Clinical Trials /

Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Patients With Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

NCT02315326

Description:

The purpose of this study is to test any good or bad effects of the study drug called of ibrutinib (also known as Imbruvica™) at 840mg daily dosing has on the patient and the lymphoma in the central nervous system.

Related Conditions:
  • Central Nervous System Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Patients With Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)
  • Official Title: A Phase I/II Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Patients With Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

Clinical Trial IDs

  • ORG STUDY ID: 14-184
  • NCT ID: NCT02315326

Conditions

  • Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL)
  • Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

Interventions

DrugSynonymsArms
IbrutinibImbruvicaIbrutinib
HD- Methotrexate (MTX)Ibrutinib
Rituximab + HD- Methotrexate (MTX)Ibrutinib

Purpose

The purpose of this study is to test any good or bad effects of the study drug called of ibrutinib (also known as Imbruvica™) at 840mg daily dosing has on the patient and the lymphoma in the central nervous system.

Trial Arms

NameTypeDescriptionInterventions
IbrutinibExperimentalThis is an open-label, non-randomized, single center, dose escalation, phase I/II study to establish the maximum-tolerated dose (MTD) of ibrutinib as a single agent in patients with refractory/recurrent PCNSL or refractory/recurrent SCNSL (Arm A). The defined MTD will then be used in an expansion cohort to further assess toxicity and clinical activity(Arm B). Arm C will investigate the MTD of ibrutinib in combination with HD-MTX and to determine the safety and tolerability of the ibrutinib/HD-MTX combination regimen in PCNSL and SCNSL patients. To minimize drug-drug interaction between HD-MTX and Ibrutinib, Ibrutinib will not be administered concurrently with HD-MTX.
  • Ibrutinib
  • HD- Methotrexate (MTX)
  • Rituximab + HD- Methotrexate (MTX)

Eligibility Criteria

        The population consists of adult patients with relapsed or refractory primary central
        nervous system lymphoma (PCNSL) or relapsed or refractory secondary central nervous system
        lymphoma (SCNSL)

        Patients eligible for inclusion in this study have to meet all the following criteria:

        Inclusion Criteria:

          -  Participants must be able to understand and be willing to sign a written informed
             consent document

          -  Men and woman who are at least 18 years of age on the day of consenting to the study

          -  Histologically documented PCNSL or histologically documented systemic diffuse large
             B-cell lymphoma (DLBCL)

          -  Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL

          -  All patients need to have received at least one prior CNS directed therapy. There is
             no restriction on the number of recurrences

          -  Patients with parenchymal lesions must have unequivocal evidence of disease
             progression on imaging (MRI of the brain or head CT) 21 days prior to study
             registration. For patients with leptomeningeal disease only, CSF cytology must
             document lymphoma cells and/or imaging findings consistent with CSF disease 21 days
             prior to study registration (at the discretion of the investigator)

          -  Participants must have an ECOG performance status of 0, 1, or 2

          -  Participants must have adequate bone marrow and organ function shown by:

               -  Absolute neutrophil count (ANC) ≥ 0.75 x 109/L

               -  Platelets ≥ 75 x 109/L and no platelet transfusion within the past 21 days prior
                  to study registration

               -  Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the
                  past 21 days prior to study registration

               -  International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper
                  limit of normal

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times
                  the upper limit of normal

               -  Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3
                  times the upper limit of normal with direct bilirubin within the normal range in
                  patients with well documented Gilbert Syndrome

               -  Serum creatinine ≤ 2 times the upper limit of normal

               -  Arm C: calculated creatinine clearance(CrCl) > 50ml/min using the
                  Cockcroft-Gault equation (Men: CrCl (min/ml) = (140-age) X (actual weight in kg)
                  / 72 X serum creatinine (mg/dL); Women: CrCl (ml/min) = (140-age) X (actual
                  weight in kg) X 0.85 / 72 X serum creatinine (mg/dL))

          -  Woman of reproductive potential must agree to use highly effective methods of birth
             control during the period of therapy and for 30 days after the last dose of the study
             drug. Men who are sexually active must agree to use highly effective contraception
             during the period of therapy and for 3 months after the last dose

          -  Female subjects of childbearing potential must have a negative plasma pregnancy test
             upon study entry. See section on Pregnancy and Reproduction

          -  Patients must be able to tolerate MRI/CT scans

          -  Patients must be able to tolerate lumbar puncture and/or Ommaya taps

          -  Participants must have recovered to grade 1 toxicity from prior therapy

          -  Participates must be able to submit 20 unstained formalin-fixed, paraffin-embedded
             (FFPE) slides from the initial tissue diagnosis prior to study registration for
             confirmation of diagnosis and correlative studies

          -  Arm C: SCNSL patient do not require one prior CNS directed treatment. Newly diagnosed
             SCNSL patient are eligible as long as there systemic disease has been treated and
             does not require any active treatment.

        NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT
        prevent patients from enrollment into the trial

        Exclusion Criteria:

          -  Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded

          -  Patient is concurrently using other approved or investigational antineoplastic agents

          -  Patient has received chemotherapy, monoclonal antibodies or targeted anticancer
             therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosurea,
             or mitomycin-C prior to starting the study drug, or the patient has not recovered
             from the side effects of such therapy Patient has received external beam radiation
             therapy to the CNSwithin 21 days of the first dose of the study drug

          -  Patient requires more than 8 mg of dexamethasone daily or the equivalent

          -  Patient has an active concurrent malignancy requiring active therapy

          -  The patient has been treated with radio- or toxin-immunoconjugates within 70 days of
             the first dose of the study drug

          -  Patient has previously taken is allergic to components of the study drug. For Arms A
             and B only: Patient has previously taken ibrutinib.

          -  Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K
             antagonists. Patients must be off warfarin-derivative anticoagulants for at least
             seven days prior to starting the study drug. Low molecular weight heparin is allowed.
             Patients with congenital bleeding diathesis are excluded

          -  Patient is taking a drug known to be a moderate and strong inhibitor or inducers of
             the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers
             for at least two weeks prior to starting the study drug

          -  Patient is using systemic immunosuppressant therapy, including cyclosporine A,
             tacrolimus, sirolimus, and other such medications, or chronic administration of > 5
             mg/day or prednisone or the equivalent. Participants must be off of immunosuppressant
             therapy for at least 28 days prior to the first dose of the study drug

          -  Patient has significant abnormalities on screening electrocardiogram (EKG) and active
             and significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis,
             or myocardial infarction within 6 months of screening

          -  Patient has a known bleeding diathesis (e.g. von Willebrand's disease) or hemophilia

          -  Patient is known to have human immunodeficiency virus (HIV) infection

          -  Patient is known to have a history of active or chronic infection with hepatitis C
             virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests

          -  Patient is known to have an uncontrolled active systemic infection

          -  Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial
             treatment or who has not recovered from the side effects of such surgery, or who plan
             to have surgery within 2 weeks of the first dose of the study drug

          -  Patient is unable to swallow capsules or has a disease or condition significantly
             affecting gastrointestinal function, such as malabsorption syndrome, resection of the
             stomach or small bowel, or complete bowel obstruction

          -  Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin >8% or
             poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of
             >8%

          -  Patient has a life-threatening illness, medical condition, or organ system
             dysfunction that, in the opinion of the investigator, could compromise the subject's
             safety or put the study outcomes at undue risk

          -  Women who are pregnant or nursing (lactating), where pregnancy is defined as a state
             of a female after conception until the termination of gestation, confirmed by a
             positive serum hCG laboratory test of > 5 mIU/mL (See section on Pregnancy and
             Reproduction)

          -  Patient has undergone prior allogenic stem cell transplant (autologous stem cell
             transplant is NOT an exclusion)

          -  The patient is unwell or unable to participate in all required study evaluations and
             procedures

          -  Patient is 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 (PHI) in accordance with national and local subject privacy
             regulations. A legal representative can consent on behalf of a patient who is able to
             understand the purpose and risk of the study but not able to provide a signature on
             the ICF and authorization to use PHI due to neurologic deficits (e.g. motor or
             language deficits)

          -  Arm C: Patients with a methotrexate allergies are excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:define the Maximum Tolerated Dose (MTD) of ibrutinib (phase I)
Time Frame:1 year
Safety Issue:
Description:A standard 3+3 design will be employed. Three dose levels of ibrutinib will be investigated. Patients will be treated in cohorts of size three to six and the dosage will be escalated if the clinical toxicity is acceptable. A dose-limiting toxicity (DLT) is defined as in any of the following during cycle 1: any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia associated with bleeding or any grade 3 non-hematologic toxicity that does not respond to supportive therapy and at least possibly related to treatment with ibrutinib.

Secondary Outcome Measures

Measure:safety/tolerability of ibrutinib in patients by assessing the frequency and severity of adverse events
Time Frame:1 year
Safety Issue:
Description:in patients by assessing the frequency and severity of adverse events. The severity grade (CTCAE Grade 1-4) Its duration (Start and end dates) Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily interrupted, permanently discontinued, unknown, ongoing, not applicable)
Measure:progression free survival
Time Frame:16 weeks, 24 weeks & 48 weeks
Safety Issue:
Description:Progression-free survival (PFS) is defined as the time from the date of treatment start to the date of the first documented PD or death due to any cause.
Measure:Duration of response
Time Frame:2 years
Safety Issue:
Description:Duration of response is defined as the time from the date of first occurrence of CR or PR to the date of the first documented PD or death due to any cause.Duration of response will be described using Kaplan-Meier curves with appropriate summary statistics

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Ibrutinib,
  • Imbruvica
  • Bruton's Tyrosine Kinase (BTK) Inhibitor
  • HD-MTX
  • 14-184

Last Updated

February 22, 2017