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JOURNAL ONKOLOGIE – STUDIE

A Global Study of Midostaurin in Combination With Chemotherapy to Evaluate Safety, Efficacy and Pharmacokinetics in Newly Diagnosed Pediatric Patients With FLT3 Mutated AML

Rekrutierend

NCT-Nummer:
NCT03591510

Studienbeginn:
März 2019

Letztes Update:
05.04.2024

Wirkstoff:
Midostaurin, Fludarabine, Cytarabine, Daunorubicin or idarubicin, Mitoxantrone, Etoposide

Indikation (Clinical Trials):
Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
Phase 2

Sponsor:
Novartis Pharmaceuticals

Collaborator:
-

Studienleiter

Novartis Pharmaceuticals
Study Director
Novartis Pharmaceuticals

Kontakt

Studienlocations
(3 von 35)

Novartis Investigative Site
93053 Regensburg
(Bayern)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
13353 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
45147 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
79106 Freiburg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
06120 Halle
(Sachsen-Anhalt)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
80045 Aurora
United StatesZurückgezogen» Google-Maps
Novartis Investigative Site
33155 Miami
United StatesZurückgezogen» Google-Maps
Novartis Investigative Site
150 06 Praha 5
CzechiaRekrutierend» Google-Maps
Novartis Investigative Site
115 27 Athens
GreeceZurückgezogen» Google-Maps
Novartis Investigative Site
650-0047 Kobe-city
JapanZurückgezogen» Google-Maps
Novartis Investigative Site
157-8535 Setagaya-ku
JapanZurückgezogen» Google-Maps
Novartis Investigative Site
330 8777 Saitama
JapanZurückgezogen» Google-Maps
Novartis Investigative Site
420 8660 Shizuoka
JapanZurückgezogen» Google-Maps
Novartis Investigative Site
03080 Seoul
Korea, Republic ofRekrutierend» Google-Maps
Novartis Investigative Site
05505 Seoul
Korea, Republic ofRekrutierend» Google-Maps
Novartis Investigative Site
620149 Ekaterinburg
Russian FederationZurückgezogen» Google-Maps
Novartis Investigative Site
117198 Moscow
Russian FederationAktiv, nicht rekrutierend» Google-Maps
Novartis Investigative Site
1000 Ljubljana
SloveniaRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

This trial is an open label, multi center single arm study to evaluate twice daily oral

midostaurin with standard induction, consolidation chemotherapy with sequential midostaurin

therapy for 5 treatment blocks (2 induction blocks, 3 consolidation blocks, followed by

single agent midostaurin post consolidation therapy for 12 cycles).

The total maximum planned duration on treatment is 17 cycles (5 blocks and 12 cycles). A

block is defined as the time from start of study treatment to the time of hematopoietic

recovery, at the latest at Day (D) 42, or determination of persistent disease, whichever

occur first.

In both Part 1 and Part 2, patients will receive the first course of induction chemotherapy

according to local standard and duration is from 8 to 12 days. Upon FLT3 mutation

confirmation, patients will receive midostaurin for 14 days. After determination of remission

and hematopoietic recovery, patients will receive Block 2.

In Part 1:

- Block 2 FLADx treatment duration is D1 to D6, and midostaurin from D8 to D21. Patients

who achieve documented CR (and hematopoietic recovery at the latest at D42 from the

first day of Block 2) will receive Block 3.

- Block 3 consolidation HAM treatment duration is D1 to D4, followed by midostaurin D8 to

D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day

of Block 3 will receive Block 4. Patients who relapse will discontinue further study

treatment.

- Block 4 HA3E treatment duration is D1 to D5 followed by midostaurin D8 to D21. Patients

who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4

will receive Block 5.

- Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients

who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post

consolidation therapy of midostaurin, during 12 cycles (28 days per cycle).

In Part 1 of the study, patients in cohorts of 3 will receive sequential midostaurin

administered at 30mg/m2bid. If the 30mg/m2 bid is well tolerated as measured by the Dose

Limited Toxicity (DLT) rate during Bock 1, additional patients in cohort of 3 will be treated

with sequential midostaurin at 60mg/m2 bid. When the recommended phase 2 dose (RP2D) is

confirmed, subsequent patients will be treated in Part 2 of the study at the RP2D.

In Part 2:

- Block 2 HAM treatment duration is D1 to D4 and midostaurin from D8 to D21. Patients who

achieve documented CR (and hematopoietic recovery at the latest at D42 from the first

day of Block 2) will receive Block 3.

- Block 3 consolidation HA3E treatment duration is D1 to D5, followed by midostaurin D8 to

D21. Patients who achieve hematopoietic recovery at the latest at D42 from the first day

of Block 3 will receive Block 4. Patients who relapse will discontinue further study

treatment.

- Block 4 HAM treatment duration is D1 to D4 followed by midostaurin D8 to D21. Patients

who achieve hematopoietic recovery at the latest at D42 from the first day of Block 4

will receive Block 5.

- Block 5 HiDAC treatment duration is D1 to D3 followed by midostaurin D8 to D21. Patients

who relapse will discontinue further study treatment.

Patients in continuous remission with hematopoietic recovery will receive continuous post

consolidation therapy of midostaurin, during 12 cycles (28 days per cycle). Patients who

relapse will discontinue further study treatment.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Documented Diagnosis of previously untreated de novo AML according to WHO 2016

criteria

- Presence of a FLT3 mutation status as measured/confirmed by a designated lab with

results available prior first dose of Midostaurin

- Patients with Lansky or Karnofsky performance status equal or superior to 60

- Patient with the following laboratory value : AST and ALT ≤ 3times ULN

- Serum Total bilirubin ≤ 1.5times ULN

- Estimated creatinine clearance ≥30ml/min

Exclusion Criteria:

- Any concurrent malignancy, AML with Philadelphia Chromosome, AML-DS, JMML

- Symptomatic leukemic CNS involvement

- Isolated extramedullary leukemia, secondary AML and MDS

- Acute Promyelocytic Leukemia with the PML RARA rearrangement

- Patient who have received prior treatment with a FLT3 inhibitor. However, up to 1 week

of FLT3 inhibitor (except midostaurin) exposure prior to study enrollment is

permissible.

Other protocol-defined inclusion/exclusion criteria may apply

Studien-Rationale

Primary outcome:

1. Part 1 of the study: Occurence of dose limiting toxicities (DLT) (Time Frame - From the start of midostaurin treatment in Block 1 to the end of Block 2, from Day 1 to Day 84):
Dose-limiting toxicity (DLT) is defined as any death due to toxicity related to study treatment (chemotherapy + midostaurin) and/or any CTCAE grade 4 non-hematological adverse event or abnormal laboratory value grade 4 related to study treatment unless the event improves sufficiently by day 42 and therefore does not further delay the next cycle of study treatment.

2. Part 2 of the study: To evaluate Safety of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. (Time Frame - From the start of treatment up to 5 years follow-up of last patient):
Safety profile includes type, frequency and severity of adverse events during the induction, consolidation and post consolidation phase. AEs are also collected during post treatment follow-up phase

3. Part 2 of the study: To evaluate Tolerability of midostaurin (30mg/m2 bid or 1 mg/kg bid for participants <10 kg body weight) in sequential combination with chemotherapy followed by 12 cycles of midostaurin post-consolidation therapy. (Time Frame - From the start of treatment up to 5 years follow-up of last patient):
Number of dose interruptions/reductions and discontinuations due to study drug

Secondary outcome:

1. Part 2 of the study: Percentage of participants with response (CR, CR/modified CRi and CR/CRi) (Time Frame - From the start of treatment in Block 1 to the end of Block 2, from Day 1 up to Day 84):
Percentage of participants with a response of CR, CRi or modified CRi at the end of Block 2

2. Part 2 of the study: Time to response (TTR) and response duration (Time Frame - From the start of treatment up to 5 years follow-up of last patient):
TTR is defined as the time between start of treatment to the date of first onset of response (CR, CRi or modified CRi). Response duration is defined as the time from CR, CRi or modified CRi to relapse or death due to any cause.

3. Part 2 of the study: Event Free Survival (EFS) (Time Frame - From the start of treatment to time when all patients have completed at least 18 months of follow up (~ 48 months)):
EFS is defined as the time from Day 1 of chemotherapy until an EFS event is observed. An EFS event is defined as a failure to obtain CR/Modified CRi within induction, relapse after CR/modified CRi, or death due to any cause, whichever occurs first. EFS will be measured after all participants completed at least 18 months of follow-up.

4. Part 2 of the study: Overall Survival (OS) (Time Frame - At each visit, every 3 months after last follow-up visit and up to 5 years after last patient first treatment):
OS is defined as the time from Day 1 of chemotherapy to the date of death due to any cause.

5. Part 2 of the study: Disease free survival (DFS) (Time Frame - From the start of treatment up to 5 years follow-up of last patient):
DFS is defined as the time from CR/modified CRi in induction to relapse or death due to any cause

6. Part 2 of the study: Percentage of participants with MRD negative status during each study phase (Time Frame - MRD is evaluated at Day 14 after end of chemotherapy induction Block 1, at Day 21 of Blocks 2, 3, 4 and 5, and Cycle 7 during post-consolidation phase (each block could last up to 42 days)):
Percentage of patient with MRD negative status by multiparameter flow cytometry

7. Part 2 of the study: Palatability of oral solution of midostaurin (Time Frame - Day 14 after end of chemotherapy induction Block 1, Day 21 of Blocks 2, 3, 4 and 5 (each block can last up to 42 days), post-consolidation Cycle 1, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11):
Palatability is assessed through questionnaires- Palatability PRO and obsPRO

8. Part 2 of the study: Percentage of blasts in bone marrow and peripheral blood (Time Frame - Parameters are assessed 14 days after end of chemotherapy induction Block 1 and Day 14 induction Block 2):
Bone marrow and peripheral blood parameters and extramedullar involvement at the end of induction Block 1 and Block 2

9. Part 1 and Part 2 of the study: Plasma concentrations of midostaurin and its metabolites (Time Frame - Days 1, 7 & 14 after end of local chemotherapy-induction in Block 1, Days 14 & 21 of Block 2, Day 21 of Blocks 3, 4 & 5 (each block can last up to 42 days), in-post consolidation Day 1 of Cycle (C)2, C3, C5, C7, C9 and C12 (each cycle = 28 days)):
Plasma concentration of midostaurin and its 2 metabolites

Geprüfte Regime

  • Midostaurin (PKC412):
    midostaurin 30mg/m2 bid
  • Fludarabine (Part 1 Block 2 induction FLADx):
    30mg/m2/day on D1-D5 of Block 2 FLADx
  • Cytarabine (Part 1: / Block 2 induction FLADx / Block 3 consolidation HAM / Block 4 consolidation HA3E / Block 5 consolidation HIDAC / Part 2: / Block 2 induction HAM / Block 3 consolidation HA3E / Block 4 consolidation HAM / ):
    Part 1: 2000mg/m2/day D1 to D5 of Block 2 FLADx 1000mg/m2 every 12 hours D1 to D3 Block 3 HAM 3000mg/m2 every 12 hours D1 to D3 Block 4 HA3E 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC Part 2: 1000mg/m2 every 12 hours D1 to D3 Block 2 HAM 3000mg/m2 every 12 hours D1 to D3 Block 3 HA3E 1000mg/m2 every 12 hours D1 to D3 Block 4 HAM 3000mg/m2 every 12 hours D1 to D3 Block 5 HIDAC
  • Daunorubicin or idarubicin (Part 1 Block 2 induction FLADx):
    daunorubicin 60 mg/m2/day OR idarubicin 12mg/m2/day On D2, D4, D6 of Block 2 FLADx
  • Mitoxantrone (Part 1: / Block 3 consolidation HAM / Part 2: / Block 2 induction HAM / Block 4 consolidation HAM / ):
    10mg/m2/day D3 and D4
  • Etoposide (Part 1: / Block 4 consolidation HA3E / Part 2: / Block 3 consolidation HA3E / ):
    100mg/m2/day D1 to D5

Quelle: ClinicalTrials.gov


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