Clinical Trial: Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase II Study of Ibrutinib in Advanced Systemic Mastocytosis

Brief Summary: This phase II 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 Summary:

PRIMARY OBJECTIVES:

I. To 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:

I. To evaluate the tolerability and safety profile of ibrutinib in patients with advanced SM.

II. To evaluate the pharmacokinetic (PK) profile of ibrutinib in a subset of patients with advanced SM.

III. To evaluate changes in histopathology (blood and bone marrow) of patients with advanced SM in response to ibrutinib therapy.

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

V. To evaluate the duration of response (DoR) and time to response (TTR). VI. To evaluate progression-free survival (PFS) and overall survival.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. 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
Sponsor: Jason Robert Gotlib

Current Primary Outcome: Overall response rate (rate of complete + partial remissions + CI) [ Time Frame: Up to 6 28-day courses of treatment ]

The rate of complete remission, partial remission, and CI will be estimated and its 95% confidence interval will be provided. Response rate per Valent criteria may be evaluated as part of an exploratory analysis.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria version 4.03 [ Time Frame: Up to 30 days post-treatment ]
    Adverse events will be summarized by presenting the number and percentage of patients having any adverse event, having an adverse event in each body system and having each individual adverse event.
  • PK profiles of ibrutinib [ Time Frame: At pre-dose, and at 1, 2, 4, and 6 hours on days 1 and 15 of course 1 and on day 1 of course 2 ]
    Plasma concentration-time profiles for each subject and mean plasma concentration-time profiles for each dose level will be plotted, plasma concentration data for ibrutinib at each time point will be summarized by descriptive statistics, and PK parameters such as maximum concentration (Cmax), minimum concentration, time at which the Cmax is reached, and area under the curve will be summarized with mean, geometric mean, medium, minimum, maximum, standard deviation, and coefficient of variation.
  • Reduction of mast cell burden [ Time Frame: Up to 2 years ]
    The burden of neoplastic mast cells will be determined by immunophenotyping and/or immunohistochemistry and will be compared between pre- and post-ibrutinib treatment samples. Reduction of mast cell burden will also be recorded pre- and post-ibrutinib therapy primarily by evaluation of peripheral blood (if mast cell leukemia) and bone marrow aspirate and core biopsy.
  • Hematologic review [ Time Frame: Up to 2 years ]
    Hematologic review will include analysis of peripheral blood smear (results of complete blood count should also be submitted). Change of serum tryptase levels from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Histopathology review [ Time Frame: Up to 2 years ]
    Histopathology review will include analysis of bone marrow core biopsy, bone marrow aspirate, and any biopsied tissue with mast cell involvement. Changes from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Change in total symptom score assessed by a modified version of the MPNSAF [ Time Frame: Baseline to 30 days post-treatment ]
    Total symptom score will be assessed by a modified version of the MPNSAF (modified for mast cell symptoms) by recording mean and median scores with ranges will be recorded pre- and post-treatment with ibrutinib.
  • Change in QOL assessed by a modified version of the MPNSAF [ Time Frame: Baseline to 30 days post-treatment ]
    QOL will be assessed by a modified version of the MPNSAF (modified for mast cell symptoms) by recording mean and median scores with ranges will be recorded pre- and post-treatment with ibrutinib.
  • DoR [ Time Frame: Time from the start of the first confirmed response until the date of the first documented and confirmed disease progression or death due to ASM or MCL, assessed up to 2 years ]
    The Kaplan-Meier product-limit method will be used to summarize the response duration. If a responder did not progress or die due to ASM or MCL at the time of the analyses, DoR will be censored at the date of the last adequate response assessment.
  • TTR [ Time Frame: Time from the date of start of treatment to the date of first confirmed response, assessed up to 2 years ]
    TTR will be censored at the date of the last adequate response assessment in patients did not progress or die due to any cause and at maximum follow-up date (i.e. date of first patient first visit to date of last patient last visit used for the analysis) in patients who progressed or died due to any cause. Kaplan-Meier product-limit estimates will be used to summarize the time to response.
  • PFS [ Time Frame: Time from the date of start of treatment until the date of first documented confirmed disease progression or death or institution of new therapy, assessed up to 2 years ]
    If a patient did not progress or die due to any cause at the time of the analyses, PFS will be censored at the date of the last adequate response assessment. Kaplan-Meier product-limit estimates will be used to summarize PFS.
  • Overall survival [ Time Frame: Up to 2 years ]


Original Secondary Outcome:

  • Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria version 4.03 [ Time Frame: Up to 30 days post-treatment ]
    Adverse events will be summarized by presenting the number and percentage of patients having any adverse event, having an adverse event in each body system and having each individual adverse event.
  • PK profiles of ibrutinib [ Time Frame: At pre-dose, and at 1, 2, 4, and 6 hours on days 1 and 15 of course 1 and on day 1 of course 2 ]
    Plasma concentration-time profiles for each subject and mean plasma concentration-time profiles for each dose level will be plotted, plasma concentration data for ibrutinib at each time point will be summarized by descriptive statistics, and PK parameters such as maximum concentration (Cmax), minimum concentration, time at which the Cmax is reached, and area under the curve will be summarized with mean, geometric mean, medium, minimum, maximum, standard deviation, and coefficient of variation.
  • Reduction of mast cell burden [ Time Frame: Up to 2 years ]
    The burden of neoplastic mast cells will be determined by immunophenotyping and/or immunohistochemistry and will be compared between pre- and post-ibrutinib treatment samples. Reduction of mast cell burden will also be recorded pre- and post-ibrutinib therapy primarily by evaluation of peripheral blood (if mast cell leukemia) and bone marrow aspirate and core biopsy.
  • Histopathology review [ Time Frame: Up to 2 years ]
    Histopathology review will include analysis of peripheral blood smear (results of complete blood count should also be submitted). Change of serum tryptase levels from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Histopathology review [ Time Frame: Up to 2 years ]
    Histopathology review will include analysis of bone marrow aspirate. Change of serum tryptase levels from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Histopathology review [ Time Frame: Up to 2 years ]
    Histopathology review will include analysis of bone marrow core biopsy. Change of serum tryptase levels from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Histopathology review [ Time Frame: Up to 2 years ]
    Histopathology review will include review of any biopsied tissue with mast cell involvement. Change of serum tryptase levels from baseline at the respective assessments will be evaluated as a surrogate marker for histopathologic response.
  • Change in total symptom score assessed by a modified version of the MPNSAF [ Time Frame: Baseline to 30 days post-treatment ]
    Total symptom score will be assessed by a modified version of the MPNSAF (modified for mast cell symptoms) by recording mean and median scores with ranges will be recorded pre- and post-treatment with ibrutinib.
  • Change in QOL assessed by a modified version of the MPNSAF [ Time Frame: Baseline to 30 days post-treatment ]
    QOL will be assessed by a modified version of the MPNSAF (modified for mast cell symptoms) by recording mean and median scores with ranges will be recorded pre- and post-treatment with ibrutinib.
  • DoR [ Time Frame: Time from the start of the first confirmed response until the date of the first documented and confirmed disease progression or death due to ASM or MCL, assessed up to 2 years ]
    The Kaplan-Meier product-limit method will be used to summarize the response duration. If a responder did not progress or die due to ASM or MCL at the time of the analyses, DoR will be censored at the date of the last adequate response assessment.
  • TTR [ Time Frame: Time from the date of start of treatment to the date of first confirmed response, assessed up to 2 years ]
    TTR will be censored at the date of the last adequate response assessment in patients did not progress or die due to any cause and at maximum follow-up date (i.e. date of first patient first visit to date of last patient last visit used for the analysis) in patients who progressed or died due to any cause. Kaplan-Meier product-limit estimates will be used to summarize the time to response.
  • PFS [ Time Frame: Time from the date of start of treatment until the date of first documented confirmed disease progression or death or institution of new therapy, assessed up to 2 years ]
    If a patient did not progress or die due to any cause at the time of the analyses, PFS will be censored at the date of the last adequate response assessment. Kaplan-Meier product-limit estimates will be used to summarize PFS.
  • Overall survival [ Time Frame: Up to 2 years ]

    • Information By: Stanford University

    Dates:
    Date Received: March 24, 2015
    Date Started: March 2015
    Date Completion: June 2017
    Last Updated: December 13, 2016
    Last Verified: December 2016