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Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Patients With Newly Diagnosed or 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 this stage of this trial, the study is investigating whether Ibrutinib can be incorporated into the established first-line chemotherapy regimen rituximab, methotrexate, vincristine, and procarbazine (R-VMP) in order to further refine the first-line induction therapy for PCNSL, as observed by a superior CRR (complete response rate) (ARM D RECRUITING ONLY)

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Patients With Newly Diagnosed or 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 Newly Diagnosed or 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

  • Adult Patients With Newly Diagnosed or Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL)
  • Or Relapsed or Refractory Secondary Central Nervous System Lymphoma (SCNSL)

Interventions

DrugSynonymsArms
IbrutinibImbruvicaArm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
HD- Methotrexate (MTX)Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
Rituximab + HD- Methotrexate (MTX)Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
procarbazineArm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL

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 this stage of this trial, the study is investigating whether Ibrutinib can be incorporated into the established first-line chemotherapy regimen rituximab, methotrexate, vincristine, and procarbazine (R-VMP) in order to further refine the first-line induction therapy for PCNSL, as observed by a superior CRR (complete response rate) (ARM D RECRUITING ONLY)

Trial Arms

NameTypeDescriptionInterventions
Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimentalThis 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).
  • Ibrutinib
  • HD- Methotrexate (MTX)
  • Rituximab + HD- Methotrexate (MTX)
Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimentalThe defined MTD from Arm A will then be used in an expansion cohort to further assess toxicity and clinical activity
  • Ibrutinib
  • HD- Methotrexate (MTX)
  • Rituximab + HD- Methotrexate (MTX)
Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimentalArm 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)
Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSLExperimentalTHIS IS ONLY ARM RECRUITING In Arm D, patients will be treated with 4 cycles of therapy. Methotrexate (3.5 g/m2) will be given at Dday 1 and Dday 15 of each cycle. Rituximab (500 mg/m2) will be given at Dday 0 and Dday 15 of each cycle. Vincristine (1.4mg/m2) will be given at Dday 1 and 15 of cycle 1 and 2 only. Procarbazine (100mg/m2) will be given of Day 1 of each cycle. Ibrutinib will be dosed at 560 mg daily. Arm D will have a safety lead-in of 6 patients. If more than 1 of 6 subjects develop a dose limiting toxicity (DLT) within the first 28 days of therapy (cycle 1), ibrutinib will be reduced to 420 mg daily dosing, and 6 additional patients will be enrolled. If more than 1 of 6 subjects develop a DLT, additional enrollment will be stopped.
  • Ibrutinib
  • HD- Methotrexate (MTX)
  • Rituximab + HD- Methotrexate (MTX)
  • procarbazine

Eligibility Criteria

        The population consists of adult patients with newly diagnosed or 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 or cystologically documented PCNSL or histologically documented
             systemic diffuse large B-cell lymphoma (DLBCL)

          -  Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL (Arm A, B,
             C) or newly diagnosed PCNSL (Arm D)

          -  All patients need to have received at least one prior CNS directed therapy. There is
             no restriction on the number of recurrences (Arm A, B , C only)

          -  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) (Arm A, B , C
             only).

          -  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 (Arm A, B , C
             only)

          -  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 C1 and C2: SCNSL patients do not
             require one prior CNS directed treatment. Newly diagnosed SCNSL patients are eligible
             as long as their systemic disease has been treated and does not require any active
             treatment.

        Arm D: PCNSL patients without one prior CNS directed treatment.

        Exclusion Criteria:

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

          -  Patient is concurrently using other approved or investigational antineoplastic agents.
             Investigational supportive agents are permitted.

          -  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 therapy (Arm
             A, B , C only)

          -  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 therapy (Arm A, B ,
             C only).

          -  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 A, B , C only)

        Arm C and D: Patients with a methotrexate allergies are excluded.

        Arm D: Patients with pre-existing peripheral motor or sensory neuropathy ≥ grade 3 (CTCAE
        5.0)
      
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

June 8, 2021