Clinical trial NCT03512197: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia (AML)
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-04-30
Enrollment: 511
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 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 evaluated 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.

Detailed description: This was a multi-center, multinational, randomized, double-blind Phase III study using a group sequential design. Subjects were stratified according to age (\<60 vs. ≥ 60 years). Subjects within each stratum were randomized in a 1:1 ratio into one of two treatment arms: Midostaurin + chemotherapy 'or' Placebo + chemotherapy.

The study consisted of the following phases:

Screening/randomization phase: Subjects had to sign informed consent form before screening for enrollment. Subjects started chemotherapy at day 1 and were randomized at day 8.

Induction phase: All subjects received at least one cycle (28 days) of induction therapy with continuous infusion cytarabine (D1 - D7) and daunorubicin or idarubicin (D1 - D3) (induction 1). Subjects who did not achieve CR or CRi with adequate blood count recovery after Induction 1 received a second cycle with intermediate-dose cytarabine (D1 - D3) and daunorubicin or idarubicin (D1 - D3) (induction 2). Subjects who did not achieve CR or CRi with adequate blood recovery after induction 2 discontinued study treatment and were followed for survival.

Consolidation phase: Subjects who achieved CR or CRi with adequate blood count recovery after induction with one or two cycles of induction proceeded to consolidation therapy with either 3 or 4 cycles respectively of intermediate-dose cytarabine (D1 - D3), or to Hematopoietic Stem Cells Transplantation (HSCT) with or without preceding consolidation cycles.

Post-consolidation phase: Subjects who maintained CR or CRi with adequate blood count recovery at the end of the consolidation phase received 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Subjects who underwent HSCT after achieving CR or CRi with adequate blood count recovery received midostaurin or placebo twice daily 50 mg post-transplant therapy, continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy began \>30 days but not later than 100 days following HSCT.

Follow-up phase: All enrolled subjects were followed through the treatment period and until relapse/treatment failure, thereafter for start of new line of therapy and survival.

Eligibility criteria: 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)

Primary outcomes:
measure: Event Free Survival (EFS)
timeFrame: From date of Randomization up to approx. 30 months
Secondary outcomes:
measure: Overall Survival (OS) (Key Secondary)
timeFrame: Between randomization to date of death up to approx. 30 months
measure: Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.
timeFrame: At maximum 93 days from induction therapy start
measure: Percentage of Participants With Minimal Residual Disease (MRD) Negative Status
timeFrame: from start of treatment up to end of post-consolidation (approximately 17 months)
measure: Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase
timeFrame: from start of post-consolidation to end of post-consolidation phase (up to 12 months)
measure: Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry
timeFrame: From date of Randomization up to approx. 17 months
measure: Disease-free Survival (DFS)
timeFrame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months
measure: Cumulative Incidence of Relapse (CIR)
timeFrame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months
measure: Cumulative Incidence of Death (CID)
timeFrame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months
measure: Time to CR or CRi With Adequate Blood Count Recovery
timeFrame: At maximum 93 days from induction therapy start
measure: Time to Partial and Full Neutrophil Recovery
timeFrame: At maximum 93 days from induction therapy start
measure: Time to Partial and Full Platelet Recovery
timeFrame: At maximum 93 days from induction therapy start
measure: Plasma Concentrations for Midostaurin and Its Metabolites: CGP52421 and CGP62221 for Non-poor Metabolizers
timeFrame: from Induction (IND) phase 0hr (predose) to Post-consolidation phase (POSTCONS) 12hr
measure: AUC0-t: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8
timeFrame: 0 - 12 hrs
measure: AUClast: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8
timeFrame: 0 - 12 hrs
measure: Cmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8
timeFrame: 0 - 12 hrs
measure: Tmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8
timeFrame: 0 - 12 hrs
measure: Total Score for Each Time Point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)
timeFrame: From date of Randomization up to approx. 18 months
measure: Scores for Each Time Point for the EQ5D-5L (a Visual Analogue Scale (VAS))
timeFrame: From date of Randomization up to approx. 18 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Medical Center .
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Portland
country: United States
facility: Oregon Health and Science Univ
state: Oregon
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Prahran
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Antwerpen
country: Belgium
facility: Novartis Investigative Site
city: Brugge
country: Belgium
facility: Novartis Investigative Site
city: Roeselare
country: Belgium
facility: Novartis Investigative Site
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Brno - Bohunice
country: Czechia
facility: Novartis Investigative Site
city: Plzen-Bory
country: Czechia
facility: Novartis Investigative Site
city: Bayonne
country: France
facility: Novartis Investigative Site
state: Bayonne Cedex
city: Angers Cedex 1
country: France
facility: Novartis Investigative Site
city: Avignon
country: France
facility: Novartis Investigative Site
city: Dijon
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 1
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Schwerin
country: Germany
facility: Novartis Investigative Site
state: Brandenburg
city: Bad Saarow
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Bonn
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city: Braunschweig
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city: Darmstadt
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city: Duesseldorf
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city: Eschweiler
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city: Essen Werden
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facility: Novartis Investigative Site
city: Flensburg
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facility: Novartis Investigative Site
city: Giessen
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facility: Novartis Investigative Site
city: Gottingen
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facility: Novartis Investigative Site
city: Hamburg
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facility: Novartis Investigative Site
city: Hamburg
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city: Homburg
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city: Leipzig
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city: Luebeck
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facility: Novartis Investigative Site
city: Magdeburg
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facility: Novartis Investigative Site
city: Mainz
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facility: Novartis Investigative Site
city: Muenchen
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facility: Novartis Investigative Site
city: Osnabrueck
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facility: Novartis Investigative Site
city: Paderborn
country: Germany
facility: Novartis Investigative Site
city: Rostock
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facility: Novartis Investigative Site
city: Siegen
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
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facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Ulm
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facility: Novartis Investigative Site
city: Wuerzburg
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facility: Novartis Investigative Site
city: Zwickau
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facility: Novartis Investigative Site
city: Haifa
country: Israel
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city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Alessandria
country: Italy
facility: Novartis Investigative Site
state: AL
city: Ancona
country: Italy
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state: AN
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Catania
country: Italy
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state: CT
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Palermo
country: Italy
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state: PA
city: Piacenza
country: Italy
facility: Novartis Investigative Site
state: PC
city: Pescara
country: Italy
facility: Novartis Investigative Site
state: PE
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Reggio Calabria
country: Italy
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state: RC
city: Roma
country: Italy
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state: RM
city: Roma
country: Italy
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state: RM
city: Roma
country: Italy
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state: RM
city: Taranto
country: Italy
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state: TA
city: Torino
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state: TO
city: Vicenza
country: Italy
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state: VI
city: Nagoya-city
country: Japan
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state: Aichi
city: Matsuyama-city
country: Japan
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state: Ehime
city: Fukuoka city
country: Japan
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state: Fukuoka
city: Fukushima city
country: Japan
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state: Fukushima
city: Gifu shi
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state: Gifu
city: Fukuyama
country: Japan
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state: Hiroshima
city: Tsukuba city
country: Japan
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state: Ibaraki
city: Isehara
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Nagasaki-city
country: Japan
facility: Novartis Investigative Site
state: Nagasaki
city: Okayama city
country: Japan
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state: Okayama
city: Hirakata-city
country: Japan
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state: Osaka
city: Osaka Sayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Hamamatsu
country: Japan
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state: Shizuoka
city: Shimotsuke
country: Japan
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state: Tochigi
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Aomori
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Yamagata
country: Japan
facility: Novartis Investigative Site
city: Bergen
country: Norway
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Lisboa
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Caceres
country: Spain
facility: Novartis Investigative Site
state: Extremadura
city: Barakaldo
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Zurich
country: Switzerland
facility: Novartis Investigative Site
city: Putzu City
country: Taiwan
facility: Novartis Investigative Site
state: Chiayi Hsien
city: Kuei Shan Chiang
country: Taiwan
facility: Novartis Investigative Site
state: Taoyuan Taiwan ROC
city: Kaohsiung City
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Aydin
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: