A randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to 10-day decitabine in unfit (i.e. HCT-CI ≥ 3) adult AML and high-risk myelodysplasia (MDS) (IPSS-R > 4.5) patients. A study in the frame of the masterprotocol of parallel randomized phase II studies in UNFIT- AML/high-risk MDS patients.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Haemato Oncology Foundation For Adults Netherlands

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

5 Dec 2019 → ongoing

Decision date (initial)

2024-10-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Johnson & Johnson Pharmaceutical · Novartis

External identifiers

EU CT number

2023-503829-18-00

EudraCT number

2018-000047-31

ClinicalTrials.gov

NCT04097470

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To assess in a randomized comparison the effect of midostaurin added to 10-day decitabine treatment on the cumulative CR/CRi rate during 3 cycles

Secondary objectives 5

1. To assess the safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards to the selected dose level of the study
2. To determine the efficacy profile: response rate (CRMRD-, CR, CRi, MLFS, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens
3. To measure MRD by immunophenotyping and PCR in relation to clinical response parameters
4. To identify gene mutations as potential biomarkers predictive of response, EFS and OS by exploratory analysis
5. To evaluate the prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL)) on treatment outcome

Conditions and MedDRA coding

Acute myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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 IPSS-R > 4.5
2. Patients 18 years and older
3. Patients NOT eligible for standard chemotherapy, defined as HCT-CI ≥ 3. (Appendix G) or Patients NOT eligible for standard chemotherapy for other reasons (wish of patient)
4. WBC ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment)
5. 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
6. WHO performance status 0, 1 or 2 (see Appendix D)
7. Patient is willing and able to use adequate contraception during and until 5 months after the last protocol treatment
8. Written informed consent
9. Patient is capable of giving informed consent

Exclusion criteria 16

1. Acute promyelocytic leukemia
2. Acute leukemia's of ambiguous lineage according to WHO 2016
3. Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement)
4. Blast crisis of chronic myeloid leukemia
5. 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
6. Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (≤ 5 days) with Hydroxyurea is allowed
7. Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea
8. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.
9. 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 (NYHA) grade IV congestive heart failure (see Appendix I) or unstable cardiac arrhythmias
10. History of stroke or intracranial hemorrhage within 6 months prior to randomization
11. Patient has a history of human immunodeficiency virus (HIV) or active infection with Hepatitis C or B
12. Patients known to be pregnant
13. Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance
14. Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study
15. Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent
16. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cumulative CR/CRi rate during 3 cycles

Secondary endpoints 9

1. Safety and tolerability of midostaurin added to 10-day decitabine treatment for AML (type, frequency, severity and relationship of adverse events to study treatment)
2. Efficacy profile (response rate after each first three cycles and best response during three cycles and after 9 months (CRMRD-, CR, CRi, MLFS, PR))
3. Event free survival (EFS)
4. Overall survival (OS)
5. Days of staying in hospital and transfusion needs during three cycles
6. Prognostic value of MRD (by flowcytometry or PCR)
7. Gene mutations predictive of response, EFS and OS by exploratory analysis
8. Prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL) on treatment outcome
9. Translational endpoints: to identify potential biomarkers (molecular) that predict for response to decitabine and/or midostaurin

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Haemato Oncology Foundation For Adults Netherlands

Sponsor organisation

Haemato Oncology Foundation For Adults Netherlands

Address

S Gravendijkwal 230

City

Rotterdam

Postcode

3015 CE

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

G. Huls

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

HOVON

Third parties 2

Locations

2 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications