HOVON 156 Treatment with Gilteritinib or Midostaurin in combination with intensive chemotherapy for patients with previously untreated acute myeloid leukemia (AML) or previously untreated myelodysplastic syndrome (MDS-EB2) with FLT3 mutation.

Australia, Austria, Belgium, Finland, France, Germany, Ireland, Lithuania, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland (ICTRP)

ID di studio ICTRP
NCT04027309 (ICTRP)

Titolo ufficiale (approvato dal comitato etico)
HOVON-156 Trial: A phase 3, multicenter, open-label, randomized, study of Gilteritinib versus Midostaurin in combination with induction and consolidation therapy followed by one-year maintenance in patients with newly diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations eligible for intensive chemotherapy (BASEC)

Titolo accademico
A Phase 3, Multicenter, Open-label, Randomized, Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes With Excess Blasts-2 (MDS-EB2) With FLT3 Mutations Eligible for Intensive Chemotherapy (HOVON 156 AML / AMLSG 28-18) (ICTRP)

Titolo pubblico
A Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndromes With Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy (ICTRP)

Malattie studiate
Acute Myeloid Leukemia;Myelodysplastic Syndrome With Excess Blasts-2 (ICTRP)

Intervento studiato
Drug: Gilteritinib;Drug: Midostaurin (ICTRP)

Tipo di studio
Interventional (ICTRP)

Disegno dello studio
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Criteri di inclusione/esclusione
Gender: All
Maximum age: N/A
Minimum age: 18 Years
Inclusion Criteria:

- Age =18 years

- Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO
criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or
ITD or both). AML may be secondary to prior hematological disorders, including MDS,
and/or therapy-related. Patients may have had previous treatment with erythropoiesis
stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of
MDS. ESA and HMAs have to be stopped at least four weeks before registration.

- FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD
mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of = 0.05
(5%).

- Considered to be eligible for intensive chemotherapy

- Patient is suitable for oral administration of study drug

- WHO/ECOG performance status = 2

- Adequate hepatic function as evidenced by

- Serum total bilirubin = 2.5 ? upper limit of normal (ULN) unless considered due
to leukemic involvement following written approval by the (co) Principal
Investigator

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) = 3.0 ? ULN, unless considered due to leukemic involvement
following written approval by the (co) Principal Investigator

- Adequate renal function as defined by creatinine clearance > 40 mL/min based on the
Cockroft-Gault glomerular filtration rate (GFR)

- Written informed consent

- Patient is capable of giving informed consent

- Female patient must either:

- Be of nonchildbearing potential:

- Postmenopausal (defined as at least 1 year without any menses) prior to
screening, or

- Documented surgically sterile or status posthysterectomy (at least 1 month
prior to screening)

- Or, if of childbearing potential,

- Agree not to try to become pregnant during the study and for 6 months
after the final study drug administration

- And have a negative urine or serum pregnancy test at screening

- And, if heterosexually active, agree to consistently use highly effective*
contraception per locally accepted standards in addition to a barrier
method starting at screening and throughout the study period and for 6
months after the final study drug administration.

- Highly effective forms of birth control include:

- Consistent and correct usage of established hormonal contraceptives
that inhibit ovulation,

- Established intrauterine device (IUD) or intrauterine system (IUS),

- Bilateral tubal occlusion,

- Vasectomy (A vasectomy is a highly effective contraception method
provided the absence of sperm has been confirmed. If not, an
additional highly effective method of contraception should be used.)

- Male is sterile due to a bilateral orchiectomy.

- Sexual abstinence is considered a highly effective method only if
defined as refraining from heterosexual activity during the entire
period of risk associated with the study drug. The reliability of
sexual abstinence needs to be evaluated in relation to the duration
of the clinical study and the preferred and usual lifestyle of the
patient.

- (*)List is not all inclusive. Prior to enrollment, the investigator is
responsible for confirming patient will utilize highly effective forms of
birth control per the requirements of the CTFG Guidance document
'Recommendations related to contraception and pregnancy testing in
clinical trials', September 2014 (and any updates thereof) during the
protocol defined period.

- Female patient must agree not to breastfeed starting at screening and
throughout the study period, and for 2 months and 1 week after the final study
drug administration.

- Female patient must not donate ova starting at screening and throughout the
study period, and for 6 months after the final study drug administration.

- Male patient and their female partners who are of childbearing potential must be
using highly effective contraception per locally accepted standards in addition to a
barrier method starting at screening and continue throughout the study period and
for 4 months and 1 week after the final study drug administration.

- Male patient must not donate sperm starting at screening and throughout the study
period and for 4 months and 1 week after the final study drug administration.

- Patient agrees not to participate in another interventional study while on treatment

Exclusion Criteria:

- Prior chemotherapy for AML or MDS-EB2, including prior treatment with
hypomethylating agents. Hydroxyurea is allowed for the control of peripheral
leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts >
30 x 10^9/L)

- Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic
variant fusion genes/chromosome translocations

- Blast crisis after CML

- Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any
excipients

- Patient requires treatment with concomitant drugs that are strong inducers of
cytochrome P450 (CYP) 3A

- Breast feeding at start of study treatment

- Active infection, including hepatitis B or C or HIV infection that is uncontrolled
at randomization. An infection controlled with an approved or closely monitored
antibiotic/antiviral/antifungal treatment is allowed.

- Patients with a currently active second malignancy. Patients are not considered to
have a currently active malignancy if they have completed therapy and are considered
by their physician to be at less than 30% risk of relapse within one year. However,
patients with the following history/concurrent conditions are allowed:

- Basal or squamous cell carcinoma of the skin;

- Carcinoma in situ of the cervix;

- Carcinoma in situ of the breast;

- Incidental histologic finding of prostate cancer

- Significant active cardiac disease within 6 months prior to the start of study
treatment, including:

- New York Heart Association (NYHA) Class III or IV congestive heart failure;

- Myocardial infarction;

- Unstable angina and/or stroke;

- Left ventricular ejection fraction (LVEF) < 40% by ECHO or MUGA scan obtained
within 28 days prior to the start of study treatment

- QTc interval using Fridericia's formula (QTcF) = 450 msec (average of triplicate
determinations) or other factors that increase the risk of QT prolongation or
arrhythmic events (e.g., heart failure, family history of long QT interval
syndrome). Prolonged QTc interval associated with bundle branch block or pa (ICTRP)

non disponibile

Endpoint primari e secondari
Overal survival (OS) (ICTRP)

Event-free survival (EFS);CR rate after remission induction;EFS with modified CR (mEFS);CR and CRi rates after induction cycle 1 and after induction cycle 2;Relapse-free survival (RFS) after CR;Cumulative incidence of relapse (CIR) after CR;Cumulative incidence of death (CID) after CR;CR without minimal residual disease (CRMRD-) rate after induction cycle 2;CR or CRi without minimal residual disease (CR/CRiMRD-) rate after induction cycle 2;Frequency and severity of adverse events according to CTCAE v5.0;Time to hematopoietic recovery after each chemotherapy treatment cycle;Allogeneic stem cell transplantation (allo-SCT) rate;Individual domain scores and visual analogue scale (VAS) score of the European Quality of Life 5 Dimensions (EQ-5D-5L) Questionnaire;Individual subdomain scores and the global health status/QoL scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (ICTRP)

Data di registrazione
non disponibile

Inclusione del primo partecipante
non disponibile

Sponsor secondari
Deutsch-?sterreichische Studiengruppe Akute Myeloische Leuk?mie (AMLSG);Astellas Pharma Global Development, Inc. (ICTRP)

Contatti aggiuntivi
M. Raaijmakers, Prof. Dr., Erasmus MC / HOVON (ICTRP)

ID secondari
2018-000624-33, AMLSG 28-18, Pasha, HO156 (ICTRP)

Risultati-Dati individuali dei partecipanti
non disponibile

Ulteriori informazioni sullo studio
https://clinicaltrials.gov/ct2/show/NCT04027309 (ICTRP)