Clinical trial NCT03379727: 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.
Official title: An Open-label, Multi-Center, Phase IIIb Study to Assess the Safety and Efficacy of Midostaurin (PKC412) in Patients 18 Years of Age or Older With Newly-diagnosed FLT3-mutated Acute Myeloid Leukemia Who Are Eligible for "7+3" or "5+2" Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-12-20
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: This Phase IIIb study was designed as a single arm study and allowed the assessment of variation of the "7+3" regimen in an extended patient population compared to RATIFY (higher dose of daunorubicin (60-90 mg/m2/day), the substitution of daunorubicin by idarubicin (12mg/m2/day), and lower dose of cytarabine (100-200 mg/m2/day) and the "5+2" reduced dose regimen). Safety was the primary endpoint. Complete Response (CR)/Complete remission with incomplete hematological recovery (CRi) in induction, consolidation and maintenance therapy was collected as secondary endpoint.

Patients who were newly diagnosed with AML, had a known FLT3 ITD (Internal tandem duplication) or TKD (Tyrosine kinase domain)(, mutation and had recently started on "7+3" or "5+2" in induction and high dose of cytarabine in consolidation were consented and screened for the clinical study.

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The protocol treatment allowed the following treatment phases:

* Induction Phase: cytarabine with anthracycline (idarubicin or daunorubicin) sequentially per HCP choice, followed by midostaurin on day 8. In the first Induction phase, a bone marrow aspiration was performed in all subjects on Days 21- 28 (according to local standard of care) to determine the need for a second induction cycle. If the marrow aspirate was inadequate to make a determination, the bone marrow assessment was repeated within one week. If the Day 21-28 (according to local standard of care) bone marrow aspiration reveals ≥ 5% leukemic blasts in a cellular marrow (\> 20%) a second induction was given. For subjects requiring a second induction, treatment began at least 3 days after completing midostaurin. Bone marrow aspiration was performed within one week after recovery of ANC ≥ 1000/μL and platelets ≥ 100,000/μL to assess for response. Subjects in CR proceeded to consolidation therapy. Subjects not achieving a marrow remission (or with persistent blasts) were to be removed from protocol therapy. Subjects with CRi proceeded to consolidation therapy as per investigator's discretion. 1 or 2 cycles of "7+3" or "5+2" regimens (switching between regimens was not allowed).
* Consolidation Phase (for subjects in CR/CRi after consolidation therapy) (up to four cycles of cytarabine consolidation per investigator's discretion, with midostaurin given sequentially during each cycle): Based upon the superior results reported for AML subjects less than 60 years old with normal karyotypes in prospective clinical trials and RATIFY, who achieved a CR/CRi after induction received further therapy with midostaurin. Subjects received up to four cycles of consolidation therapy. Each consolidation cycle was four weeks in duration, and was to begin within two weeks following hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL), but not sooner than 31 days from the beginning of the previous cycle. A bone marrow aspiration was to be performed prior to the first consolidation cycle (C1D1) and later could be performed if necessary per investigator's decision at any time during Consolidation Phase.
* Maintenance Phase (for subjects in CR/CRi after consolidation therapy): Subjects who continued in CR/CRi (by bone marrow aspiration and blood evaluation) after four cycles of consolidation therapy received midostaurin. Prior to maintenance therapy, all significant acute toxicity from consolidation therapy was to be resolved to ≤ grade 2. Subjects with CRi proceeded to maintenance therapy as per investigator's discretion and for CR subjects maintenance therapy began after hematologic recovery (ANC ≥ 1000/μL, platelet count ≥ 100,000/μL) from remission consolidation, and at least 3 days after the last dose of midostaurin during consolidation. Subjects who were unable to complete four courses of HiDAC consolidation because of toxicity could still be eligible for maintenance therapy at the discretion of the principal investigator after the last dose of consolidation after recovery from hematologic and other significant acute toxicity. A bone marrow examination was to be performed prior to the first maintenance and every 3 months during Maintenance phase. Maintenance phase was up to 12 cycles of maintenance therapy with single-agent midostaurin or until relapse, unacceptable toxicity, or death, physician's decision, subject/guardian's 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 occured first.

Eligibility criteria: Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Written informed consent must be obtained prior to any screening procedures.
2. Patients must be 18 years of age or older at the time of signing informed consent.
3. 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).
4. 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.
5. Patients must have started "7+3" or "5+2" first induction chemotherapy regimen.
6. Patients must have a documented FLT3 mutation (ITD or TKD).).
7. Patients must have an ECOG Performance Status of ≤ 2
8. Patients requiring intrathecal chemotherapy must have a minimum washout of 48 hours prior to the first dose of midostaurin
9. Patients must have Total Bilirubin ≤ 2.5 x ULN
10. Patients must have Serum Creatinine ≤ 2.5 x ULN
11. Patients must be able to communicate well with the investigator to understand and comply with the requirements of the study
12. Women of child-bearing potential must have a negative pregnancy test before starting use of midostaurin.

Exclusion criteria:

Patients eligible for this study must not meet any of the following criteria:

1. Prior therapy for AML with the following exceptions:

   1. emergency leukapheresis
   2. emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 7 days
   3. cranial RT for CNS leukostasis (one dose only)
   4. growth factor/cytokine support
2. 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
3. Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolved to ≤ Grade 1 within screening timeframe)
4. Patients with any uncontrolled illness, including, but not limited to, acute or chronic pancreatitis or uncontrolled infection
5. QTc \>470 msec on screening ECG.
6. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study treatment.
7. 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.
8. 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
   * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
   * Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
   * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception.

   In case of use of oral contraception women should also add a barrier method of contraception, particularly as it is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives.

   Sexually-active males unless they use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment to avoid conception or embryo-fetal harm.
9. Patients enrolled in this study are not permitted to participate in additional parallel study drug or device studies.

Primary outcomes:
measure: 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).
timeFrame: Baseline up to approximatly 24 months
Secondary outcomes:
measure: Percentage of Patients With Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (CRi) as Per Local Assessment
timeFrame: Baseline up to approximately 24 months
Other outcomes:
Locations:
city: Pleven
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Varna
country: Bulgaria
facility: Novartis Investigative Site
city: Zagreb
country: Croatia
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Tallinn
country: Estonia
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Oulu
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Bayonne
country: France
facility: Novartis Investigative Site
state: Bayonne Cedex
city: Saint Priest en Jarez
country: France
facility: Novartis Investigative Site
state: Loire
city: Besancon cedex
country: France
facility: Novartis Investigative Site
city: Clamart
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Dijon
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Limoges cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Metz
country: France
facility: Novartis Investigative Site
city: Nice Cedex
country: France
facility: Novartis Investigative Site
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Ancona
country: Italy
facility: Novartis Investigative Site
state: AN
city: Avellino
country: Italy
facility: Novartis Investigative Site
state: AV
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Cuneo
country: Italy
facility: Novartis Investigative Site
state: CN
city: Cosenza
country: Italy
facility: Novartis Investigative Site
state: CS
city: San Giovanni Rotondo
country: Italy
facility: Novartis Investigative Site
state: FG
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Lecce
country: Italy
facility: Novartis Investigative Site
state: LE
city: Latina
country: Italy
facility: Novartis Investigative Site
state: LT
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Piacenza
country: Italy
facility: Novartis Investigative Site
state: PC
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Pescara
country: Italy
facility: Novartis Investigative Site
state: PE
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Parma
country: Italy
facility: Novartis Investigative Site
state: PR
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Salerno
country: Italy
facility: Novartis Investigative Site
state: SA
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Venezia
country: Italy
facility: Novartis Investigative Site
state: VE
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Bergen
country: Norway
facility: Novartis Investigative Site
city: Craiova
country: Romania
facility: Novartis Investigative Site
city: Iasi
country: Romania
facility: Novartis Investigative Site
city: Belgrade
country: Serbia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Banska Bystrica
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Palma De Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Pozuelo de Alarcon
country: Spain
facility: Novartis Investigative Site
state: Madrid
city: Gasteiz
country: Spain
facility: Novartis Investigative Site
state: País Vasco
city: La Laguna
country: Spain
facility: Novartis Investigative Site
state: Santa Cruz De Tenerife
city: Las Palmas de Gran Canaria
country: Spain
facility: Novartis Investigative Site
city: Leon
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: Boras
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: