A Phase 2 Study of Epcoritamab and Rituximab for first-line treatment of follicular lymphoma

The purpose of this study is to determine how effective and safe the combination of rituximab
and epcoritamab is in treating patients with Follicular Lymphoma (FL) and who have not
received other treatments for their lymphoma.

The names of the study drugs involved in this study are:

- Rituximab (a type of monoclonal antibody therapy)

- Epcoritamab (a T-cell bispecific antibody)

Inclusion Criteria:

- Histologically confirmed diagnosis of CD20+ FL (grade 1-3A) with review of the
diagnostic pathology specimen at one of the participating institutions. Patients with
current or prior histologic transformation are excluded.

- No prior systemic therapy for FL. Prior treatment with radiation therapy or short
course steroids is allowed.

- Meets at least one criterion to begin treatment based on the modified GELF (Groupe
d'Etude des Lymphomes Folliculaires) criteria:

- Symptomatic adenopathy

- Organ function impairment due to disease involvement, including cytopenias due to
marrow involvement (WBC <1.5x109/L; absolute neutrophil count [ANC] <1.0x109/L,
Hgb <10g/dL; or platelets <100x109/L)

- Constitutional symptoms (defined as persistent fevers >100.4 F, shaking chills,
drenching night sweats, or loss of >10% of body weight within a 6 month period)

- Any nodal or extranodal tumor mass >7 cm in maximum diameter

- >3 nodal sites of involvement >3 cm

- Local compressive symptoms or imminent risk thereof

- Splenomegaly (craniocaudal diameter > 16cm on CT imaging)

- Clinically significant pleural or peritoneal effusion

- Leukemic phase (>5x109/L circulating malignant cells)

- Rapid generalized disease progression

- Renal infiltration

- Bone lesions

- Patients cannot be in need of urgent cytoreductive chemotherapy (in the opinion of the
treating investigator).

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A)

- Age ≥18 years.

- Adequate hematologic and organ function:

1. Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by
lymphoma in which case ANC must be >0.5x109/L

2. Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which
case platelets must be >50 x109/L

3. Estimated CrCl (Cockcroft Gault) ≥ 45ml/min

4. Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct
bilirubin must be < 1.5 x ULN

5. AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in which
case AST/ALT must be <5 x ULN

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

- Willingness to provide a pre-treatment tumor sample by core needle or excisional
surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is
acceptable if the following provisions are met: 1) availability of a tumor-containing
formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE
tissue block cannot be provided in total, sections from this block should be provided
that are freshly cut and mounted on positively-charged glass slides. Preferably, 25
slides should be provided; if not possible, a minimum of 15 slides is required.
Exceptions to this criterion may be made with approval of the Sponsor-Investigator.

- Willingness to remain abstinent or to use two effective contraceptive methods that
result in a failure rate of <1% per year from screening until: (a) at least 3 months
after pre-treatment with rituximab or 12 months after the last dose of epcoritamab,
whichever is longer, if the patient is a male or (b) until at least 18 months after
pre-treatment with rituximab or 12 months after the last dose of epcoritamab,
whichever is longer, if patient is a female. Examples of contraceptive methods with a
failure rate of <1% per year include:

- Tubal ligation, male sterilization, hormonal implants, established proper use of
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine
devices, and copper intrauterine devices.

- Alternatively, two methods (e.g., two barrier methods such as a condom and a
cervical cap) may be combined to achieve a failure rate of <1% per year. Barrier
methods must always be supplemented with the use of a spermicide.

Exclusion Criteria:

- Patients who require systemic immunosuppressive therapy for an ongoing medical
condition will be excluded. For corticosteroids, patients receiving a prednisone dose
of >10 mg daily (or equivalent) will not be eligible. A short course of steroids (up
to 14 days) for symptom palliation is allowed, in which case patients should be off
steroids prior to treatment start.

- Patients with bulky cervical adenopathy that is compressing the upper airway or could
result in significant airway compression during a tumor flare event.

- Patients with stage I follicular lymphoma

- Patients who are candidates for radiation therapy with curative intent (in the opinion
of the treating investigator)

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia).

- Active HBV (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection). Subjects
with evidence of prior HBV but who are PCR-negative are permitted in the trial but
should receive prophylactic antiviral therapy. Subjects who received treatment for HCV
that was intended to eradicate the virus may participate if hepatitis C RNA levels are
undetectable.

- Known history of seropositivity for human immunodeficiency virus (HIV). Note: HIV
testing is required at screening only if required per local health authorities or
institutional standards.

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at trial enrolment or significant
infections within 2 weeks prior to the first dose of epcoritamab.

- Prior history of another malignancy (except for non-melanoma skin cancer or in situ
cervical or breast cancer) unless disease free for at least 2 years.

- Patients should not have received immunization with attenuated live vaccine within one
week of study entry or during study period.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study or limit adherence to
study requirements.

- Patients with any one of the following currently on or in the previous 6 months will
be excluded: myocardial infarction, congenital long QT syndrome, torsade de pointes,
unstable angina, coronary/peripheral artery bypass graft, cardiac arrhythmia (CTCAE
grade 3 or higher), clinically significant ECG abnormalities, or cerebrovascular
accident.

- Patients with New York Heart Association Class III or IV heart failure or known
ejection fraction of <45%.

- Inability to comply with protocol mandated hospitalizations and restrictions.

- Patients who are pregnant, breast-feeding, or intending to become pregnant during the
study.

- Prior solid organ or allogeneic stem cell transplantation.

- History of known or suspected hemophagocytic lymphohistiocytosis (HLH).

- History of autoimmune disease, including but not limited to myocarditis, pneumonitis,
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

• Patients with a remote history of, or well controlled, autoimmune disease who meet
above criteria may be eligible to enroll after consultation with the
Sponsor-Investigator.

- History of severe allergic or anaphylactic reactions to anti-CD20 mAb therapy or known
allergy or intolerance to any component or excipient of epcoritamab.

- Vaccination with live vaccines within 28 days prior to the first dose of epcoritamab.

- Active CNS lymphoma

- Neuropathy > grade 2. (CTCAE)

- Treatment with CAR-T therapy within 100 days prior to first dose of epcoritamab.

- Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is
longer, prior to the first dose of epcoritamab.

- Chemotherapy and other non-investigational anti-neoplastic agents (except CD20 mAbs)
within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of
epcoritamab.

- Screening 12-lead ECG showing a baseline QTcF >470 msec.