Adult Patients With Newly Diagnosed or Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL)Phase 1/2NCT02315326

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 1/2 study testing Ibrutinib, HD- Methotrexate (MTX) and Rituximab + HD- Methotrexate (MTX) in people with Adult Patients With Newly Diagnosed or Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL) and Or Relapsed or Refractory Secondary Central Nervous System Lymphoma (SCNSL), run by Memorial Sloan Kettering Cancer Center at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: 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)
What is being tested?: Ibrutinib, HD- Methotrexate (MTX) and Rituximab + HD- Methotrexate (MTX)
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 93 participants
Where: 7 sitesUnited States
Study dates: 8 Dec 2014to 28 Jan 2026
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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).

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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
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.

Who cannot join

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

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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)

Trial locations and contacts

7 sites in 1 country.

City, postcode or hospital

7 sites in 1 country

United States7 sites

Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
Basking Ridge, New Jersey
Memorial Sloan Kettering Commack (Limited Protocol Activities)
Commack, New York, 11725
Memorial Sloan Kettering Westchester (Limited Protocol Activities)
Harrison, New York, 10604
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen (Limited Protocol Activities)
Montvale, New Jersey, 07645
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Memorial Sloan Kettering Nassau (Limited Protocol Activities)
Uniondale, New York, 11553

Other trials in United States

About this study

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)

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)
Being tested: Ibrutinib, HD- Methotrexate (MTX), Rituximab + HD- Methotrexate (MTX), procarbazine
Keywords: Ibrutinib,, Imbruvica™, Bruton's Tyrosine Kinase (BTK) Inhibitor, HD-MTX, 14-184
Medical subject headings: Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

IbrutinibDrug
Also called Imbruvica™
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.
HD- Methotrexate (MTX)Drug
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)
Rituximab + HD- Methotrexate (MTX)Drug
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.
procarbazineDrug
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.

Study groups in NCT02315326
Study group	Role	What they receive
Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	This 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). Receives: Drug: Ibrutinib; Drug: HD- Methotrexate (MTX); Drug: Rituximab + HD- Methotrexate (MTX)
Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	The defined MTD from Arm A will then be used in an expansion cohort to further assess toxicity and clinical activity Receives: Drug: Ibrutinib; Drug: HD- Methotrexate (MTX); Drug: Rituximab + HD- Methotrexate (MTX)
Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	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. Receives: Drug: Ibrutinib; Drug: HD- Methotrexate (MTX); Drug: Rituximab + HD- Methotrexate (MTX)
Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	THIS 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. Receives: Drug: Ibrutinib; Drug: HD- Methotrexate (MTX); Drug: Rituximab + HD- Methotrexate (MTX); Drug: procarbazine

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 1 year

Secondary outcomes (3)

safety/tolerability of ibrutinib in patients by assessing the frequency and severity of adverse events
in patients by assessing the frequency and severity of adverse events.
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily interrupted, permanently discontinued, unknown, ongoing, not applicable)
Measured: 1 year
progression free survival
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.
Measured: 16 weeks, 24 weeks & 48 weeks
Duration of response
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
Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

8 Dec 201428 Jan 2026

First posted11 Dec 2014 (estimated)
Study start8 Dec 2014
Primary completion28 Jan 2026
Study completion28 Jan 2026

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Adult Patients With Newly Diagnosed or Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL)Studies of the same condition, open and under way.
More trials run by Memorial Sloan Kettering Cancer CenterThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Enrolment: 93 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02315326
Sponsor's protocol ID: 14-184
Status last verified: Jan 2026
First submitted: 9 Dec 2014
Last updated: 2 Feb 2026
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

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.
PubMed 33966087
Grommes 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.
PubMed 30567753

Study at a glance

From the registry record, last updated by the sponsor on 2 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT02315326
Acronym / sponsor ID: 14-184
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)
Keywords: Ibrutinib,, Imbruvica™, Bruton's Tyrosine Kinase (BTK) Inhibitor, HD-MTX, 14-184
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 93 participants (actual)
Lead sponsor: Memorial Sloan Kettering Cancer CenterUniversity, hospital or other
Collaborators: Pharmacyclics LLC., Janssen Biotech, Inc.
Study start: 8 Dec 2014 (actual)
Primary completion: 28 Jan 2026 (actual)
Study completion: 28 Jan 2026 (actual)
First posted: 11 Dec 2014 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 4

Arm	Type	Receives
Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	Drug: Ibrutinib, Drug: HD- Methotrexate (MTX), Drug: Rituximab + HD- Methotrexate (MTX)This 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	Experimental	Drug: Ibrutinib, Drug: HD- Methotrexate (MTX), Drug: Rituximab + HD- Methotrexate (MTX)The 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	Experimental	Drug: Ibrutinib, Drug: HD- Methotrexate (MTX), Drug: Rituximab + HD- Methotrexate (MTX)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.
Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL	Experimental	Drug: Ibrutinib, Drug: HD- Methotrexate (MTX), Drug: Rituximab + HD- Methotrexate (MTX), Drug: procarbazineTHIS 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (23 listed)

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)

Key exclusion criteria (25 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
IbrutinibAlso: Imbruvica™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.	Drug	Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
HD- Methotrexate (MTX)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)	Drug	Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
Rituximab + HD- Methotrexate (MTX)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.	Drug	Arm A: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm B: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm C: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL, Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL
procarbazineArm 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.	Drug	Arm D: Participants with refractory/recurrent PCNSL or refractory/recurrent SCNSL

Primary outcome

define the Maximum Tolerated Dose (MTD) of ibrutinib (phase I)
Time frame: 1 year
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.
progression free survival (phase II)
Time frame: 2 years
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.
define the Maximum Tolerated Dose (MTD) of ibrutinib in combination with high-dose Methotrexate (HD-MTX)
Time frame: 1 year
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.

3 secondary outcomes

safety/tolerability of ibrutinib in patients by assessing the frequency and severity of adverse events
Time frame: 1 year
progression free survival
Time frame: 16 weeks, 24 weeks & 48 weeks
Duration of response
Time frame: 2 years

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2026.
Derived from this study: PubMed 33966087Krebs 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.
Derived from this study: PubMed 30567753Grommes 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.
Memorial Sloan Kettering Cancer CenterLink provided by the sponsor.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Christian Grommes, MD principal investigator

Memorial Sloan Kettering Cancer Center

7 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

define the Maximum Tolerated Dose (MTD) of ibrutinib (phase I) (time frame: 1 year). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02315326, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2026.