Phase 1b Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes in Previously Treated Patients or in Untreated Patients Unfit for or Who Refuse Intense Therapy
Overview
- Phase
- Phase 1
- Intervention
- Azacitidine
- Conditions
- Chronic Myelomonocytic Leukemia
- Sponsor
- Brian Jonas
- Enrollment
- 21
- Locations
- 5
- Primary Endpoint
- Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Investigators
Brian Jonas
Principal Investigator
University of California, Davis
Eligibility Criteria
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
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/exclusion criteria with the exception of alopecia
- •History of other malignancies, except:
- •Malignancy treated with curative intent and with no known active disease present for \>= 1 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated carcinoma in situ without evidence of disease
- •Low-risk prostate cancer after curative surgery
Arms & Interventions
azacitidine, ibrutinib
Patients receive azacitidine intravenous infusion over 10-40 minutes or subcutaneous on days 1-7 or 1-5 and 8-9, and ibrutinib by mouth one daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
azacitidine, ibrutinib
Patients receive azacitidine intravenous infusion over 10-40 minutes or subcutaneous on days 1-7 or 1-5 and 8-9, and ibrutinib by mouth one daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Ibrutinib
Outcomes
Primary Outcomes
Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events
Time Frame: 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 Outcomes
- Disease response per modified International Working Group (IWG) 2006 response criteria for MDS(Up to 96 weeks)
- 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)
- 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)
- 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)
- 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)