Clinical trial NCT04097470: Tolerability and Efficacy of Midostaurin to 10-day Decitabine in Unfit Adult AML and High Risk MDS Patients
Official title: A Randomized Phase II Multicenter Study to Assess the Tolerability and Efficacy of the Addition of Midostaurin to 10-day Decitabine Treatment in Unfit Adult Acute Myeloid Leukemia and High Risk Myelodysplasia Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: AML/MDS
Lead sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
Sponsor class: OTHER
Collaborators: name: Swiss Group for Clinical Cancer Research
First posted: 2019-09-20
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this study is to investigate how safe and effective the addition of the new medicine midostaurin to decitabine is for the treatment of unfit acute myeloid leukemia (AML) and high-risk myelodysplasia (MDS) patients. Patients who are ineligible for intensive chemotherapy because of accompanying diseases may opt for gentler treatment. This does not produce a cure but serves to allow the quality of life to be acceptable for as long as possible. Decitabine is an example of a gentler treatment. It is effective against leukemia and has fewer side effects than intensive chemotherapy. Given in courses of 5 successive days, decitabine is registered for the treatment of AML. There is scientific research to suggest that decitabine is more effective and generally well tolerated when given in courses of 10 successive days. Therefore, treatment with 10-day courses of decitabine is the standard treatment in this scientific research. The aim is to investigate whether this standard treatment can be improved by adding a new product, midostaurin. Midostaurin is a medicine that is directed against a specific protein on leukaemia cells (FLT3).

Detailed description: This trial aims to develop effective treatments for unfit (i.e. Hematopoietic cell transplantation co-morbidity index (HCT-CI) ≥ 3) in adult (≥ 18 yrs) AML patients, for whom current treatment strategies are highly unsatisfactory. Therefore new treatment modalities are introduced and evaluated in multiple parallel randomized phase II studies that will be conducted within the frame of a master protocol. The scheme of this new design consists of one arm with one of the currently considered best available treatments for unfit AML patients (i.e. 10-day decitabine). After a maximum of 3 10-day courses, or less in case of good response, treatment will be continued with 5-day decitabine courses. This treatment will be compared to investigational treatments in combination with decitabine.

The competitor of the 10-day decitabine schedule will be 10-day decitabine combined (sequential) with the tyrosine kinase inhibitor midostaurin (independent of the presence of FLT3 mutations). The rationale for midostaurin is: 1) single agent midostaurin has shown efficacy in both FLT3 wild type and mutant AML; 2) it has shown efficacy in a phase III randomized controlled trial when combined with intensive chemotherapy in FLT3-mutated AML (RATIFY study); 3) midostaurin has been successfully combined with hypomethylating agents (azacitidine and decitabine) and improved the response compared with historical response rates of these drugs, suggesting at least additive affects of midostaurin with hypomethylating agents.

Eligibility criteria: Inclusion Criteria:

* Patients with:

  * a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
  * a diagnosis of myelodysplastic syndrome with excess of blasts (MDS) and International Prognostic Score System (IPSS) \> 4.5
* Patients 18 years and older.
* Patients NOT eligible for standard chemotherapy, defined as hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 3.

or Patients NOT eligible for standard chemotherapy for other reasons (wish of patient).

* White blood cell (WBC) ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment)
* Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:

  * Serum creatinine ≤ 221.7 µmol/L (≤ 2.5 mg/dL ), unless considered AML-related
  * Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert's syndrome
  * Alanine transaminase (ALT) ≤ 2.5 x ULN, unless considered AML-related
* WHO performance status 0, 1 or 2.
* Patient is willing and able to use adequate contraception during and until 5 months after the last protocol treatment.
* Written informed consent.
* Patient is capable of giving informed consent.

Exclusion Criteria:

* Acute promyelocytic leukemia.
* Acute leukemia's of ambiguous lineage according to WHO 2016
* Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement)
* Blast crisis of chronic myeloid leukemia.
* Diagnosis of any previous or concomitant malignancy is an exclusion criterion:
* except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization. OR
* except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
* Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period ( ≤ 5 days) with Hydroxyurea is allowed
* Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea
* Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
* Cardiac dysfunction as defined by:

  * Myocardial infarction within the last 3 months of study entry, or
  * Reduced left ventricular function with an ejection fraction \< 40% as measured by MUGA scan or echocardiogram or
  * Unstable angina or
  * New York Heart Association grade IV congestive heart failure or
  * Unstable cardiac arrhythmias.
* History of stroke or intracranial hemorrhage within 6 months prior to randomization.
* Patient has a history of human immunodeficiency virus or active infection with Hepatitis C or B.
* Patients known to be pregnant
* Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
* Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.
* Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Primary outcomes:
measure: Cumulative Complete Remission (CR) / CR with incomplete blood count (CRi) rate
timeFrame: 4-5 months
Secondary outcomes:
measure: Safety and tolerability of midostaurin determined by the type, frequency, severity and relationship of adverse events to study treatment
timeFrame: 5 years
measure: Efficacy profile
timeFrame: 4-9 months
measure: Event free survival (EFS)
timeFrame: 5 years
measure: Overall survival (OS)
timeFrame: 5 years
measure: Hospital stay duration
timeFrame: 4-5 months
measure: Transfusion need
timeFrame: 4-5 months
measure: Prognostic value of MRD
timeFrame: 9 months and at relapse
measure: Predictive value of gene mutations
timeFrame: 5 years
measure: Prognostic value of baseline physical conditions as measured by the short physical performance battery
timeFrame: 5 years
measure: Prognostic value of baseline functional conditions as measured by the activities of daily living
timeFrame: 5 years
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: BE-Antwerpen-ZNASTUIVENBERG
city: Haine-Saint-Paul
country: Belgium
facility: BE-Haine-Saint-Paul-JOLIMONT
city: Roeselare
country: Belgium
facility: BE-Roeselare-AZDELTA
city: Magdeburg
country: Germany
facility: DE-Magdeburg-OVGU
city: Amersfoort
country: Netherlands
facility: NL-Amersfoort-MEANDERMC
city: Amsterdam
country: Netherlands
facility: NL-Amsterdam-OLVG
city: Amsterdam
country: Netherlands
facility: NL-Amsterdam-VUMC
city: Arnhem
country: Netherlands
facility: NL-Arnhem-RIJNSTATE
city: Breda
country: Netherlands
facility: NL-Breda-AMPHIA
city: Delft
country: Netherlands
facility: NL-Delft-RDGG
city: Den Bosch
country: Netherlands
facility: NL-Den Bosch-JBZ
city: Den Haag
country: Netherlands
facility: NL-Den Haag-HAGA
city: Doetinchem
country: Netherlands
facility: NL-Doetinchem-SLINGELAND
city: Dordrecht
country: Netherlands
facility: NL-Dordrecht-ASZ
city: Ede
country: Netherlands
facility: NL-Ede-ZGV
city: Eindhoven
country: Netherlands
facility: NL-Eindhoven-CATHARINA
city: Eindhoven
country: Netherlands
facility: NL-Eindhoven-MAXIMAMC
city: Enschede
country: Netherlands
facility: NL-Enschede-MST
city: Groningen
country: Netherlands
facility: NL-Groningen-UMCG
city: Leeuwarden
country: Netherlands
facility: NL-Leeuwarden-MCL
city: Maastricht
country: Netherlands
facility: NL-Maastricht-MUMC
city: Nieuwegein
country: Netherlands
facility: NL-Nieuwegein-ANTONIUS
city: Nijmegen
country: Netherlands
facility: NL-Nijmegen-CWZ
city: Nijmegen
country: Netherlands
facility: NL-Nijmegen-RADBOUDUMC
city: Rotterdam
country: Netherlands
facility: NL-Rotterdam-ERASMUSMC
city: Utrecht
country: Netherlands
facility: NL-Utrecht-UMCUTRECHT
city: Zwolle
country: Netherlands
facility: NL-Zwolle-ISALA
city: Aarau
country: Switzerland
facility: CH-Aarau-KSA
city: Basel
country: Switzerland
facility: CH-Basel-USB
city: Bellinzona
country: Switzerland
facility: CH-Bellinzona-IOSI
city: Bern
country: Switzerland
facility: CH-Bern-INSEL
city: Fribourg
country: Switzerland
facility: CH-Fribourg-HFR
city: Geneve
country: Switzerland
facility: CH-Geneve (14)-HCUGE
city: Lausanne
country: Switzerland
facility: CH-Lausanne-CHUV
city: Luzern
country: Switzerland
facility: CH-Luzern-LUKS
city: Saint Gallen
country: Switzerland
facility: CH-St. Gallen-KSSG
city: Zürich
country: Switzerland
facility: CH-Zürich-USZ
Study officials:
affiliation: UMCG / HOVON
name: Gerwin Huls, Prof
role: PRINCIPAL_INVESTIGATOR
References: