Tolerability and Efficacy of Midostaurin to 10-day Decitabine in Unfit Adult AML and High Risk MDS Patients

NCT04097470 | Active Not Recruiting Phase 2 DMC

• 4 other identifiers: HOVON 155 AML2018-000047-312018-674NL64632.042.18
• Study Type: interventional
• Target: 140
• Locations: 4 countries
• Sites: 37

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).

Conditions

AML/MDS

Outcome Measures

Primary Outcomes (1)

• Cumulative Complete Remission (CR) / CR with incomplete blood count (CRi) rate

  Cumulative CR/CRi rate during 3 cycles

  4-5 months

Secondary Outcomes (10)

• Safety and tolerability of midostaurin determined by the type, frequency, severity and relationship of adverse events to study treatment

  5 years

• Efficacy profile

  4-9 months

• Event free survival (EFS)

  5 years

• Overall survival (OS)

  5 years

• Hospital stay duration

  4-5 months

Study Arms (2)

Arm A: Decitabine

ACTIVE COMPARATOR

Cycles 1-3: Decitabine 10-day; depending on day +28 bone marrow (BM) blasts after the previous cycle, next cycle consists of either 5-day (BM blasts \< 5%) or 10-day (BM blasts ≥5%) decitabine. Cycles 4 and beyond: 5-day decitabine (in cycles of 4-8 weeks); continuation of these cycles until progression. Dosage for Decitabine 20 mg/m2 i.v.

Drug: Decitabine

Arm B: Decitabine and Midostaurin

EXPERIMENTAL

Cycle 1:Decitabine; 10-day schedule (start day +1) + midostaurin (start day +11). Midostaurin is given until 2 days before start next cycle of decitabine. Cycles 2-3: Decitabine 5 or 10-day schedule; depending on day +28 bone marrow blasts of the previous cycle, next cycle consist of either 5-day (BM blasts \< 5%) or 10-day (BM blasts ≥5%) decitabine + midostaurin (daily, starting the day after the last dose of decitabine (i.e. day +6 or +11). Midostaurin is given until 2 days before start next cycle. Cycles 4 and beyond: 5-day decitabine (in cycles of 4-8 weeks) followed by midostaurin starting at day +6 until two days before start of next cycle of decitabine; continuation of these cycles until progression. Midostaurin is given until 2 days before start next cycle of decitabine. Dosage for Decitabine 20 mg/m2 i.v. Dosage for Midostaurin 50 mg b.i.d.

Drug: Decitabine; Drug: Midostaurin

Interventions

Decitabine DRUG

Decitabine dosage 20mg/m2 i.v.

Also known as: Dacogen

Arm A: Decitabine; Arm B: Decitabine and Midostaurin

Midostaurin DRUG

Midostaurin 50 mg b.i.d.

Also known as: Rydapt

Arm B: Decitabine and Midostaurin

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Stichting Hemato-Oncologie voor Volwassenen Nederland: lead
• Swiss Cancer Institute: collaborator

Study Sites (37)

BE-Antwerpen-ZNASTUIVENBERG

Antwerp, Belgium

Location

BE-Haine-Saint-Paul-JOLIMONT

Haine-Saint-Paul, Belgium

Location

BE-Roeselare-AZDELTA

Roeselare, Belgium

Location

DE-Magdeburg-OVGU

Magdeburg, Germany

Location

NL-Den Bosch-JBZ

's-Hertogenbosch, Netherlands

Location

NL-Amersfoort-MEANDERMC

Amersfoort, Netherlands

Location

NL-Amsterdam-OLVG

Amsterdam, Netherlands

Location

NL-Amsterdam-VUMC

Amsterdam, Netherlands

Location

NL-Arnhem-RIJNSTATE

Arnhem, Netherlands

Location

NL-Breda-AMPHIA

Breda, Netherlands

Location

NL-Delft-RDGG

Delft, Netherlands

Location

NL-Doetinchem-SLINGELAND

Doetinchem, Netherlands

Location

NL-Dordrecht-ASZ

Dordrecht, Netherlands

Location

NL-Ede-ZGV

Ede, Netherlands

Location

NL-Eindhoven-CATHARINA

Eindhoven, Netherlands

Location

NL-Eindhoven-MAXIMAMC

Eindhoven, Netherlands

Location

NL-Enschede-MST

Enschede, Netherlands

Location

NL-Groningen-UMCG

Groningen, Netherlands

Location

NL-Leeuwarden-MCL

Leeuwarden, Netherlands

Location

NL-Maastricht-MUMC

Maastricht, Netherlands

Location

NL-Nieuwegein-ANTONIUS

Nieuwegein, Netherlands

Location

NL-Nijmegen-CWZ

Nijmegen, Netherlands

Location

NL-Nijmegen-RADBOUDUMC

Nijmegen, Netherlands

Location

NL-Rotterdam-ERASMUSMC

Rotterdam, Netherlands

Location

NL-Den Haag-HAGA

The Hague, Netherlands

Location

NL-Utrecht-UMCUTRECHT

Utrecht, Netherlands

Location

NL-Zwolle-ISALA

Zwolle, Netherlands

Location

CH-Aarau-KSA

Aarau, Switzerland

Location

CH-Basel-USB

Basel, Switzerland

Location

CH-Bellinzona-IOSI

Bellinzona, Switzerland

Location

CH-Bern-INSEL

Bern, Switzerland

Location

CH-Fribourg-HFR

Fribourg, Switzerland

Location

CH-Geneve (14)-HCUGE

Geneva, Switzerland

Location

CH-Lausanne-CHUV

Lausanne, Switzerland

Location

CH-Luzern-LUKS

Lucerne, Switzerland

Location

CH-St. Gallen-KSSG

Sankt Gallen, Switzerland

Location

CH-Zürich-USZ

Zurich, Switzerland

Location

Related Links

• HOVON website

MeSH Terms

Interventions

Decitabine; midostaurin

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Gerwin Huls, Prof

  UMCG / HOVON

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2019
• First Posted: September 20, 2019
• Study Start: December 5, 2019
• Primary Completion: November 15, 2021
• Study Completion (Estimated): November 1, 2026
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

CH (10); DE (1); NL (23); BE (3)