Chiayi Hsien	Taiwan	61363
128	Novartis Investigative Site	Kuei-Shan Chiang	Taoyuan/ Taiwan ROC	Taiwan	33305
129	Novartis Investigative Site	Kaohsiung City		Taiwan	83301
130	Novartis Investigative Site	Taipei		Taiwan	10002
131	Novartis Investigative Site	Adana		Turkey	01330
132	Novartis Investigative Site	Ankara		Turkey	06100
133	Novartis Investigative Site	Aydin		Turkey	09100

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03512197
• Other Study ID Numbers: CPKC412E2301; 2017-003540-21
• First Posted: Apr 30, 2018
• Last Update Posted: Feb 7, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Newly diagnosed FLT3-mutation negative; PKC412; midostaurin; cytarabine; daunorubicin; idarubicin; acute myeloid leukemia; AML; FLT3-MN (SR<0.05); combination treatment; induction failure; event free survival; EFS; minimal residual disease
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Midostaurin; Staurosporine

Study Results

No Results Posted as of Feb 7, 2022