Pembrolizumab, Ibrutinib, and Rituximab for the Treatment of Recurrent Primary Central Nervous System Lymphoma
- Participant must be able to understand and willing to sign a written informed consent document
- Participant must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care
- Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study
- Subjects with pathologically confirmed PCNSL who progressed after at least 1 line of central nervous system (CNS)-directed therapy (for phase Ib patients, an unlimited amount of progressions is allowed and can also include relapse; for phase II, only first recurrence is allowed). Recurrent subjects (for phase II only) that have previously responded to and completed initial therapy at least 4 weeks prior to screening
- PCNSL subjects should have evidence of measurable or evaluable enhancing disease on magnetic resonance imaging (MRI)
- Able to submit at least 10 but up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial or most recent tissue diagnosis for correlative studies. Histologically confirmed tissue will be required from the time of relapse or at the time of initial surgery. If tissue is unavailable and/or diagnosis was made from CSF or vitreal biopsy, approval from the overall principal investigator (PI) is needed
- Subjects must have a Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (evaluation of ECOG is to be performed within 7 days prior to the date of registration)
- Life expectancy of > 3 months (in the opinion of the investigator)
- Toxicities due to prior therapy must be stable and recovered to =< grade 1
- Must be able to tolerate lumbar puncture and/or Ommaya taps
- White blood count (WBC) >= 2 K/uL (within 14 days of treatment initiation)
- Platelet count >= 100 K/uL (within 14 days of treatment initiation)
- Absolute neutrophil count >= 1.5 K/uL (within 14 days of treatment initiation)
- Hemoglobin > 9.0 g/dL or >= 5.6 mmol/L (criteria must be met without erythropoietin dependency and without packed red blood cell [pRBC] transfusion within last 2 weeks) (within 14 days of treatment initiation)
- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (creatinine clearance should be calculated per institutional standard) (within 14 days of treatment initiation)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 14 days of treatment initiation)
- Total bilirubin (TBILI) =< 1.5 x institutional ULN (except subjects with Gilbert syndrome who must have a total bilirubin level of < 3.0 x institutional ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN) (within 14 days of treatment initiation)
- International normalized ratio (INR) OR prothombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x institutional ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
- Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy within 72 hours prior to registration. Women in the following categories are not considered WOCBP: * Premenarchal * Premenopausal female with 1 of the following: ** Documented hysterectomy ** Documented bilateral salpingectomy ** Documented bilateral oophorectomy ** Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview * Postmenopausal female ** A postmenopausal state is defined as no menses for 12 months without an alternative medical cause *** A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required * Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
- Women of child-bearing potential (WOCBP; see definition above), must agree to use a highly effective method of contraception consistently and correctly as described below during study treatment and for 120 days after study discontinuation * Highly effective contraceptive methods that are user dependent (failure rate of < 1% per year when used consistently and correctly.) ** Combined (estrogen- and progestogen- containing) hormonal contraception *** Oral *** Intravaginal *** Transdermal *** Injectable ** Progestogen-only hormonal contraception *** Oral *** Injectable * Highly effective methods that have low user dependency (failure rate of < 1% per year when used consistently and correctly) ** Progestogen- only contraceptive implant ** Intrauterine hormone-releasing system (IUS) ** Intrauterine device (IUD) ** Bilateral tubal occlusion ** Vasectomized partner *** A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used ** Sexual abstinence *** Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant * NOTES: Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies ** Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly) ** If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, condoms must be used in addition to the hormonal contraception during the treatment period and for at least during study treatment and for 120 days after study discontinuation after the last dose of study treatment ** If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation
- Male participants must agree to use at least one of the following methods of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy: * Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent * Use a male condom plus partner use of a contraceptive method with a failure rate of < 1% per year when having penilevaginal intercourse with a woman of childbearing potential who is not currently pregnant ** Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration
- Patients who cannot undergo MRI brain
- Patients with large brain stem lesions
- Intraocular PCNSL without evidence of brain or spinal cord disease
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
- Previous ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor use
- Subjects that have progressed while on initial line therapy (refractory) are not allowed for phase II part of the study
- Patients with >= grade 2 intracranial hemorrhage
- Subjects on anticoagulation are excluded, but the use of anticoagulants for the treatment of thromboembolism is allowed, if pulmonary embolism (PE)/deep vein thrombosis (DVT) is diagnosed while on study
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
- Active autoimmune disease requiring immunosuppressive agents or steroids (prednisone > 10 mg or equivalent)
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Requires treatment for PCNSL with high dose systemic corticosteroids defined as dexamethasone > 4 mg/day or bioequivalent for > 3 consecutive days within 2 weeks of registration
- Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to dosing. OR 5 half-lives, whichever is shorter Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible
- Patients who underwent major surgery =< 2 weeks before starting study treatment are excluded. If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Patients who plan to undergo surgery within 2 weeks of first dose of study treatment are excluded
- Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease. Has received prior radiotherapy to CNS disease within 2 weeks of start of study treatment
- Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
- Has severe hypersensitivity (>= grade 3) to study agents and/or any of its excipients
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Patient is known to have an uncontrolled active systemic infection (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and recent infection requiring intravenous anti-infective treatment that was completed =< 14 days before the first dose of study drug
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association > class 2), unstable angina, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional classification
- Uncontrolled hypertension despite optimal medical management (per investigator’s assessment)
- Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin > 8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of > 8%
- Non-healing wound, ulcer or bone fracture
- Known bleeding diathesis (e.g., von Willebrand’s disease) or hemophilia
- Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction
- Concurrent administration of medications or foods that are moderate or strong inhibitors or strong inducers of cytochrome P450 (CYP) 3A4/5 (need to be discontinued 2 weeks before starting study treatment)
- Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a non-EIAED 2 weeks prior to starting on trial drugs
- Has known history of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
- Has a known history of active TB (Bacillus tuberculosis)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent)
- Patients who have undergone prior allogeneic stem cell transplant
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
I. To assess the clinical efficacy of the combination of pembrolizumab, rituximab and ibrutinib in recurrent primary central nervous system lymphoma (PCNSL) as measured by progression-free survival rate at 6 months (PFS-6).
I. To assess the safety and tolerability of the combination of pembrolizumab, ibrutinib and rituximab in recurrent PCNSL.
II. To assess the anti-tumor activity of the combination of pembrolizumab, ibrutinib, and rituximab, as determined objective response rate (ORR).
III. To assess duration of response (DOR), progression-free survival (PFS) and overall survival (OS) in patients treated with the combination of pembrolizumab, ibrutinib and rituximab.
IV. To assess tolerability throughout study therapy with pembrolizumab, ibrutinib, and rituximab, including beyond the maximum tolerated dose (MTD) interval with the following measure of cumulative treatment-related toxicities:
IVa. Frequency of toxicities leading to missed doses or delays
IVb. Percentage of cycles given or not within 7 days of their scheduled times
IVc. Percentage of actual planned dosage administration
IVd. Percentage of patients that discontinue study drugs due to treatment-related toxicity.
I. To assess tumor tissue and cerebrospinal fluid (CSF) specifically for recurrent somatic mutations (such as MYD88 and CD79B), key copy number alterations (9p24.1) and structural rearrangements associated with PCNSL in addition to PDL1/PDL2 status and correlate with response or resistance to treatment.
II. To assess peripheral blood and CSF immune cell subsets by conventional flow cytometry and single cell ribonucleic acid sequencing (RNAseq) and correlate with response or resistance to treatment.
III. To evaluate neurologic function and response of patients on treatment using the neurologic assessment in neurooncology (NANO) scale.
IV. To correlate apparent diffusion coefficient (ADC)/diffusion weighted imaging (DWI)/perfusion magnetic resonance (MR) imaging to clinical response.
OUTLINE: This is a phase I, dose-escalation study of ibrutinib followed by a phase II study.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, and ibrutinib orally (PO) once daily (QD) on days 1-21. Patients also receive rituximab IV on days 1, 8, and 15 of cycle 1 and day 1 of cycle 2. Treatment with pembrolizumab and ibrutinib repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 90 days, and then every 12 weeks thereafter.
Trial Phase Phase I/II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 20-144
- Secondary IDs NCI-2020-06772
- Clinicaltrials.gov ID NCT04421560