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)

Acute Myeloid Leukemia (AML) Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03512197
• Other study ID #: CPKC412E2301
• Secondary ID: 2017-003540-21
• Status: Completed
• Phase: Phase 3
• Start date: July 20, 2018
• Est. completion date: February 12, 2021

Study information

• Verified date: August 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 511
• Est. completion date: February 12, 2021
• Est. primary completion date: February 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Midostaurin
Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally.
• Placebo
Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally.
• Chemotherapy
Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Australia	Novartis Investigative Site	Murdoch	Western Australia
Australia	Novartis Investigative Site	Prahran	Victoria
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Vienna
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Antwerpen
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Roeselare
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo
Bulgaria	Novartis Investigative Site	Sofia
Czechia	Novartis Investigative Site	Brno - Bohunice
Czechia	Novartis Investigative Site	Plzen-Bory
France	Novartis Investigative Site	Angers Cedex 1
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Bayonne	Bayonne Cedex
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Nantes Cedex 1
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Toulouse
Germany	Novartis Investigative Site	Bad Saarow
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Braunschweig
Germany	Novartis Investigative Site	Darmstadt
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Duisburg
Germany	Novartis Investigative Site	Eschweiler
Germany	Novartis Investigative Site	Essen Werden
Germany	Novartis Investigative Site	Flensburg
Germany	Novartis Investigative Site	Giessen
Germany	Novartis Investigative Site	Gottingen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Homburg
Germany	Novartis Investigative Site	Karlsruhe
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Luebeck
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Osnabrueck
Germany	Novartis Investigative Site	Paderborn
Germany	Novartis Investigative Site	Regensburg	Bavaria
Germany	Novartis Investigative Site	Rostock
Germany	Novartis Investigative Site	Schwerin	Brandenburg
Germany	Novartis Investigative Site	Siegen
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Ulm
Germany	Novartis Investigative Site	Wuerzburg
Germany	Novartis Investigative Site	Zwickau
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Alessandria	AL
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Pescara	PE
Italy	Novartis Investigative Site	Piacenza	PC
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Taranto	TA
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Vicenza	VI
Japan	Novartis Investigative Site	Aomori
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Fukushima city	Fukushima
Japan	Novartis Investigative Site	Fukuyama	Hiroshima
Japan	Novartis Investigative Site	Gifu shi	Gifu
Japan	Novartis Investigative Site	Hamamatsu	Shizuoka
Japan	Novartis Investigative Site	Hirakata-city	Osaka
Japan	Novartis Investigative Site	Isehara	Kanagawa
Japan	Novartis Investigative Site	Kyoto
Japan	Novartis Investigative Site	Matsuyama-city	Ehime
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Okayama city	Okayama
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka Sayama	Osaka
Japan	Novartis Investigative Site	Shimotsuke	Tochigi
Japan	Novartis Investigative Site	Tsukuba city	Ibaraki
Japan	Novartis Investigative Site	Yamagata
Norway	Novartis Investigative Site	Bergen
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Gdansk
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Spain	Novartis Investigative Site	Barakaldo	Pais Vasco
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Caceres	Extremadura
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Zaragoza
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Zurich
Taiwan	Novartis Investigative Site	Kaohsiung City
Taiwan	Novartis Investigative Site	Kuei Shan Chiang	Taoyuan Taiwan ROC
Taiwan	Novartis Investigative Site	Putzu City	Chiayi Hsien
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Aydin
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of Chicago Medical Center .	Chicago	Illinois
United States	Oregon Health and Science Univ	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Czechia,  France,  Germany,  Israel,  Italy,  Japan,  Norway,  Poland,  Portugal,  Spain,  Switzerland,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event Free Survival (EFS)	EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurred first as assessed by the investigator.	From date of Randomization up to approx. 30 months
Secondary	Overall Survival (OS) (Key Secondary)	OS was defined as the time from randomization to date of death due to any cause. Patients entered the survival follow-up phase once they completed the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or if they had relapsed during post-treatment follow-up. Patients were then contacted by telephone every 3 months +/- 2 weeks or had a visit to follow up on their survival status, per Kaplan-Meier estimates.	Between randomization to date of death up to approx. 30 months
Secondary	Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.	Assessment was based on the International Working Group (IWG) criteria for AML as per investigator assessment.; CR: Bone marrow: < 5% blasts no blasts with Auer rods; Peripheral blood: neutrophils = 1.0 x 109/L platelets = 100 x 109/L, no blasts; No evidence of extramedullary disease (such as central nervous system (CNS) or soft tissue involvement); Transfusion independent.; CRi with adequate blood count recovery is defined as the following: Bone marrow < 5% blasts no blasts with Auer rods Peripheral blood Neutrophils >= 1.0 x 109/L and 50 x 109/L <=platelets < 100 x 109/L no blasts No evidence of extramedullary disease (such as CNS or soft tissue involvement).	At maximum 93 days from induction therapy start
Secondary	Percentage of Participants With Minimal Residual Disease (MRD) Negative Status	MRD- rate was defined as the rate of participants reaching MRD at any timepoint. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).; MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.	from start of treatment up to end of post-consolidation (approximately 17 months)
Secondary	Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase	MRD- rate was defined as the rate of participants reaching MRD at any timepoint during Post-consolidation phase. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).; MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.	from start of post-consolidation to end of post-consolidation phase (up to 12 months)
Secondary	Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry	Time to MRD- is defined as time from randomization to first occurrence of MRD-. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP).; MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.	From date of Randomization up to approx. 17 months
Secondary	Disease-free Survival (DFS)	DFS as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death due to any cause, whichever occurred first. Participants who did not relapse nor die were censored at the last adequate response assessment. Assessment was based on the IWG criteria for AML as per investigator assessment	From date of CR or CRi with adequate blood count recovery up to approx. 30 months
Secondary	Cumulative Incidence of Relapse (CIR)	Cumulative Incidence of Relapse (CIR) was defined for participants with CR or CRi with adequate blood count recovery and was the time from achieving the CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Participants without relapse were censored at the last adequate response assessment. Participants who died without relapse were counted as a competing cause of failure.	From date of CR or CRi with adequate blood count recovery up to approx. 30 months
Secondary	Cumulative Incidence of Death (CID)	Cumulative Incidence of Death (CID) was defined for all participants 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. Participants not known to have died were censored on the last contact date. Participants who experienced relapse were counted as a competing cause of failure.	From date of CR or CRi with adequate blood count recovery up to approx. 30 months
Secondary	Time to CR or CRi With Adequate Blood Count Recovery	Time to CR or CRi with adequate blood count recovery was defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurred first	At maximum 93 days from induction therapy start
Secondary	Time to Partial and Full Neutrophil Recovery	The time to neutrophil recovery was assessed for the following criteria: Partial neutrophil recovery: Number of days from start of treatment to the first day neutrophils =0.5 x 10^9/L.; Full neutrophil recovery: Number of days from start of treatment to the first day neutrophils =1.0 x 10^9/L	At maximum 93 days from induction therapy start
Secondary	Time to Partial and Full Platelet Recovery	Time to platelet recovery was assessed for the following criteria: Partial platelet recovery: Number of days from start of treatment to the first day platelets =50 x 10^9/L.; Full platelet recovery: Number of days from start of treatment to the first day platelets =100 x 10^9/L.	At maximum 93 days from induction therapy start
Secondary	Plasma Concentrations for Midostaurin and Its Metabolites: CGP52421 and CGP62221 for Non-poor Metabolizers	Serial pharmacokinetics (PK) samples were collected in Non-poor metabolizer participants to assess the plasma concentrations of midostaurin, CGP52421 and CGP62221.	from Induction (IND) phase 0hr (predose) to Post-consolidation phase (POSTCONS) 12hr
Secondary	AUC0-t: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8	The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time was at 12 h, AUC0-12h was determined after the first dose, reported at Cycle 1, Day 8	0 - 12 hrs
Secondary	AUClast: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8	The AUC from time zero to the last measurable concentration sampling time after the first dose reported at Cycle 1, Day 8	0 - 12 hrs
Secondary	Cmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8	The maximum (peak) observed plasma drug concentration after the first dose administration reported at Cycle 1, Day 8	0 - 12 hrs
Secondary	Tmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8	The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration reported at Cycle 1, Day 8	0 - 12 hrs
Secondary	Total Score for Each Time Point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)	The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better health-related quality of life ( HRQoL). Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.	From date of Randomization up to approx. 18 months
Secondary	Scores for Each Time Point for the EQ5D-5L (a Visual Analogue Scale (VAS))	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.	From date of Randomization up to approx. 18 months

External Links

•   A Plain Language Trial Summary is available on novctrd.com