A Phase 2 Trial Investigating Epcoritamab in Patients with Previously Treated Waldenstrom Macroglobulinemia (WM)

This study is being done to determine if epcoritamab can be used to treat participants
with previously treated Waldenstrom Macroglobulinemia (WM).

The names of the study drug involved in this study is:

-Epcoritamab (a type of antibody)

Inclusion Criteria:

- A diagnosis of lymphoplasmacytic lymphoma/WM that is CD20+ by immunophenotype or
immunohistochemistry confirmed by bone marrow biopsy/aspirate (fresh or archival
tissue acceptable) at time of most recent progression. All degrees of CD20
positivity will be accepted.

- Serum IgM level >2x upper limit of normal (ULN)

- Meeting criteria for initiation of treatment per IWWM2 criteria [Kyle Semin Oncol
2002], including but not limited to hyperviscosity syndrome, peripheral neuropathy,
cold agglutinin disease, cryoglobulinemia, amyloidosis, cytopenias due to bone
marrow infiltration, symptomatic or bulky lymph nodes, symptomatic splenomegaly,
constitutional symptoms not otherwise explained by other causes, signs of organ
dysfunction secondary to WM

- At least one prior line of treatment that was discontinued either due to intolerance
or disease progression

- Prior therapies must have included an anti-CD20 antibody (e.g. rituximab) and a BTK
inhibitor (e.g. ibrutinib, zanubrutinib). Patients who received ibrutinib and
rituximab in combination as first line therapy will be eligible. BTKi should be
stopped to allow a washout period of no less than 4 half-lives prior to epcoritamab.

- Age ≥18 years

- ECOG performance status £ 2

- Life expectancy of greater than 2 years

- Participants must meet the following organ and marrow function as defined below:

- absolute neutrophil count ≥1000 cells/mcl (G-CSF allowed)

- absolute lymphocyte count ≥200 cells/mcl

- platelets ≥75,000 cells/mcl OR ≥50,000 cells/mcl in the presence of bone marrow
involvement or splenomegaly (Note: no PLT transfusions within 7 days prior to
screening)

- hemoglobin ≥ 8 g/dL (transfusion allowed)

- total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). In patients
with suspected/known Gilbert's disease total bilirubin up to 3x ULN will be
allowed but direct bilirubin must be ≤ 2 x ULN

- AST(SGOT)/ALT(SGPT) ≤3× institutional ULN

- creatinine ≤ institutional ULN OR

- creatinine clearance >45 ml/min (by Cockcroft-Gault estimate or 24-hr
creatinine clearance measurement)

- Subject does not have an active (PCR-positive) Hepatitis B virus (HBV) or Hepatitis
C virus (HCV) infection. If laboratory evidence for a chronic infection with
hepatitis B, close monitoring and prophylactic therapy is required as described in
Section 5.4.

- Participants with a history of prior malignancy will be eligible if all treatment of
that malignancy was completed at least 2 years before registration, the treatment
was considered "curable-intent", and there is no evidence of disease.

- Ability to understand and the willingness to sign a written informed consent
document.

- Females of childbearing potential must agree to practice a highly effective method
of birth control (as defined by the EU Clinical Trial Facilitation Group) consistent
with local regulations regarding the use of birth control methods for patients
participating in clinical trials:

- Established use of oral, injected or implanted combined (estradiol and
progesterone containing) hormonal contraception;

- Placement of an intrauterine device (IUD) or intrauterine system (IUS);

- Male partner sterilization (the vasectomized partner should be the sole partner
for that patient)

- True abstinence (when this is in line with the preferred and usual lifestyle of
the patient)

- Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the trial and for 12 months after receiving the last dose of
epcoritamab. Men must also not donate sperm during the trial and for 12 months after
receiving the last dose of epcoritamab.

- A man who is sexually active with a woman of childbearing potential must agree to
use a barrier method of birth control (i.e. use of condom) during the trial and for
12 months after receiving the last dose of epcoritamab.

- Patients with HIV may be enrolled if they are on stable antiretroviral therapy, have
an undetectable viral load, and CD4 count > 250 cells/mm3.

Exclusion Criteria:

- Participants who have disease that has transformed to aggressive lymphoma

- Participants with symptomatic or suspected hyperviscosity syndrome or IgM levels
greater than 4000 mg/dL who are unable to undergo plasmapheresis to decrease the
risk of an IgM flare. Participants who can undergo plasmapheresis will be eligible
as long as they undergo the procedure prior to first treatment dose.

- Participants who are receiving any other investigational agent

- Washout from prior therapy: BTKi: no less than5 half-lives prior to epcoritamab to
prevent BTKi rebound and rituximab: no less than 4 weeks (28 days) from last dose.

- Participants who have not recovered from adverse events due to prior anti-cancer
therapy (i.e., have residual toxicities > Grade 1) except for alopecia and
peripheral neuropathy

- Uncontrolled intercurrent active infection requiring hospitalization or intravenous
antimicrobial agents within 4 weeks of start of treatment

- Uncontrolled underlying cardiac conditions including but not limited to: congestive
heart failure grade III or IV (by NYHA) or EF < 45%, unstable angina pectoris, acute
myocardial infarction < 6 months, uncontrolled cardiac arrhythmia

- History of uncontrolled neurologic condition including but not limited to: seizure
disorder, stroke, psychosis, dementia, CNS vasculitis, encephalitis

- Need for supplemental O2 at rest to maintain SaO2>92%

- Chronic immunosuppressive therapy for non-WM-related indication within 28 days of
initiation of treatment, including systemic corticosteroids 20 mg/day or greater
prednisone-equivalent

- Patients with known or suspected CNS involvement or leptomeningeal disease (i.e.
BingNeel Syndrome) are excluded given concern for potentially increased risk of
neurologic toxicity with epcoritamab. Patients with history of CNS malignancy from
separate malignancy must have completed CNS-directed therapy and must currently have
no evidence of disease

- Pregnant or breastfeeding women or participants unwilling to adhere to institutional
guidelines for highly effective contraception for the duration of the therapy are
excluded. This is because of the unknown but potential risk of teratogenic or
abortifacient effects, as well as potential for adverse events in nursing infants
secondary to treatment of the mother, as epcoritamab has not yet been studied in
this patient population. A female can be determined to not be of childbearing
potential if she meets any of the following criteria:

- Premenarchal

- Postmenopausal (>45 years of age with amenorrhea for at least 12 months or any
age with amenorrhea for at least 6 months and a serum follicle stimulating
hormone [FSH] level >40 IU/L or mIU/mL)

- Permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal
ligation procedures as consistent with local regulations], hysterectomy,
bilateral salpingectomy, bilateral oophorectomy) Note: If the childbearing
potential changes after start of the trial (e.g., woman who is not
heterosexually active becomes active, premenarchal woman experiences menarche)
a woman must begin a highly effective method of birth control, as described
under 3.1.13.

- Known current alcohol or drug abuse, psychiatric illness, or unstable social
situation that is likely to limit compliance with study requirements

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to epcoritamab

- Exposure to a live or a live attenuated vaccine within 4 weeks