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)
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)
1 other identifier
interventional
93
1 country
7
Brief Summary
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 Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Dec 2014
Longer than P75 for phase_1
7 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
December 8, 2014
CompletedFirst Submitted
Initial submission to the registry
December 9, 2014
CompletedFirst Posted
Study publicly available on registry
December 11, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 28, 2026
CompletedStudy Completion
Last participant's last visit for all outcomes
January 28, 2026
CompletedFebruary 2, 2026
January 1, 2026
11.1 years
December 9, 2014
January 29, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
define the Maximum Tolerated Dose (MTD) of ibrutinib (phase I)
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.
1 year
progression free survival (phase II)
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.
2 years
define the Maximum Tolerated Dose (MTD) of ibrutinib in combination with high-dose Methotrexate (HD-MTX)
Three patients with PCNSL or SCNSL will be treated with daily oral ibrutinib +/- HD-MTX for a 28-day cycle starting at dose level 1 and observed for toxicities for a minimum of 4 weeks. Dose-limiting toxicity (DLT) will be defined as any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia associated with bleeding as well as any grade 3 non-hematologic toxicity that does not respond to supportive therapy and at least possibly related to ibrutinib. If no DLT is observed in any of the 3 treated patients, we will escalate to the next dose level.
1 year
Secondary Outcomes (3)
safety/tolerability of ibrutinib in patients by assessing the frequency and severity of adverse events
1 year
progression free survival
16 weeks, 24 weeks & 48 weeks
Duration of response
2 years
Study Arms (4)
Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
EXPERIMENTALThis 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).
Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
EXPERIMENTALThe defined MTD from Arm A will then be used in an expansion cohort to further assess toxicity and clinical activity
Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
EXPERIMENTALArm 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.
Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
EXPERIMENTALTHIS 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.
Interventions
Arm A: Ibrutinib will be given once daily. The starting dose cohort (level 1) will receive 560 mg/day (4 x 140 mg capsules). During the dose escalation period of the study, the "3+3" design will be applied (see Table 3). Participants will be assigned to cohorts of increasing oral daily doses of ibrutinib (560mg, 840mg) until disease progression, intolerable toxicity or death. Three patients with recurrent/refractory PCNSL or recurrent/refractory SCNSL will be treated with daily oral ibrutinib for a 28-day cycle starting at dose level 1 and observed for toxicities during cycle 1. Arm B: Ibrutinib will be given at the MTD defined in Arm A.
Arm C1: HD-MTX at 3.5g/m2 (standard hydration/leucovorin support) will be given on day 1 and 15 of each 28-day cycle for a total of 4 cycles totaling 8 HD-MTX administrations. Ibrutinib will be given between days 5 and 14 as well as days 19 and 28 of each cycle and continued daily after completion of HD-MTX treatments.The starting dose of ibrutinib is 560 mg/day (4x140mg capsules)
Arm C2: Intravenous rituximab (500mg/m2) will be given on day 0, 14, and 28 of cycle 1 and day 14 and 28 of all following cycles. HD-MTX at 3.5g/m2 (standard hydration/leucovorin support) will be given on day 1 and 15 of each 28-day cycle for a maximum of 4 cycles totaling 8 HD-MTX administrations. Ibrutinib will be given between days 5 and 14 as well as days 19 and 28 of each cycle and continued daily after completion of HD-MTX treatments. The starting dose of ibrutinib is 560 mg/day (4x140mg capsules; dose level 1) (see Table 4). Filgrastim will be given at days 7-11 and 22-26.
Arm D: THIS IS THE ONLY ARM RECRUITING: : Oral procarbazine (100mg/m2/day) will be given on Day 1 through 7 during each cycle. Patients will be maintained on a tyramine-free diet during procarbazine administration.
Eligibility Criteria
You may qualify if:
- 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
- Within the past 21 days prior to study registration (for Arm D: prior to treatment initiation) 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
- +8 more criteria
You may not qualify if:
- 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
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Memorial Sloan Kettering Cancer Centerlead
- Pharmacyclics LLC.collaborator
- Janssen Biotech, Inc.collaborator
Study Sites (7)
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
Middletown, New Jersey, 07748, United States
Memorial Sloan Kettering Bergen (Limited Protocol Activities)
Montvale, New Jersey, 07645, United States
Memorial Sloan Kettering Commack (Limited Protocol Activities)
Commack, New York, 11725, United States
Memorial Sloan Kettering Westchester (Limited Protocol Activities)
Harrison, New York, 10604, United States
Memorial Sloan Kettering Cancer Center
New York, New York, 10065, United States
Memorial Sloan Kettering Nassau (Limited Protocol Activities)
Uniondale, New York, 11553, United States
Related Publications (2)
Krebs S, Mauguen A, Yildirim O, Hatzoglou V, Francis JH, Schaff LR, Mellinghoff IK, Schoder H, Grommes C. Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies. Eur J Nucl Med Mol Imaging. 2021 Nov;48(12):3940-3950. doi: 10.1007/s00259-021-05386-0. Epub 2021 May 8.
PMID: 33966087DERIVEDGrommes C, Tang SS, Wolfe J, Kaley TJ, Daras M, Pentsova EI, Piotrowski AF, Stone J, Lin A, Nolan CP, Manne M, Codega P, Campos C, Viale A, Thomas AA, Berger MF, Hatzoglou V, Reiner AS, Panageas KS, DeAngelis LM, Mellinghoff IK. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019 Jan 31;133(5):436-445. doi: 10.1182/blood-2018-09-875732. Epub 2018 Dec 19.
PMID: 30567753DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Christian Grommes, MD
Memorial Sloan Kettering Cancer Center
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 9, 2014
First Posted
December 11, 2014
Study Start
December 8, 2014
Primary Completion
January 28, 2026
Study Completion
January 28, 2026
Last Updated
February 2, 2026
Record last verified: 2026-01