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EUCTR2017-003540-21 | SNCTP000003003

Studie zur Behandlung von Patienten mit akuter myeloischer Leukämie (AML) ohne FLT3-Mutation mit Standard-Chemotherapie in Kombination mit Midostaurin (PKC412) oder Placebo

Data source: BASEC (Imported from 28.01.2020), WHO (Imported from 26.01.2020)
Changed: 14.01.2020
Disease category: Leukämie

Brief description of trial (Source of data: BASEC)

Ziel dieser Studie ist es festzustellen, ob die kombinierte Behandlung mit Midostaurin und der Standard-Chemotherapie (einschliesslich Daunorubicin oder Idarubicin und Cytarabin) bei der Behandlung von AML ohne FLT3-Mutation sicher ist und zu vergleichen, ob sie auch wirksamer ist als die Behandlung mit Placebo und Standard-Chemotherapie. Midostaurin ist ein Hemmer des FLT3-Proteins (sowohl in mutierter als auch nicht mutierter Form) und anderer Proteine, die an der Entstehung von AML beteiligt sein könnten.
An dieser Studie werden weltweit ca. 502 erwachsene Patienten in verschiedenen Ländern teilnehmen.
Patienten werden nach dem Zufallsprinzip einer Behandlung mit Midostaurin oder Placebo zugewiesen, jeweils in Kombination mit der Standard-Chemotherapie, Daunorubicin oder Idarubicin und Cytarabin. Die Wahrscheinlichkeit ist für jede Behandlung «gleich hoch», d. h. jeweils 50 % (wie beim Werfen einer Münze). Ein Placebo ist ein Scheinmedikament ohne Wirkstoff und wird verwendet, um sicherzustellen, dass die Beobachtungen während dieser Studie nicht rein zufällig sind.
Die Behandlungsphase kann insgesamt 17 bis 20 Monate andauern. Midostaurin- oder Placebo-Kapseln werden zweimal täglich eingenommen. An den Tagen mit Chemotherapiebehandlung und ab 2 Tage vor der nächsten Chemotherapiebehandlung wird Midostaurin oder das entsprechende Placebo nicht eingenommen. Nach Abschluss der Chemotherapie werden weiterhin zweimal pro Tag eine Midostaurin- oder Placebo-Kapsel eingenommen.
Nach Abschluss der Behandlung oder frühzeitigem Abbruch der Studie findet eine Visite zum Behandlungsende statt, gefolgt von einer Visite oder einem Telefongespräch als Sicherheitsnachkontrolle, ca. 30 Tage nach der letzten Medikamenteneinnahme. Anschliessend wird alle 3 Monate eine Nachkontrolle stattfinden, um den Gesundheitsstatus zu beurteilen. Diese Nachkontrollphase dauert bis zu 5 Jahre nach der letzten Behandlung des letzten Studienpatienten.

Health conditions investigated (Source of data: BASEC)

In dieser Studie werden Patienten untersucht, die an neu diagnostizierter akuter myeloischer Leukämie (AML) ohne FLT3-Mutation (FLT3 negativ) leiden.

Health conditions (Source of data: WHO)

newly diagnosed FLT3 non-mutated acute myeloid leukemia
MedDRA version: 20.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864 ;Therapeutic area: Diseases [C] - Cancer [C04]

Rare disease (Source of data: BASEC)

No

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

Midostaurin oder Placebo werden in Form von 50 mg Kapseln zweimal täglich ungefähr zur selben Zeit eingenommen. Zwischen den einzelnen Einnahmen morgens und abends sollen ungefähr 12 Stunden liegen. Die Medikamente sollten beim Essen mit einem Glas Wasser eingenommen werden.

Interventions (Source of data: WHO)


Trade Name: Rydapt
Product Code: PKC412
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: midostaurin
CAS Number: 120685-11-2
Other descriptive name: MIDOSTAURIN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, soft
Route of administration of the placebo: Oral use

Criteria for participation in trial (Source of data: BASEC)

- Patienten über 18, die an neu diagnostizierter akuter myeloischer Leukämie (AML) ohne FLT3-Mutation (FLT3 negativ) leiden Behandlung mit mindestens 2 vorherigen Tyrosinkinase-Inhibitoren (TKI)

- Patienten müssen geeignet für Chemotherapie sein

Exclusion criteria (Source of data: BASEC)

- AML aufgrund vorheriger Therapien

- Vorbehandlung mit bestimmten Medikamenten

- Schwangere oder stillende Frauen, sowie gebärfähige Frauen, die keine hochwirksame Verhütung anwenden. Männliche Teilnehmer müssen ein Kondom verwenden.

Inclusion/Exclusion Criteria (Source of data: WHO)

Inclusion criteria:
1. Diagnosis of AML (=20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL (acute promyelocytic leukemia) 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 FLT3 screening laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type ratio.
4. Age = 18 years
5. Laboratory values that indicate adequate organ function assessed locally at the screening visit:
• AST = 3 times ULN
• Alanine aminotransferase (ALT) = 3 times ULN
• Serum total bilirubin = 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome
• Estimated (by Cockcroft-Gault) creatinine clearance = 30ml/min
6. Written informed consent must be obtained prior to any screening procedures.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 452
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50

Exclusion criteria:
1. Central nervous system (CNS) leukemia
2. Therapy-related secondary AML
3. Isolated extramedullary leukemia
4. Prior therapy for leukemia or myelodysplasia with the following exceptions:
a) Emergency leukapheresis
b) Emergency treatment for hyperleukocytosis with hydroxyurea or low-dose cytarabine for = 7 days
c) Cranial RT for CNS leukostasis (one dose only)
d) Hematopoietic Growth factor/cytokine support
e) Other supportive therapy including antibiotics at the discretion of the investigator
5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
6. Any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to Day 1. An investigational agent is defined as an agent with no approved medical use in adults or in pediatric patients.
7. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
8. Strong CYP3A4/5 enzyme inducing drugs unless they can be discontinued or replaced prior to enrollment.
9. Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study.
10. Abnormal chest X-ray with corresponding clinical symptoms or findings that indicate an active infection, or other pulmonary conditions that are currently clinically significant.
11. Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.
12. Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not mandatory to exclude these viral infections).
13. Cardiovascular abnormalities, including any of the following:
• History of MI, angina pectoris, CABG within 6 months prior to starting study treatment
• Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
• Uncontrolled congestive heart failure
• Left ventricular ejection fraction of <50%,
• Poorly controlled hypertension
14. Pregnant or nursing (lactating) women
15. 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.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
16. Sexually active males unless the

Further information on the trial in WHO primary registry

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003540-21

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2017-003540-21-HU

Further information on trial

Date trial registered

22.06.2018

Incorporation of the first participant

21.06.2018

Recruitment status

Not Recruiting

Academic title (Source of data: WHO)

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)

Type of trial (Source of data: WHO)

Interventional clinical trial of medicinal product

Design of the trial (Source of data: WHO)

Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Phase (Source of data: WHO)

Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Primary end point (Source of data: WHO)

Main Objective: To determine if the addition of midostaurin to standard induction and consolidation therapy, followed by single agent post-consolidation therapy improves EFS in patients with newly diagnosed FLT3-MN (SR<0.05) AML.;
Secondary Objective: Key: determine if addition of midostaurin to standard induction + consolidation, followed by single agent post-consolidation improves OS in pts with newly diagnosed FLT3-MN AML
1. Compare CR + CRi with adequate recovery rate in the 2 treatment groups
2. Compare percentage of pts who reached MRD neg status in the 2 groups
3. Compare percentage of pts with MRD neg status in the post-consolidation phase in the 2 groups
4. Compare time to MRD neg bone marrow between the 2 treatment arms in the 2 groups
5. Compare DFS, as well as CIR and CID in the 2 groups
6. Compare time to CR or CRi
7. Compare time to neutrophil recovery in the 2 groups
8. Compare time to platelet recovery in the 2 treatment groups
9. Assess safety and tolerability of midostaurin in combination with chemotherapy and as monotherapy during post-consolidation
10. Characterize PK of midostaurin, CGP52421 and CGP62221
11. Assess impact of midostaurin on health related quality of life and AML symptom reduction
;
Primary end point(s): EFS defined as the time from randomization to failure to obtain a CR or 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 occurs first as assessed by the investigator.
;
Timepoint(s) of evaluation of this end point: Response disease assessment at end of each cycle and every 3 months during post-treatment follow-up
Interim analysis at 12 and 20 months, final analysis at 39 months

Secundary end point (Source of data: WHO)


Secondary end point(s): Key secondary endpoint: Overall survival is defined as the time from randomization to date of death due to any cause.
1. CR and CRi with adequate recovery rate according to the International Working Group (IWG) for AML (Cheson et al 2003, ELN 2017) as per investigator assessment.
2. Percentage of patients with MRD negative status.
3. Percentage of patients with MRD negative status during post-consolidation phase
4. Number of days from date of randomization to first documented MRD negative
5. DFS, as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death from any cause, whichever occurs first.
CIR is defined for patients with CR or CRi with adequate blood count recovery: time from achieving CR or CRi with adequate blood count recovery until onset of relapse. Patients without relapse are censored at the last adequate response assessment. Patients who died without relapse are counted as a competing cause of failure.
CID is defined for patients with CR or CRi with adequate blood count recovery: time from achieving CR or CRi with adequate blood count recovery until death. Patients who did not die are censored at the last contact date. Patients who relapsed are counted as a competing cause of failure.
6. Number of days from date of randomization to first documented CR or
CRi with adequate blood count recovery.
7. Number of days from the first day of a chemotherapy cycle to first day neutrophils =0.5 x 10^9/L.
Number of days from day 1 of commencing induction therapy to first day neutrophils =1.0 x 10^9/L.
8. Number of days from the first day of a chemotherapy cycle to first day platelets =50 x 10^9/L.
Number of days from day 1 of commencing induction therapy to first day platelets =100 x10^9/L.
9. Frequency/severity of AEs, and laboratory abnormalities.
10. Plasma concentrations and pharmacokinetic parameters for midostaurin, CGP52421 and CGP62221.
11. Change from baseline score for each time point for the FACT-Leu and
the EQ5D-5L (visual analogue scale (VAS)) by treatment arm.
;
Timepoint(s) of evaluation of this end point: Key secondary endpoint: at 20, 39 and 64 months
1. at end of each cycle and every 3 months during post-treatment follow-up
2.-4. MRD assessed at end of each induction cycle, first cycle of consolidation, end of consolidation phase, cycle 4, cycle 7 and cycle 10 of post-consolidation and every 3 months during post-treatment
5. at end of each cycle and every 3 months during post-treatment follow-up
6. at end of each induction cycle
7. and 8. at various points throughout the duration of the trial (see protocol for details)
9. throughout the trial
10. at various points throughout the duration of the trial (see protocol for details)
11. start of each induction cycle, end of each consolidation cycle, start of each post-consolidation cycle, every 6 months during post-treatment follow-up

Contact information (Source of data: WHO)

Novartis Pharma AG

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Bern, Zürich

Countries (Source of data: WHO)

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

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

Patrick Seitz
+41 79 461 09 24
patrick.seitz@novartis.com

Contact for general information (Source of data: WHO)

Public Information Desk
Bartók Béla út 43-47.
Novartis Hungary Kft.
00 36 1 457-6500
infoph.hungary@novartis.com

Contact for scientific information (Source of data: WHO)

Public Information Desk
Bartók Béla út 43-47.
Novartis Hungary Kft.
00 36 1 457-6500
infoph.hungary@novartis.com

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Novartis Pharma AG

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2018-00606

Secondary ID (Source of data: WHO)

CPKC412E2301;2017-003540-21-BE