Primary objectives1. 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 objectives1. To assess the safety and tolerability of Ibrutinib added to 10…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Cumulative CR/CRi rate after 3 cycles
Secondary outcome
• Safety and tolerability (frequency and severity of toxicities and the
durations of neutropenia and thrombocytopenia).
• Efficacy profile (response rate (CR, CRi, PR), event free survival (EFS) and
overall survival (OS)).
• Days of staying in hospital and transfusion needs.
• Prognostic value of MRD (by flowcytometry or PCR).
• Gene mutations predictive of response, EFS and OS by exploratory analysis.
• 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.
Translational endpoints
• To determine the impact of 3 days ibrutinib monotherapy (pre-treatment) on
WBC count, circulating blast count, and kinome (using mass cytometry kinome).
• To identify potential biomarkers (using mass cytometry kinome; methylome) in
bone marrow and peripheral blood which are of prognostic importance in both
arms, and whether they are of predictive importance for response.
• To identify methylome profiles in CD34+ bone marrow blasts and stroma cells
which are of prognostic importance in both arms, and whether they are of
predictive importance for response.
Background summary
This trial aims to develop effective treatments for UNFIT (i.e. hematopoietic
cell transplantation co-morbidity index (HCT-CI) >= 3) in older (>= 66 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 older 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 first competitor of the 10-day decitabine schedule will be 10-day
decitabine combined (sequential) with the BTK inhibitor ibrutinib. The
rationale for ibrutinib is:1) its high expression and phosphorylation in AML
cell lines and CD34+ AML blasts; 2) the central role of BTK within many
important signaling pathways in AML (e.g. CXCR4, TLR, Flt3-ITD); 3) the
in-vitro activity of ibrutinib against AML blasts; 4) extensive experience with
ibrutinib combined with chemotherapy in mantle cell lymphoma and CLL.
Study objective
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).
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.
Intervention
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.
Study burden and risks
The benefit of this study is that older AML patients with co-morbidities: 1) do
not receive toxic intensive chemotherapy (which has been shown to be associated
with an almost 30% day-28 mortality); 2) do receive treatment (instead of not
being considered for treatment at all).
The burden and risks associated with participation mainly involve an additional
bone marrow aspirate and blood draw at day+1 in arm B and taking off additional
material during routine examinations (blood draws/bone marrow aspirates).
Furthermore, a geriatric assessment will be performed.
VUMC, HOVON Centraal Bureau, De Boelelaan 117
Amsterdam 1081 HV
NL
VUMC, HOVON Centraal Bureau, De Boelelaan 117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
• Patients with:
- a diagnosis of AML and related precursor neoplasms according to WHO 2008
classification (excluding acute promyelocytic leukemia) including secondary AML
(after an antecedent hematological disease (e.g. MDS) and therapy-related AML,
or
- acute leukemia's of ambiguous lineage according to WHO 2008 or
- a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R >
4.5
• Patients 66 years and older.
• Patients NOT eligible for standard chemotherapy, defined as HCT-CI >= 3.
OR patient NOT eligible for standard chemotherapy for other reasons (wish of
patient).
• WBC <= 30 x10^9/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
• WHO performance status 0, 1 or 2
• Male patients must use an effective contraceptive method during the study and
for a minimum of 6 months after study treatment.
• Written informed consent.
Exclusion criteria
• Acute promyelocytic leukemia.
• Patients previously treated for AML (any antileukemic therapy including
investigational agents), a short treatment period ( <= 5 days) with Hydroxyurea
is allowed
• 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.
• Blast crisis of chronic myeloid leukemia.
• Inability to discontinue anti-coagulants
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled
diabetes, infection, hypertension, pulmonary disease etc.)
• Cardiac dysfunction
• Patient has had major surgery within the past 4 weeks or a major wound that
has not fully healed.
• Vaccinated with live, attenuated vaccines within 4 weeks prior to
randomization.
• History of stroke or intracranial hemorrhage within 6 months prior to
randomization.
• Patient has a history of human immunodeficiency virus (HIV) or active
infection with Hepatitis C or B.
• Patient has symptomatic central nervous system (CNS) leukemia (NO routinely
lumbar puncture required to investigate CNS involvement)
• 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.
• Current concomitant chemotherapy, radiation therapy, or immunotherapy; other
than hydroxyurea
• Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002855-85-NL |
| CCMO | NL55164.042.15 |