Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

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Brief Title

Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

Official Title

A Phase 2 Study of Ibrutinib in Advanced Systemic Mastocytosis

Brief Summary

      This phase 2 trial studies ibrutinib to see how well it works in treating patients with
      systemic (affecting the entire body) mastocytosis that has spread to other parts of the body
      and usually cannot be cured or controlled with treatment (advanced). Systemic mastocytosis is
      a disease in which too many mast cells (a type of immune system cell) are found throughout
      the body. Mast cells give off chemicals such as histamine that can cause flushing (a hot, red
      face), itching, abdominal cramps, muscle pain, nausea, vomiting, diarrhea, low blood
      pressure, and shock. Ibrutinib may stop the growth of mast cells by blocking some of the
      enzymes needed for cell growth.
    

Detailed Description

      PRIMARY OBJECTIVE:

      Evaluate the response rate to ibrutinib in patients with advanced systemic mastocytosis (SM)
      (aggressive systemic mastocytosis [ASM] or mast cell leukemia [MCL], or SM-associated
      hematologic non-mast cell disorder [AHNMD]) by the end of 6 cycles (6 months).

      SECONDARY OBJECTIVES:

        -  Evaluate the tolerability and safety profile of ibrutinib in patients with advanced SM.

        -  Evaluate the pharmacokinetic (PK) profile of ibrutinib in a subset of patients with
           advanced SM.

        -  Evaluate changes in histopathology (blood and bone marrow) of patients with advanced SM
           in response to ibrutinib therapy.

        -  Evaluate changes in mastocytosis related symptom scores and quality-of-life (QOL) using
           a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF).

        -  Evaluate the duration of response (DoR) and time to response (TTR).

        -  Evaluate progression-free survival (PFS) and overall survival.

      OUTLINE:

      Patients receive ibrutinib orally (PO) once daily (QD) on days 1 to 28. Treatment repeats
      every 28 days for up to 6 months in the absence of disease progression or unacceptable
      toxicity. Patients achieving an unconfirmed or confirmed clinical improvement (CI), partial
      response (PR), or complete response (CR) by the end of course 6 will be permitted to continue
      maintenance courses of ibrutinib on an ongoing basis until loss of response/progressive
      disease, or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days and then every 6
      months thereafter.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Response Rate (ORR)

Secondary Outcome

 Number of Participants With Adverse Events

Condition

Aggressive Systemic Mastocytosis

Intervention

Ibrutinib

Study Arms / Comparison Groups

 Ibrutinib 420 mg/day
Description:  Participants receive ibrutinib daily on days 1 to 28, at 420 mg/day in 28-day cycles

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

4

Start Date

March 2015

Completion Date

June 14, 2017

Primary Completion Date

November 4, 2016

Eligibility Criteria

        INCLUSION CRITERIA

          -  Diagnosis of systemic mastocytosis per 2008 World Health Organization (WHO) criteria.
             Those with advanced systemic mastocytosis (ASM); mast cell leukemia (MCL); or systemic
             mastocytosis-associated hematological clonal non-mast cell lineage disease (SM-AHNMD)
             required to have at least 1 organ damage finding

          -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit
             of normal (ULN); if considered related to ASM/MCL ≤ 5 x ULN

          -  Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault)

          -  Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin); if considered related to ASM/MCL ≤ 3 x ULN

          -  Female subjects must be of non-reproductive potential, or if of childbearing potential
             must have a negative serum pregnancy test upon study entry

          -  Must agree to use highly effective methods of birth control

          -  Written informed consent

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3

          -  Life expectancy > 12 weeks

        EXCLUSION CRITERIA

          -  Received any investigational agent, chemotherapy, interferon-alpha, or
             2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to day 1; or
             monoclonal antibody ≤ 6 weeks prior to first administration of study treatment
             (patients with an AHNMD with progressive leukocytosis who require control of their
             counts are permitted to receive hydroxyurea)

          -  Diagnosis of AHNMD requiring immediate cytoreductive therapy or targeted drugs (eg,
             acute myeloid leukemia [AML])

          -  History of other malignancies, except:

               -  Malignancy treated with curative intent and with no known active disease present
                  for ≥ 3 years before the first dose of study drug, and at low risk for recurrence

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease

          -  Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,
             or chronic administration [> 14 days] of > 10 mg/day of prednisone) within 28 days of
             the first dose of study drug

          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

          -  Systemic treatment for infection completed ≤ 14 days before the 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), grade 0 or 1, or
             to the levels dictated in the inclusion/exclusion criteria with the exception of
             alopecia

          -  Known bleeding disorders (eg, severe von Willebrand's disease) or severe hemophilia

          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment

          -  Known history of human immunodeficiency virus (HIV) or

          -  Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

          -  Major surgery within 4 weeks of first dose of study drug

          -  Any life-threatening illness, medical condition, or organ system dysfunction that
             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 randomization

          -  Unable to swallow capsules or malabsorption syndrome

          -  Disease significantly affecting gastrointestinal function

          -  Resection of the stomach or small bowel

          -  Symptomatic inflammatory bowel disease

          -  Ulcerative colitis

          -  Partial or complete bowel obstruction

          -  Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor

          -  Lactating or pregnant

          -  Unwilling or unable to participate in all required study evaluations and procedures

          -  Unable to understand the purpose and risks of the study and to provide a signed and
             dated informed consent form (ICF) and authorization to use protected health
             information (in accordance with national and local subject privacy regulations)

          -  Known hypersensitivity to any excipient contained in the drug

          -  Received hematopoietic growth factor support within 14 days of day 1 of ibrutinib
             (Jehovah's witnesses may be given an erythropoiesis-stimulating agent before and
             during the trial in lieu of red blood cell transfusions but anemia and/or red blood
             cell (RBC) transfusion dependence cannot be used for response assessment in these
             patients)

          -  Presence of the factor interacting with poly(A) polymerase alpha (PAPOLA) and cleavage
             and polyadenylation specific factor 1 (CPSF1) (FIP1L1)-platelet-derived growth factor
             receptor, alpha polypeptide (PDGFRalpha) fusion even with resistance to imatinib (such
             patients are no longer defined as systemic mastocytosis by the WHO)

          -  Received any treatment with ibrutinib prior to study entry

          -  The concomitant use of warfarin or other vitamin K antagonists unless felt to be of
             significant clinical need; low molecular weight heparin or other anticoagulants may be
             used instead if anticoagulation is required
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jason Gotlib, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02415608

Organization ID

IRB-31815

Secondary IDs

NCI-2014-02341

Responsible Party

Sponsor-Investigator

Study Sponsor

Jason Robert Gotlib

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Jason Gotlib, Principal Investigator, Stanford University Hospitals and Clinics


Verification Date

August 2018