Epcoritamab plus dose‑adjusted EPOCH‑R for aggressive B‑cell lymphoma

A Pilot Study of Epcoritamab With Dose Adjusted Etoposide, Cyclophosphamide, Vincristine, Doxorubicin, Prednisone and Rituximab (EPOCH-R) for Upfront Treatment of Aggressive B-Cell Non-Hodgkin Lymphomas

This trial tests whether adding epcoritamab to dose‑adjusted EPOCH‑R chemotherapy can safely improve outcomes for adults with untreated aggressive B‑cell non‑Hodgkin lymphoma.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Washington (Academic / other)
• Drugs / interventions: epcoritamab, chemotherapy, methotrexate, prednisone, rituximab, cyclophosphamide, doxorubicin
• Locations: 1 site (Seattle, Washington)
• Trial ID: NCT07097363 on ClinicalTrials.gov

What this trial studies

Epcoritamab, a bispecific antibody that brings T cells into contact with CD20‑positive B cells, is being given subcutaneously together with dose‑adjusted EPOCH‑R chemotherapy in this phase II trial to determine safety, dosing, and activity. Patients receive rituximab, prednisone, etoposide, doxorubicin, cyclophosphamide on a defined schedule and epcoritamab on specified days across six 21‑day cycles. Response and toxicity are monitored with PET/CT imaging, cardiac evaluation (MUGA or echocardiography), blood tests, and bone marrow assessment when indicated, with follow‑up for up to five years after treatment. The trial is run at the Fred Hutch/University of Washington Cancer Consortium with drug collaboration from industry.

Who should consider this trial

Good fit: Adults with untreated aggressive large B‑cell lymphomas (including high‑grade B‑cell lymphoma with MYC/BCL2 and/or BCL6 rearrangements, DLBCL, primary mediastinal B‑cell lymphoma, and similar WHO‑listed histologies) who are planned to receive full‑course DA‑EPOCH‑R are ideal candidates, with up to one prior cycle sometimes allowed.

Not a fit: Patients who have already received full systemic therapy for their aggressive lymphoma, who cannot tolerate intensive chemotherapy or a bispecific antibody, or who have contraindications to the study drugs are unlikely to receive benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could increase response rates and produce more durable remissions than standard DA‑EPOCH‑R alone.

How similar studies have performed: Early‑phase studies of epcoritamab in relapsed/refractory B‑cell lymphomas have shown promising response rates, but combining it with frontline DA‑EPOCH‑R represents a relatively new strategy.

Eligibility criteria

Inclusion Criteria:

* Untreated aggressive large-B cell lymphoma (non-Hodgkin lymphoma) with adverse features that may predict sub-optimal response to R-CHOP and in the opinion of the investigator would be treated with dose adjusted (DA)-EPOCH-R as standard of care. Subjects must be planned to receive full course (6 cycles) chemoimmunotherapy as per clinical standard of care. 1 prior cycle of chemoimmunotherapy may be allowed. Composite lymphomas are not excluded provided that the subject has not received prior systemic therapy for the indolent component and would receive DA-EPOCH-R as the standard of care regimen for the aggressive component. Eligible histologies based on 2016 World Health Organization (WHO) classification include:

  * High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations
  * High grade B-cell lymphoma, not otherwise specified (NOS)
  * Diffuse large b-cell lymphoma (DLBCL) NOS
  * Primary mediastinal B-cell lymphoma
  * T-cell/histiocyte-rich large-B-cell lymphoma
  * Epstein Barr virus (EBV) + DLBCL, NOS
  * Burkitt lymphoma
  * B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
* Be willing and able to provide written informed consent for the trial
* Be ≥ 18 years of age on day of signing informed consent
* Have measurable disease, including at least 1 nodal site measuring 1.5 cm or 1 extranodal site measuring 1.0 cm in longest dimension on CT or FDG-PET
* Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale (PS) at time of enrollment
* Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
* Absolute neutrophil count (ANC) ≥ 1,000/μL except in cases of marrow infiltration by lymphoma
* Platelets ≥ 75,000 / mcL except in cases of marrow infiltration by lymphoma or hypersplenism
* Hemoglobin ≥ 8 g/dL except in cases of marrow infiltration by lymphoma without red blood cell (RBC) transfusion within 14 days of first treatment
* Measured or calculated\* creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine clearance \[CrCl\]) ≥ 45 mL/min

  * Creatinine clearance should be calculated per institutional standard
* Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (Patients with documented Gilbert disease may be enrolled if total bilirubin ≤ 3.0 x ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver involvement
* International Normalized Ratio (INR) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants or prothrombin Time (PT) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of ≤ 1% per year during the treatment period and for at least 12 months after the last dose of study treatment. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≤ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of ≤ 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
* For women of childbearing potential, a negative serum pregnancy test result during screening period. Women who are considered not to be of childbearing potential are not required to have a pregnancy test
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. Male patients considering preservation of fertility should bank sperm before study treatment

Exclusion Criteria:

* Contraindication to any of the individual components of EPOCH-R, including, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products or if receiving an additional 6 cycles of anthracycline would place patient over the anthracycline lifetime cumulative dose (400 mg/m\^2)
* Prior systemic treatment for lymphoma. Prior radiotherapy is allowed provided that this site is not used as a measurable site to assess response
* Transformation from indolent lymphoma is allowed provided that the subject has not received prior systemic therapy for their lymphoma and the aggressive component meets one of the criteria listed in inclusion criterion
* Prior organ transplantation
* Current grade \> 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
* Prior systemic therapy for indolent lymphoma
* Prior therapy for large B-cell lymphoma except for patients who require lymphoma symptom control during screening may receive steroids and/or 1 cycle of chemoimmunotherapy in the following manner:

  * Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment). If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of \> 30-100 mg/day of prednisone or equivalent. Prednisone \> 30-100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phase treatment. If patients exceed the allowed dosing of corticosteroids, patients may still be eligible for the study provided that baseline imaging is performed (or repeated) after completion of the course of higher dose of steroids. Allowed corticosteroid dosing resets from the point of imaging forward and patients who do not exceed the allowed corticosteroid dosing from the point of imaging until initiation of study treatment may enroll. A maximum of 1 cycle of chemoimmunotherapy is allowed if needed for urgent disease stabilization if patient had staging PET/CT and LVEF evaluation prior to chemoimmunotherapy; in this situation patients will receive therapy on study starting with cycle (C)1 day (D)8 epcoritamab provided the next cycle of EPOCH-R chemotherapy will not be delayed by \> 7 days. In this situation, the date of receiving the first dose of EPOCH-R is considered C1D1 of the study treatment. Labs collected prior to C1D1, in accordance with SOC for the administration of these drugs, can be used for screening purposes
* History of other malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. The following are eligible without a specific waiver:

  * Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible.
  * Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible.
  * Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
* Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
* Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis
* History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction in the last 6 months
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment. Patients may proceed with screening during treatment for infection, but systemic treatment must be completed by cycle 1 day 1.

  * If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a negative molecular (e.g., polymerase chain reaction \[PCR\]) test or 2 negative antigen test results at least 24 hours apart. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen-failed and may only rescreen if the following have been met:

    * At least 10 days since first positive test result have passed in asymptomatic patients or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms
* Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology):

  * Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated by institutional standard
* Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)

  * Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
* History of uncontrolled HIV

  * Patients with known diagnosis of HIV must have undetectable viral load and be on anti-retroviral therapy
* Patients with a history of progressive multifocal leukoencephalopathy
* Patients with known active central nervous system lymphoma
* Patients needing a treatment regimen which would require use of mid-cycle high dose IV methotrexate for central nervous system (CNS) prophylaxis in the opinion of the treating provider
* Pregnancy or lactation or intending to become pregnant during study

Where this trial is running

Seattle, Washington

• Fred Hutch/University of Washington Cancer Consortium — Seattle, Washington, United States (Recruiting)

Study contacts

• Principal investigator: Mengyang Di, MD, PhD — Fred Hutch/University of Washington Cancer Consortium
• Study coordinator: Mengyang Di, MD, PhD

Conditions B-Cell Non-Hodgkin Lymphoma; Burkitt Lymphoma; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements; High Grade B-Cell Lymphoma, Not Otherwise Specified; Primary Mediastinal Large B-Cell Lymphoma; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma