A Study of Epcoritamab and Ibrutinib in People With Central Nervous System Lymphoma (CNSL)

Inclusion Criteria:

• >/= 18 years of age on the day of consenting to the study.

• Histologically documented DLBCL at enrolling institution (biopsy or CSF samples inPCNSL; biopsy of CNS or non-CNS sample in SCNSL)

• 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) ≥ 1 x 109/L

• Platelets ≥ 75 x 109/L and no platelet transfusion within the past 21 daysprior to study consent

• Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within thepast 21 days prior to study consent

• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upperlimit of normal (unless receiving anticoagulation)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 timesthe upper limit of normal

• Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3times the upper limit of normal with direct bilirubin within the normal rangein patients with well documented Gilbert Syndrome.

• Creatinine clearance (CLCr) ≥ 30 ml/min (based on the following formularCreatinine clearance= ((140-age)wt)/(creatinine72); multiply by 0.85 forwomen)

• Women of reproductive potential must agree to use highly effective methods of birthcontrol during the period of therapy and for 30 days after the last dose of thestudy drug. Men who are sexually active must agree to use highly effectivecontraception during the period of therapy and for 3 months after the last dose

• Female subjects of childbearing potential must have a negative serum pregnancy testupon study entry. See section on Pregnancy and Reproduction.

• Patients must be able to tolerate MRI/CT scans.

• Due to the nature of this disease, we will allow patients with impaireddecision-making ability to enroll into all cohorts.

Exclusion Criteria:

• Newly diagnosed PCNSLs or SCNSLs and patients with non-CNS disease are excluded.

• Patients with existing chronic moderate and severe hepatic impairment (Child-Pughclass B or C) are excluded

• Patient is concurrently using other approved or investigational antineoplasticagents.

• Patient has an active concurrent malignancy requiring active therapy

• Patient has received chemotherapy, monoclonal antibodies or targeted anticancertherapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosoureaor mitomycin-C prior to starting the study drug, or the patient has not recoveredfrom the side effects of such therapy.

• Patient has received external beam radiation therapy to the CNS within 21 days ofthe first dose of the study drug.

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

• Patient is using warfarin or any other warfarin-derivative anticoagulant or vitaminK antagonists. Patients must be off warfarin-derivative anticoagulants for at leastseven days prior to starting the study drug. Low molecular weight heparin isallowed. Patients with congenital bleeding diathesis are excluded.

• Subject has consumed grapefruit, grapefruit products, Seville oranges (includingmarmalade containing Seville oranges), or starfruit for at least 3 days prior toCycle 1 Day 1

• Patient is taking a drug known to be a moderate or strong inhibitor or inducers ofthe P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors andinducers for at least 5 half-lives or at least two weeks, whichever is shorter,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 > 5mg/day of prednisone or the equivalent (for more than 12 months). Participants mustbe off of immunosuppressant therapy for at least 28 days prior to the first dose ofthe study drug.

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

• Patient has an ejection fraction of <50%

• Patient has a known bleeding diathesis (e.g. von Willebrand's disease) orhemophilia.

• Patient is documented to have human immunodeficiency virus (HIV) infection.

• Patient is documented to have a history of active or chronic infection withhepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.

• Patient is known to have an uncontrolled active systemic infection.

• Patient is unable to swallow capsules or has a disease or condition significantlyaffecting gastrointestinal function, such as malabsorption syndrome, resection ofthe stomach or small bowel, or complete bowel obstruction.

• Patient has a life-threatening illness, medical condition, or organ systemdysfunction that, in the opinion of the investigator, could compromise the subject'ssafety or put the study outcomes at undue risk.

• Patient has not received vaccination with live vaccines within 28 days prior tofirst dose of study drug or is expected to need any live vaccination during studyparticipation including at least 3 months following the last dose of studytreatment. Note: COVID-19 non-replicating adenoviral vaccines are permitted with aminimum period of 3 days between the vaccine and a dose of study drug. It is highlyrecommended that every patient enrolled onto this trial has updated vaccinationstatus (e.g. flu, hepatitis, polio, pertussis, tetanus; when is doubt please contactthe PI or side-PI).

• Women who are pregnant or nursing (lactating), where pregnancy is defined as a stateof a female after conception until the termination of gestation, confirmed by apositive serum hCG laboratory test of > 5 mIU/mL

Pregnancy and Reproduction

Women:

• Women are considered post-menopausal and not of childbearing potential if they havehad 12 months of natural (spontaneous) amenorrhea with an appropriate clinicalprofile (i.e. age appropriate, history of vasomotor symptoms) or six months ofspontaneous amenorrhea with serum FSH levels >40 mIU/mL and estradiol < 20 pg/mL orhave had surgical bilateral oophorectomy with or without hysterectomy at least sixweeks prior to enrollment in the study. In the case of oophorectomy alone, only whenthe reproductive status of the woman has been confirmed by follow up of hormonelevel assessment is she considered not of childbearing potential.

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, must use highly effective contraception during study treatmentand for 4 months after study discontinuation. Highly effective contraception isdefined as either

• True abstinence: When this is the line with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Sterilization: Surgical bilateral oophorectomy, with or without hysterectomy,or tubal ligation at least six weeks prior to study enrollment.

• Male partner sterilization (with appropriate post-vasectomy documentation ofthe absence of sperm in the ejaculate). For female patients participating inthe study, the vasectomized male partner should be the sole partner for thatpatient.

• Use of a combination of any two of the following:

• Placement of an intrauterine device (IUD) or intrauterine system (IUS)

• Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervicalvault caps) with spermicidal form/gel/film/cream/vaginal suppository

• Women of child-bearing potential must have one negative serum pregnancy tests atscreening

• In addition to having a negative pregnancy test confirmed at screening, all femaleparticipants of child bearing potential must have a negative pregnancy testconfirmed within 48 hours prior to dosing with the study drug.

Men:

• Fertile males, defined as all male subjects physiologically capable of conceivingoffspring, must use a condom during study treatment and for 4 months after studydiscontinuation and should not father a child in this period.

• Female partner of a male study subject should use a highly effective method ofcontraception while the male partner is receiving the study agent and for 4 monthsafter the final dose of the study therapy.

Inclusion of women, minorities or other underrepresented populations

• Ibrutinib and epcoritamab are not known to differentially affect subpopulations,including women, minorities, or other underrepresented groups. The eligibility andexclusion criteria are not expected to differentially impact recruitment orretention of these subpopulations.

Covid-19 eligibility criteria

Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection.

Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:

• No signs/symptoms suggestive of active SARS-CoV-2 infection

• Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24hours apart

Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g. mRNA, non-replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infections may be administered during screening or the treatment period, as long as components of the vaccine are not contraindicated. COVID-19 vaccines are permitted and strongly recommended.

The decision to receive a locally available vaccine should be based on local guidance and an individual discussion between the treating physician and the subject.

The potential impact of epcoritamab on SARS-CoV-2 vaccination is unknown. Therefore, study drug should be administered as follows:

• The first dose of study drug, when possible, is preferred to be given at least 14days from SARS-CoV-2 vaccine administration.

• A minimum period of 3 days must occur between the administration of an appropriateCOVID-19 vaccine and the administration od epcoritamab (to avoid overlapping AEs).

Note: The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete vaccination course.

These recommendations may be subject to change based on the evolving knowledge around the use of SARS-Cov-2 vaccines in subjects with recurrent/refractory DLBCL or cFL and as more data are collected in real-world scenarios and clinical trials.