Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Combination With Standard Chemotherapy During Induction and Consolidation Followed by 12 Months of Maintenance Monotherapy in Patients With Newly-diagnosed FMS-like Tyrosine 3 (FLT3) Kinase Receptor-mutated Acute Myeloid Leukemia.

NCT03379727 | Completed Phase 3 Results

• 2 other identifiers: CPKC412A24082016-004440-12
• Study Type: interventional
• Target: 301
• Locations: 13 countries
• Sites: 83

Brief Summary

The purpose of this study was 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 were eligible for standard induction and consolidation

Conditions

Acute Myeloid Leukemia

Keywords

Midostaurin; PKC412; FMS-like tyrosine kinase receptor; FLT3; Acute Myeloid Leukemia; AML; 7+3 chemotherapy; 5+2 chemotherapy; Daunorubicin; Idarubicin; Cytarabine

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients With Adverse Events (AEs), Grade 3 & 4 AEs, Serious Adverse Events (SAEs), AEs Leading to Discontinuation, and Deaths up to 24 Months (M24).

  Safety of Midostaurin was represented by various types of AEs, SAEs \& death up to M24. AE: the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. AE grades to characterize the severity of AEs were based on the Common Terminology Criteria for AEs ver. 4.03 with Grade (Gr) 1: mild; Gr 2: moderate; Gr 3: severe; Gr 4: life-threatening; Gr 5: death related to AE. AEs not related to hematological toxicities were generally of grade 1 or 2 severity. SAE: 1 of the following: is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, i.e. an event that jeopardizes the patient or may require medical or surgical intervention to prevent 1 of the outcomes listed above, requires inpatient hospitalization or prolongation of existing hospitalization with a few exceptions.

  Baseline up to approximatly 24 months

Secondary Outcomes (1)

• Percentage of Patients With Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (CRi) as Per Local Assessment

  Baseline up to approximately 24 months

Study Arms (1)

Midostaurin

EXPERIMENTAL

Patients went through 3 phases: Induction phase - Day (D)8 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; Drug: Cytarabine; Drug: anthracycline ((daunorubicin or idarubicin): Induction Phase only

Interventions

Midostaurin DRUG

Induction Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for 1 - 2 cycles; a cycle = 28 days; Consolidation Phase: 50 mg (two 25 mg capsules) twice a day by mouth on days 8-28, for up to 4 cycles; Maintenance Phase: Continuous dosing (days 1 - 28) for up yo 12 cycles or until relapse, unacceptable toxicity, death, physician's decision, subject/guardian decision, protocol deviation, study termination by Sponsor, lost to follow-up, technical problems, pregnancy, subject withdrew consent, or until the end of study, whichever event occurred first.

Also known as: PKC412

Midostaurin

Cytarabine DRUG

Induction Phase (standard dose) (7 + 3 arm): 100-200 mg/m2/day by Continuous intravenous infusion (CIVI) days 1-7 (168 hours infusion); Induction Phase (5 + 2 arm): 100 mg/m2/day by CIVI days 1-5; Consolidation Phase: 1-3 g/m2 infusion over 3 hours every 12 h on days 1, 3 and 5, up to 4 cycles based on age and per investigator discretion

Midostaurin

anthracycline ((daunorubicin or idarubicin): Induction Phase only DRUG

daunorubicin (7 + 3 arm): 60-90 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); daunorubicin (5 + 2 arm): 60 mg/m2/day by IV push on days 1-2; idarubicin (7 + 3 arm): 12 mg/m2/day by IV push on days 1-3 (with standard-dose cytarabine); idarubicin (5 + 2 arm): 12 mg/m2/day by IV push on days 1-2

Midostaurin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (86)

Novartis Investigative Site

Pleven, 5800, Bulgaria

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Novartis Investigative Site

Sofia, 1413, Bulgaria

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Novartis Investigative Site

Sofia, 1756, Bulgaria

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Novartis Investigative Site

Varna, 9000, Bulgaria

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Novartis Investigative Site

Zagreb, 10000, Croatia

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Novartis Investigative Site

Brno, 625 00, Czechia

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Novartis Investigative Site

Prague, 100 34, Czechia

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Novartis Investigative Site

Tallinn, 13419, Estonia

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Novartis Investigative Site

Helsinki, FIN 00290, Finland

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Novartis Investigative Site

Oulu, FIN-90220, Finland

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Novartis Investigative Site

Tampere, 33521, Finland

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Novartis Investigative Site

Bayonne, Bayonne Cedex, 64109, France

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Novartis Investigative Site

Saint Priest En Jarez, Pays de la Loire Region, 42270, France

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Novartis Investigative Site

Besançon, 25030, France

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Novartis Investigative Site

Clamart, 92141, France

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Novartis Investigative Site

Créteil, 94010, France

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Novartis Investigative Site

Dijon, 21034, France

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Novartis Investigative Site

Lille, 59037, France

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Novartis Investigative Site

Limoges, 87042, France

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Novartis Investigative Site

Lyon, 69373, France

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Novartis Investigative Site

Metz, 57085, France

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Novartis Investigative Site

Nice, 06202, France

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Novartis Investigative Site

Paris, 75012, France

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Novartis Investigative Site

Paris, 75475, France

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Novartis Investigative Site

Pierre-Bénite, 69495, France

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Novartis Investigative Site

Poitiers, 86000, France

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Novartis Investigative Site

Villejuif, 94800, France

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Novartis Investigative Site

Budapest, 1085, Hungary

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Novartis Investigative Site

Szeged, H 6725, Hungary

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Novartis Investigative Site

Ancona, AN, 60126, Italy

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Novartis Investigative Site

Avellino, AV, 83100, Italy

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Novartis Investigative Site

Bergamo, BG, 24127, Italy

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Novartis Investigative Site

Bologna, BO, 40138, Italy

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Novartis Investigative Site

Brescia, BS, 25123, Italy

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Novartis Investigative Site

Cuneo, CN, 12100, Italy

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Novartis Investigative Site

Cosenza, CS, 87100, Italy

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Novartis Investigative Site

San Giovanni Rotondo, FG, 71013, Italy

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Novartis Investigative Site

Florence, FI, 50134, Italy

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Novartis Investigative Site

Genova, GE, 16132, Italy

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Novartis Investigative Site

Lecce, LE, 73100, Italy

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Novartis Investigative Site

Latina, LT, 04100, Italy

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Novartis Investigative Site

Monza, MB, 20900, Italy

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Novartis Investigative Site

Milan, MI, 20122, Italy

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Novartis Investigative Site

Milan, MI, 20132, Italy

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Novartis Investigative Site

Milan, MI, 20162, Italy

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Novartis Investigative Site

Rozzano, MI, 20089, Italy

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Novartis Investigative Site

Modena, MO, 41124, Italy

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Novartis Investigative Site

Palermo, PA, 90146, Italy

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Novartis Investigative Site

Piacenza, PC, 29100, Italy

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Novartis Investigative Site

Padua, PD, 35128, Italy

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Novartis Investigative Site

Pescara, PE, 65124, Italy

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Novartis Investigative Site

Perugia, PG, 06100, Italy

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Novartis Investigative Site

Parma, PR, 43100, Italy

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Novartis Investigative Site

Reggio Emilia, RE, 42123, Italy

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Novartis Investigative Site

Roma, RM, 00128, Italy

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Novartis Investigative Site

Roma, RM, 00133, Italy

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Novartis Investigative Site

Roma, RM, 00161, Italy

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Novartis Investigative Site

Roma, RM, 00168, Italy

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Novartis Investigative Site

Salerno, SA, 84131, Italy

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Novartis Investigative Site

Siena, SI, 53100, Italy

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Novartis Investigative Site

Torino, TO, 10128, Italy

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Novartis Investigative Site

Venezia, VE, 30174, Italy

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Novartis Investigative Site

Verona, VR, 37126, Italy

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Novartis Investigative Site

Napoli, 80131, Italy

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Novartis Investigative Site

Napoli, 80132, Italy

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Novartis Investigative Site

Vilnius, LT-08661, Lithuania

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Novartis Investigative Site

Bergen, 5021, Norway

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Novartis Investigative Site

Craiova, 200136, Romania

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Novartis Investigative Site

Iași, 700483, Romania

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Novartis Investigative Site

Belgrade, 11000, Serbia

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Novartis Investigative Site

Bratislava, Slovak Republic, 833 10, Slovakia

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Novartis Investigative Site

Banská Bystrica, 975 17, Slovakia

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Novartis Investigative Site

Bratislava, 85107, Slovakia

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Novartis Investigative Site

Palma de Mallorca, Balearic Islands, 07120, Spain

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Novartis Investigative Site

Vitoria-Gasteiz, Basque Country, 01009, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08026, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

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Novartis Investigative Site

Pozuelo de Alarcón, Madrid, 28223, Spain

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Novartis Investigative Site

San Cristóbal de La Laguna, Santa Cruz De Tenerife, 38320, Spain

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Novartis Investigative Site

Las Palmas de Gran Canaria, 35010, Spain

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Novartis Investigative Site

León, 24080, Spain

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Novartis Investigative Site

Madrid, 28006, Spain

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Novartis Investigative Site

Madrid, 28046, Spain

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Novartis Investigative Site

Valencia, 46026, Spain

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Novartis Investigative Site

Borås, 501 82, Sweden

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Novartis Investigative Site

Uppsala, SE-751 85, Sweden

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Related Publications (1)

• Sierra J, Montesinos P, Thomas X, Griskevicius L, Cluzeau T, Caillot D, Legrand O, Minotti C, Luppi M, Farkas F, Bengoudifa BR, Gilotti G, Hodzic S, Rambaldi A, Venditti A. Midostaurin plus daunorubicin or idarubicin for young and older adults with FLT3-mutated AML: a phase 3b trial. Blood Adv. 2023 Nov 14;7(21):6441-6450. doi: 10.1182/bloodadvances.2023009847.

  PMID: 37581981 DERIVED

Related Links

• Plain Language Trial Summary

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

midostaurin; Cytarabine; Anthracyclines; Daunorubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2017
• First Posted: December 20, 2017
• Study Start: February 13, 2018
• Primary Completion: July 9, 2021
• Study Completion: July 9, 2021
• Last Updated: February 29, 2024
• Results First Posted: February 8, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

SL (3); FR (16); RO (2); ES (11); HU (2); CZ (2); NO (1); BU (4); IT (36); LI (1); SE (1); CR (1); FI (3)