A randomized phase II multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in UNFIT (i.e. HCT-CI >= 3) AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) patients aged >= 66 years.
A study in the frame of the masterprotocol of parallel randomized phase II studies in UNFIT-older AML/high-risk MDS patients.

Randomized phase II study



Primary objectives

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

Secondary objectives

1. To assess the safety and tolerability of Ibrutinib added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia).

2. To determine the efficacy profile:
response rate (CR, CRi, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens (i.e. decitabine vs decitabine + ibrutinib.

3. To determine the impact of 3 days ibrutinib monotherapy (pre-treatment) on WBC count, circulating blast count, and translational endpoints (mass cytometry).

4. To measure MRD by immunophenotyping and PCR in relation to clinical response parameters.

5. To identify potential biomarkers predictive of response, EFS and OS by exploratory analysis (gene mutations, kinome, methylome).

6. 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).

Patient population:

Patients with AML (except FAB M3) or high risk MDS (IPSS-R > 4.5), previously untreated, age >= 66 yrs AND Hematopoietic Cell Transplantation Co-morbidity Index (HCT-CI) >= 3.



Study design:

This is a prospective, open label, multicenter study that is conducted in the frame of a masterprotocol with multiple parallel randomized phase II arms.
The scheme of this design consists of one arm with the standard treatment for AML (the 10-day decitabine schedule) as compared to various arms with experimental treatments.



Duration of treatment:

Expected duration of 3 cycles of 10-day decitabine with or without Ibrutinib, including evaluation, is about 4-5 months. Continuation treatment (5-day decitabine with or without Ibrutinib) will last until progression

All patients will be followed until 5 years after registration. Patients who are still on continuation treatment at 5 years after registration will be followed until progression or death.



Target number of patients:

Per treatment arm a maximum of 70 patients at the final dose level.

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

To assess the safety and tolerability of Ibrutinib added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia).

To determine the efficacy profile: response rate (CR, CRi, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens (i.e. decitabine vs decitabine + ibrutinib.

To determine the impact of 3 days ibrutinib monotherapy (pre-treatment) on WBC count, circulating blast count, and translational endpoints.

To measure MRD by immunophenotyping and PCR in relation to clinical response parameters.

To identify potential biomarkers predictive of response, EFS and OS by exploratory analysis.

To evaluate the prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools

Clinical, laboratory and questionnaire evaluations:
1; at entry
2; after cycle 1, 2 and 3
3; during continuation treatment
4; at off protocol treatment or relapse
5; during follow up (evry 3-6 months)

Patients in this study are treated with 10-day decitabine treatment with or without ibrutinib. The starting dose of ibrutinib will be 560 mg once daily. During the part A run-in phase the dose level of ibrutinib will be established.