Ibrutinib and Azacitidine for Treatment of Higher Risk Myelodysplastic Syndrome

NCT ID: NCT02553941

Last Updated: 2022-10-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-17
• Study Completion Date: 2019-11-07

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.

Conditions

Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts in Transformation; Secondary Myelodysplastic Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Given intravenous or subcutaneous

Ibrutinib

Intervention Type: DRUG

Given by mouth once daily

Interventions

Azacitidine

Given intravenous or subcutaneous

Intervention Type: DRUG

Ibrutinib

Given by mouth once daily

Intervention Type: DRUG

Other Intervention Names

Vidaza; BTK Inhibitor

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
• 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
• 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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pharmacyclics LLC.

INDUSTRY

Sponsor Role: collaborator

Brian Jonas

OTHER

Sponsor Role: lead

Responsible Party

Brian Jonas

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Brian Jonas

Role: PRINCIPAL_INVESTIGATOR

University of California, Davis

Locations

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, United States

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

University of California San Diego

San Diego, California, United States

University of California, San Francisco

San Francisco, California, United States

Countries

United States

Other Identifiers

UCDCC#256

Identifier Type: OTHER

Identifier Source: secondary_id

PCI-32765

Identifier Type: OTHER

Identifier Source: secondary_id

UCDCC#256

Identifier Type: OTHER

Identifier Source: secondary_id

755461

Identifier Type: -

Identifier Source: org_study_id