Prospective evaluation of a continuation therapy with Midostaurin in adult patients withcore-binding factor leukemia and integrated genetic analysis: a multi-center phase II study

Phase 1

• Conditions: Acute Myeloid Leukemia (AML); MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2017-002094-18-IT
• Lead Sponsor: AZIENDA OSPEDALIERA AO OSPEDALE NIGUARDA CA' GRANDA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-06-17
• Last Update Posted: 2 August 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 39

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 to 65 years of age at the time of signing informed consent.
3. Patients must have an unequivocal diagnosis of de novo-CBFL, prior to start Midostaurin,
documented by rearrangement of Core Binding Factor (CBF) genes, namely AML1-ETO and CBFBMYH11,
either with observation of t(8;21)(q22;q22) or inv(16)(p13; q32)/t(16;16)(p13; q32) by
conventional cytogenetics or hybridization techniques or detection of fusion genes by PCR
4. Patients must be fit to receive an anthracyclin/AraC-based induction therapy (i.e. Ara-C 100
mg/m2 or 200 mg/m2 i.v. day, by continuous infusion for 7 days and Idarubicin 12 mg/m2 i.v. day or
daunomycin 60 mg/m2 on days 1, 3 and 5)
5. Patients must have an ECOG Performance Status of = 2.
6. Patients must have Total Bilirubin = 1.5 x ULN, and AST or ALT = 2.5 x ULN.
7. Patients must have Serum Creatinine = 1.5 x ULN.
8. Women of child-bearing potential must have a negative pregnancy test before starting the
protocol.
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 39
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 39

Exclusion Criteria

Patients eligible for this study must not meet any of the following criteria:
1. Prior therapy for AML with the following exceptions:
a. emergency leukapheresis
b. emergency treatment for hyperleukocytosis with hydroxyurea for = 7 days
2. Central nervous system involvement
3. Presence of any uncontrolled bacterial, viral or fungal infection
4. Known human immunodeficiency virus (HIV) positive
5. An active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Patients whose disease is
controlled under antiviral therapy should not be excluded.
6. Presence of other active malignancies
7. QTc > 470 msec (Bazett formula) on screening ECG
8. Presence of significant uncontrolled or active cardiovascular disease, specifically including,
but not restricted to:
a. Myocardial infarction, unstable angina and/or congestive heart failure within 3 months prior to
randomization
b. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any
ventricular arrhythmia
c. Uncontrolled hypertension
d. Taking medications that are known to be associated with Torsades de Pointes.
9. History of hypersensitivity to any drugs or metabolites of similar chemical classes as the study
treatment.
10. 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the clinical efficacy of midostaurin in combination with chemoteraphy regimes in induction and consolidation and as single agent in maintenence phase, in patient with CBF-Acute Myeloid Leucemia ;Secondary Objective: To assess the safety of midostaurin in combination with chemotherapy in induction and consolidation , and as single agent in maintenance phase <br>To futher assess the efficacy of the protocol treatment, compared to a cohort of historical controls.;Primary end point(s): To demonstrate that 2-years Relapse Incidence (RI) in patients treated according to the protocol<br>treatment plan is 28% or below.;Timepoint(s) of evaluation of this end point: two years

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): · Proportion of patients with AEs, Grade 3 and 4 AEs, SAEs, AEs leading to discontinuation, and deaths.<br>· To evaluate the Overall Survival rate in the study cohort, compared to a cohort of historical controls.<br>· To evaluate the Disease Free Survival rate in the study cohort, compared to a cohort of historical controls.<br>· To evaluate the Event Free Survival rate in the study cohort, compared to a cohort of historical controls.<br>· To analyze the clinical relevance of molecular mutations (KIT, DNMT3A, FLT3, NPM1, TRKA) in<br>homogeneously treated CBFL .<br>· To analyze the kinetics of minimal residual disease (MRD), as measured with PCR techniques and flow<br>cytometry.;Timepoint(s) of evaluation of this end point: seven years