Ibrutinib and Azacitidine for Treatment of Higher Risk Myelodysplastic Syndrome

NCT02553941 | Completed Phase 1 DMC

• 3 other identifiers: 755461UCDCC#256PCI-32765
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 5

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events

  For each adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be summarized.

  Within 30 days following the last dose of study drug or the first date starting new anticancer therapy

Secondary Outcomes (5)

• 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

• 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

• 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

• 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

Other Outcomes (2)

• 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

• 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

Study Arms (1)

azacitidine, ibrutinib

EXPERIMENTAL

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; Drug: Ibrutinib

Interventions

Azacitidine DRUG

Given intravenous or subcutaneous

Also known as: Vidaza

azacitidine, ibrutinib

Ibrutinib DRUG

Given by mouth once daily

Also known as: BTK Inhibitor

azacitidine, ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brian Jonas: lead
• Pharmacyclics LLC.: collaborator

Study Sites (5)

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

University of California San Diego

San Diego, California, 92103, United States

Location

University of California, San Francisco

San Francisco, California, 94118, United States

Location

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic

Interventions

Azacitidine; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Brian Jonas

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 27, 2015
• First Posted: September 18, 2015
• Study Start: May 17, 2016
• Primary Completion: May 25, 2019
• Study Completion: November 7, 2019
• Last Updated: October 6, 2022

Record last verified: 2022-10

Locations

US (5)