Inclusion Criteria:
- - >/= 18 years of age on the day of consenting to the study.
- - Histologically documented DLBCL at enrolling institution (biopsy or CSF samples in
PCNSL; 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 days
prior to study consent.
- - Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the
past 21 days prior to study consent.
- - International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper
limit of normal (unless receiving anticoagulation)
- 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.
- - Creatinine clearance (CLCr) ≥ 30 ml/min (based on the following formular
Creatinine clearance= ((140-age)*wt)/(creatinine*72); multiply by 0.85 for
women)
- Women 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 serum pregnancy test
upon 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 impaired
decision-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-Pugh
class B or C) are excluded.
- - Patient is concurrently using other approved or investigational antineoplastic
agents.
- - Patient has an active concurrent malignancy requiring active therapy.
- - Patient has received chemotherapy, monoclonal antibodies or targeted anticancer
therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosourea
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 CNS within 21 days of
the 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 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.
- - Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges), or starfruit for at least 3 days prior to
Cycle 1 Day 1.
- - Patient is taking a drug known to be a moderate or strong inhibitor or inducers of
the P450 isoenzyme CYP3A.
Participants must be off P450/CYP3A inhibitors and
inducers 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 > 5
mg/day of prednisone or the equivalent (for more than 12 months).
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 an ejection fraction of <50%
- Patient has a known bleeding diathesis (e.g. von Willebrand's disease) or
hemophilia.
- - Patient is documented to have human immunodeficiency virus (HIV) infection.
- - Patient is documented 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 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 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.
- - Patient has not received vaccination with live vaccines within 28 days prior to
first dose of study drug or is expected to need any live vaccination during study
participation including at least 3 months following the last dose of study
treatment.
Note: COVID-19 non-replicating adenoviral vaccines are permitted with a
minimum period of 3 days between the vaccine and a dose of study drug. It is highly
recommended that every patient enrolled onto this trial has updated vaccination
status (e.g. flu, hepatitis, polio, pertussis, tetanus; when is doubt please contact
the PI or side-PI).
- - 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.
Pregnancy and Reproduction.Women:
- - Women are considered post-menopausal and not of childbearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (i.e. age appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum FSH levels >40 mIU/mL and estradiol < 20 pg/mL or
have had surgical bilateral oophorectomy with or without hysterectomy at least six
weeks prior to enrollment in the study.
In the case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up of hormone
level assessment is she considered not of childbearing potential.
- - Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during study treatment
and for 4 months after study discontinuation.
Highly effective contraception is
defined as either.
- - True abstinence: When this is the line with the preferred and usual lifestyle
of the subject.
Periodic abstinence (e.g. calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception.
- - 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 of
the absence of sperm in the ejaculate).
For female patients participating in
the study, the vasectomized male partner should be the sole partner for that
patient.
- - 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 cervical
vault caps) with spermicidal form/gel/film/cream/vaginal suppository.
- - Women of child-bearing potential must have one negative serum pregnancy tests at
screening.
- - In addition to having a negative pregnancy test confirmed at screening, all female
participants of child bearing potential must have a negative pregnancy test
confirmed within 48 hours prior to dosing with the study drug.
Men:
- - Fertile males, defined as all male subjects physiologically capable of conceiving
offspring, must use a condom during study treatment and for 4 months after study
discontinuation and should not father a child in this period.
- - Female partner of a male study subject should use a highly effective method of
contraception while the male partner is receiving the study agent and for 4 months
after 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 and
exclusion criteria are not expected to differentially impact recruitment or
retention 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 24
hours 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 14
days from SARS-CoV-2 vaccine administration.
- - A minimum period of 3 days must occur between the administration of an appropriate
COVID-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.
