Phase II Open‑Label Multicenter Study of Subcutaneous Epcoritamab in Relapsed/Refractory Marginal Zone Lymphoma (EPOS‑1)
- Trial ID
- 2025-524879-23-00
- Protocol
- EPOS-1
Trial statistics
Objectives
The primary objective is to evaluate the therapeutic efficacy and safety of subcutaneously administered epcoritamab in adult patients with relapsed or refractory Marginal Zone Lymphoma. Efficacy will be measured by the proportion of participants achieving a complete remission after treatment, indicating potential for durable disease control. Safety assessment will include documentation of treatment‑related adverse events, analysis of health‑related quality of life, and determination of the cumulative incidence of secondary malignancies to define the overall risk profile.
Participants
The trial enrolled adult participants of both sexes with relapsed or refractory Marginal Zone Lymphoma. The sponsor did not provide the total number of participants. Eligible individuals were ≥18 years old, had a life expectancy > 3 months, and required systemic therapy for symptomatic disease. Inclusion required a pathology‑confirmed diagnosis of CD20‑positive relapsed/refractory extranodal, splenic, or nodal disease, measurable lesions per imaging criteria, and prior exposure to at least one anti‑CD20 monoclonal antibody with documented treatment failure. Baseline laboratory thresholds included platelet count > 50 × 10⁹/L, ANC > 1 × 10⁹/L, hemoglobin ≥ 8 g/dL, liver enzymes < 3‑5 × ULN, bilirubin ≤ 1.5 × ULN, creatinine ≤ 1.5 × ULN or GFR ≥ 50 mL/min, and fibrinogen ≥ 1 g/L. Participants needed to follow contraception requirements: men agreed not to father a child during therapy and for 4 months after the last dose, and women of child‑bearing potential used highly effective birth control and tested negative for β‑hCG. General health status required adequate organ function and absence of uncontrolled infections.
Plans and Procedures
The study is a multicenter open‑label single‑arm phase II trial evaluating subcutaneous epcoritamab (Tepkinly 4 mg/0.8 ml and 48 mg solutions) in adults with relapsed/refractory marginal zone lymphoma. After a screening visit that confirms pathology, eligibility criteria, and baseline assessments, participants receive weekly subcutaneous injections according to the protocol for up to 12 treatment cycles. Subsequent study visits are scheduled regularly to perform safety monitoring, laboratory tests, imaging, and quality‑of‑life evaluations, culminating in an end‑of‑study visit performed 4 weeks after the last dose or earlier if treatment is discontinued. Participant involvement therefore extends for approximately one year, encompassing treatment and follow‑up. The primary efficacy endpoint is the complete remission (CR) rate assessed at the end‑of‑treatment visit; secondary endpoints include overall response rate, progression‑free survival, overall survival, and safety. Early termination may occur, with the primary endpoint evaluated at the early‑termination visit. Recruitment is planned to commence in September 2026 and conclude in September 2032.
Treatment
The investigational product, Tepkinly, is supplied as a solution for injection containing the monoclonal antibody Epcoritamab. Two dose strengths are utilized in the study: a 4 mg/0.8 ml preparation administered by subcutaneous injection, and a 48 mg preparation also given subcutaneously. Each dose is delivered according to the protocol‑specified schedule, with the volume corresponding to the labeled concentration.
No concomitant investigational agents, placebo, or alternative comparator therapies are incorporated; participants receive only the assigned Tepkinly doses as the sole study treatment.
Drug administration is performed by qualified personnel, and dosing times are recorded in the electronic case report form. Compliance is assessed through documented injection dates, verification of administered volume, and review of any missed or delayed doses. Safety monitoring includes observation for injection‑site reactions and collection of adverse‑event data throughout the treatment period.
Efficacy
Efficacy will be evaluated primarily by the complete remission (CR) rate, assessed 4 weeks after the end of treatment, which corresponds to the completion of 12 treatment cycles or the early‑termination visit if treatment ends prematurely. Secondary efficacy parameters include overall response rate (ORR) after 12 cycles, best response (both CR and ORR), time to best response, time to first response, progression‑free survival, time to treatment failure, duration of response, cause‑specific survival, overall survival, and quality‑of‑life measures.
Response assessments will be performed at the end of the 12‑cycle treatment period and at the predefined 4‑week post‑treatment visit for the primary endpoint. Additional evaluations for secondary endpoints will be conducted throughout the study according to the scheduled follow‑up visits, enabling calculation of time‑to‑event outcomes such as progression‑free survival and overall survival. All efficacy data will be analyzed in accordance with the trial’s statistical analysis plan.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must have a proven pathological diagnosis of MZL, confirmed by a reference pathology center: -Confirmed CD20-positive relapsed/refractory extranoda Lymphoma or -Confirmed CD20-positive relapsed/refractory splenic MZL or -Confirmed CD20-positive relapsed/refractory nodal MZL A tumor biopsy not older than 12 months is required at screening for confirming diagnosis in all participants.
- Circulating lymphocytes < 25 G/l
- ASAT (SGOT): < 3.0 times the upper limit of institutional laboratory normal value or < 5 times the upper limit of institutional laboratory normal value in subjects with lymphoma in the liver
- ALAT (SGPT): < 3.0 times the upper limit of institutional laboratory normal value or < 5 times the upper limit of institutional laboratory normal value in subjects with lymphoma in the liver
- Serum total bilirubin: ≤ 1.5 × ULN OR Direct bilirubin ≤ 2 x ULN for subjects with total bilirubin levels > 1.5 ULN (unless clearly related to the disease)
- Serum creatinine ≤1.5 × ULN OR ≥ 50 mL/min GFR or CrCl for subjects with creatinine levels > 1.5 × institutional ULN
- Fibrinogen must be ≥ 1 g/L
- For women of child-bearing potential (WOCBP) only: Pregnancy β-HCG negative. Serum or urine β-HCG must be negative during screening and at study enrolment visit.
- WOCBP (criteria listed in Appendix C) must agree to use a highly effective method of birth control and to a monthly pregnancy test for the duration of the therapy up to 4 months after the last dose of Epcoritamab. A highly effective method of birth control is defined as those which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence. Contraception and pregnancy testing are required according the CTFG recommendations (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)
- Men must agree not to father a child for the duration of therapy and 4 months after the last dose of Epcoritamab as well as to advice a female partner to use a highly effective method of birth control. According to CTFG recommendations, men must use condoms.
- Measurable and/or evaluable disease: at least one bi-dimensionally measurable lesion (a measurable node must have a longest transverse diameter of a lesion (LDi) > 1.5 cm. A measurable extranodal lesion should have an LDi > 1.0 cm by CT/ PET-CT scan or MRI. Please refer to Appendix D, Splenomegaly > 13 cm is considered to be measurable disease (splenic MZL), for gastric MZL without any other lymphoma manifestations gastric infiltration as determined by gastroendoscopy is considered to be measurable disease (see Appendix E)
- Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions
- Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.
- symptomatic participants in need of systemic treatment
- Previously treated with at least one anti-CD20 monoclonal antibody at least 2 cycles, unless discontinued earlier due to documented disease progression or unacceptable toxicity. Must have a documented failure to achieve at least PR during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. Systemic therapy does not include Helicobacter pylori eradication or local involved field radiotherapy.
- Age ≥ 18 years
- Life expectancy >3 months.
- Baseline platelet count >50x109/L (if not due to BM infiltration by the lymphoma)
- ANC > 1x109//G (unless lower counts are due to lymphoma infiltration).
- Hemoglobin ≥ 8.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks)
Exclusion Criteria
- ECOG performance status ≥ 3
- Breastfeeding or Pregnancy
- Clinically significant cardiovascular disease, including the following: • Myocardial infarction within 1 year or stroke within 6 months prior to randomization OR • The following conditions within 3 months prior to randomization: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina (angina symptoms at rest; new onset angina starting within the last 3 months), congestive heart failure > New York Heart Association (NYHA) class II), uncontrolled cardiac arrhythmia, or other clinically significant electrocardiogram (ECG) abnormalities in the opinion of the investigator
- Uncontrolled arterial hypertension despite optimal medical management
- Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results
- Vaccination with a live vaccine within 30 days prior to start of therapy
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication.
- History of severe concurrent interstitial lung and/or severely impaired lung function (as judged by the investigator)
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
- Has a history of non-infectious pneumonitis that required steroids, or current pneumonitis
- History of anaphylaxis in association with previous administration of monoclonal antibodies or severe hypersensitivity (≥ Grade 3) to the investigational medicinal product and/or any of its excipients
- History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥1 year prior to study enrolment visit, other Stage 1 cancer treated with a curative intent and currently in complete remission, for ≥3 years
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Systemic corticosteroid treatment <20 mg/day prednisone or equivalent and inhaled corticosteroids are permitted. Last dose of corticosteroid ≥20 mg/day prednisone or equivalent will not be permitted during the last 7 days before inclusion.
- Has a known history of TB (Bacillus Tuberculosis)
- Ongoing alcohol or drug addiction or known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- History of Diagnosis of Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)
- Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma
- Has had prior chemotherapy (systemic anti-cancer therapy) or targeted small molecule therapy within 28 days prior to study Day 1. Non-hematologic toxicity must be recovered to ≤ grade 1 before inclusion.
- Has received prior therapy with a bi-specific anti-CD20xCD3 antibody
- Treatment with any other investigational agent or participating in another clinical trial with an investigational product within 4 weeks prior to entering this study or within 5 x the half-life (t1/2) of the investigational product, whichever is longer
- Has received prior radiotherapy within 2 weeks of start of study treatment.
- Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of study enrolment visit, such as CMV, HIV, SARS-COV-2.
- Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring IV antibiotics. Participants with serologic markers of HBV immunization due to vaccination (HBsAg negative, Anti-HBc negative, and Anti-HBs positive) will be eligible. Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrolment. Those who are PCR positive will be excluded.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 01 Sept 2026 | 53 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Tepkinly 4 mg/0.8 ml solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 3 | 3 | PRD10859915 |
Tepkinly 48 mg solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 48 | 44 | PRD10859919 |