Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, Refractory Anemia With Excess Blasts in Transformation, Secondary Myelodysplastic Syndrome
Conditions
Brief summary
This phase Ib trial studies the side effects and best dose of ibrutinib when given together with azacitidine in treating patients with myelodysplastic syndrome that is likely to occur or spread (higher risk) and who were previously treated or untreated and unfit for or refused intense therapy. Ibrutinib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ibrutinib in combination with azacitidine in patients with higher risk myelodysplastic syndrome (MDS) and to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of ibrutinib combined with azacitidine. SECONDARY OBJECTIVES: I. To do an early assessment of the efficacy of the combination of ibrutinib and azacitidine in higher risk MDS. Specific secondary endpoints include: disease response per modified International Working Group (IWG) 2006 response criteria for MDS, hematologic normalization rate (HNR = complete remission \[CR\] + partial remission \[PR\] + hematologic improvement \[HI\]), overall survival (OS), progression free survival (PFS), disease free survival (DFS), and time to response (TTR). TERTIARY OBJECTIVES: I. To evaluate the pharmacodynamic and biological effects and impact of quality of life (QoL) of the combination of ibrutinib and azacitidine in patients with higher risk MDS is the exploratory objective of this study. Exploratory endpoints include: laboratory biomarker analysis and effect on QoL assessments. OUTLINE: This is a dose-escalation study of ibrutinib. Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) once daily (QD) on days 1-7 or 1-5 and 8-9, and ibrutinib orally (PO) QD on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 6 months.
Interventions
DRUGAzacitidine
Given intravenous or subcutaneous
DRUGIbrutinib
Given by mouth once daily
Sponsors
Pharmacyclics LLC.
Brian Jonas
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed diagnosis of myelodysplastic syndrome * Revised international prognostic scoring system (IPSS-R) intermediate, high or very high * For the dose escalation cohorts, any prior number of MDS therapies, including hypomethylating agents, are permitted; for the dose expansion cohort, subjects must be azacitidine naïve, but otherwise any prior number of MDS therapies are permitted; treatment naïve patients are eligible for both the dose escalation and expansion cohorts if they are unfit for or refuse intense therapy * No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm\^3 * Serum aspartate transaminase (AST) and alanine transaminase (ALT) =\< 3.0 x upper limit of normal (ULN) * Estimated creatinine clearance \>= 30 ml/min (Cockcroft-Gault) * Bilirubin =\< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Prothrombin time (PT)/international normalized ratio (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) (activated \[a\]PTT) \< 1.5 x ULN * Karnofsky performance status (KPS) performance status of 60% or greater * Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for \>= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); or, female subjects of childbearing potential must have a negative serum pregnancy test upon study entry * Male and female subjects who agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of study drug
Exclusion criteria
* Known bleeding disorders, active bleeding disorders or clinical signs of bleeding (grade \>= 2) * Prior bone marrow transplant within 3 months or with acute graft versus host disease (GVHD) * Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor * Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives prior to first dose of study drug * Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade =\< 1, or to the levels dictated in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events | Within 30 days following the last dose of study drug or the first date starting new anticancer therapy | For each adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival | From the time of first documented Complete Response until relapse or the date of death from any cause, assessed up to 6 months post-treatment | For subjects achieving a Complete Response, Disease Free Survival will be calculated to determine durability of response. Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots). |
| Disease response per modified International Working Group (IWG) 2006 response criteria for MDS | Up to 96 weeks | Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. |
| HNR, defined as the proportion of treated subjects who achieve a CR, PR or HI as best response as assessed by the investigator and as defined by the modified IWG 2006 response criteria for MDS | Up to 96 weeks | Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. |
| Overall survival | From the time of first study drug administration until the date of death from any cause, assessed up to 6 months post-treatment | Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots). |
| Progression Free Survival | From the time of first study drug administration until the date of progression or death from any cause, assessed up to 6 months post-treatment | Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in biomarker levels including BTK, phosphatidylinositol 3 kinase, cluster of differentiation 34, mitogen-activated protein kinase, nuclear transcription factor kappa-B, interleukin 2-inducible T-cell kinase, and peripheral T cells and subsets | Baseline up to 96 weeks | Laboratory tests will be summarized separately for hematology and serum chemistry. Descriptive statistics will be provided for the values of selected clinical laboratory tests at each scheduled on-treatment evaluation including the final value. Percent change from baseline to each scheduled on-treatment evaluation and to the final value will also be summarized. For selected variables, the mean value and mean percent change over time will be presented graphically. All laboratory values will be converted to standard international units and will be graded using the NCI CTCAE version 4.03. |
| Quality of LIfe of the combination of ibrutinib and azacitidine, assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires | Up to 30 days from last dose | — |
Countries
United States
Outcome results
None listed