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Ibrutinib and Azacitidine for Treatment of Higher Risk Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT02553941
Recruitment Status : Recruiting
First Posted : September 18, 2015
Last Update Posted : January 16, 2019
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Brian Jonas, University of California, Davis

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.

Condition or disease Intervention/treatment Phase
Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome Refractory Anemia With Excess Blasts in Transformation Secondary Myelodysplastic Syndrome Drug: Azacitidine Drug: Ibrutinib Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : April 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Experimental: 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.
Drug: Azacitidine
Given intravenous or subcutaneous
Other Name: Vidaza

Drug: Ibrutinib
Given by mouth once daily
Other Name: BTK Inhibitor




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Disease Free Survival [ Time Frame: 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).

  2. Disease response per modified International Working Group (IWG) 2006 response criteria for MDS [ Time Frame: 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.

  3. 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 [ Time Frame: 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.

  4. Overall survival [ Time Frame: 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).

  5. Progression Free Survival [ Time Frame: 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 Outcome Measures:
  1. 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 [ Time Frame: 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.

  2. 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 [ Time Frame: Up to 30 days from last dose ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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/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
  • Concurrent systemic immunosuppressant therapy
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
  • Recent infection requiring intravenous systemic treatment
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
  • Major surgery within 4 weeks of first dose of study drug
  • Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
  • Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
  • Concomitant use of warfarin or other vitamin K antagonists
  • Requires treatment with a strong cytochrome P450 (CYP) family 3, subfamily A, polypeptide 4/5 (3A4/5) inhibitor
  • Lactating or pregnant
  • Unwilling or unable to participate in all required study evaluations and procedures
  • Unable to understand informed consent form (ICF)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02553941


Locations
Layout table for location information
United States, California
UCLA / Jonsson Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90095
Contact: Gary J. Schiller    888-798-0719    garyjs@ucla.edu   
Principal Investigator: Gary J. Schiller         
UC Irvine Health/Chao Family Comprehensive Cancer Center Active, not recruiting
Orange, California, United States, 92868
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Brian A. Jonas    916-734-3772    bajonas@ucdavis.edu   
Principal Investigator: Brian A. Jonas         
University of California San Diego Recruiting
San Diego, California, United States, 92103
Contact: Matthew J. Wieduwilt    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Matthew J. Wieduwilt         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94118
Contact: Aaron C. Logan    415-502-2110    aclogan@medicine.ucsf.edu   
Principal Investigator: Aaron C. Logan         
Sponsors and Collaborators
Brian Jonas
Pharmacyclics LLC.
Investigators
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Principal Investigator: Brian Jonas University of California, Davis

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Responsible Party: Brian Jonas, Principal Investigator, University of California, Davis
ClinicalTrials.gov Identifier: NCT02553941     History of Changes
Other Study ID Numbers: 755461
UCDCC#256 ( Other Identifier: UC Davis )
PCI-32765 ( Other Identifier: UCDCC )
UCDCC#256 ( Other Identifier: University of California Davis Comprehensive Cancer Center )
First Posted: September 18, 2015    Key Record Dates
Last Update Posted: January 16, 2019
Last Verified: January 2019

Additional relevant MeSH terms:
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Syndrome
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Anemia, Aplastic
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Myelodysplastic-Myeloproliferative Diseases
Anemia
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors