Response-adaptive to Epcoritamab In First Relapse: Study to Evaluate the Efficacy of Eptoritamab in Patients With Relapse/Refractory Large B Cell Lymphoma

Not Applicable

Recruiting

• Conditions: Large B Cell Lymphoma
• Interventions: Drug: Epcoritamab; Drug: Epcoritamab, tafasitamab and lenalidomide

• Registration Number: NCT07126236
• Lead Sponsor: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

Brief Summary

phase II, response-adaptive, open-label, multicenter study aiming to include 80 patients in 78 months. Patients will receive 3 cycles of epcoritamab monotherapy and, since cycle 4, they can continue with epcoritamab monotherapy until cycle 12 or change to combination therapy (epcoritamab + tafasitamab + lenalidomide) until cycle 15. Patients will be followed up to 5 years.

Detailed Description

Epcoritamab is a full-length bispecific IgG1 antibody directed against two proteins, CD3 on the T lymphocyte and CD20 on the lymphoma cell. This antibody redirects and activates T cells, generating an immune synapse that eventually eliminates malignant cells expressing CD20.

Previous studies have demonstrated that Epcoritamab has potent antitumor activity as a monotherapy agent, with a favorable and manageable safety profile.

Since its efficacy is so favorable it is reasonable to think that it could be an excellent option for first-relapse patients. However, to date, there is no data on this therapy's usefulness as second-line treatment. Therefore we intend to evaluate the efficacy of Epcoritamab as a treatment option for patients with first-relapse LBCL.

The purpose of this study is to determine the efficacy of Epcoritamab as second line treatment for LBCL patients. On the basis of the clinical experience, it is hypothesized that Epcoritamab would provide a better complete response rate (CRR) in comparison to Platinum-based immunochemotherapy (CRR=25%), Polatuzumab-Bendamustin Rituximab (CRR=40%) and Tafasitamab-Lenalidomide (CRR=43%).

Study Timeline

• Study First Submitted: 2025-07-10
• Status Verified: 2025-08
• Study Start: 2025-08-04
• Study First Submitted QC: 2025-08-09
• Last Update Submitted: 2025-08-09
• Study First Posted: 2025-08-17
• Last Update Posted: 2025-08-17
• Primary Completion: 2031-12
• Study Completion: 2031-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Written informed consent must be obtained before any study-specific assessment is performed.

2. Age >18 years

3. Patients with Relapse/Refractory histologically confirmed LBCL, including, Diffuse Large B Cell Lymphoma (DLBCL); Primary Mediastinal Large B Cell Lymphoma (PMBCL), High-grade B-cell lymphoma (HGBCL); and grade 3B Follicular Lymphoma.

   Relapsed disease is defined as complete remission to first line therapy followed by a recurrence of the disease after a minimum of 6 months of completion of first-line therapy. A biopsy at the time of relapse is recommended but not mandatory.

   Refractory disease is defined as no objective response to first line therapy (biopsy not mandatory if diagnostic sample available). Four groups of patients are eligible:

   • PD as best response to first line therapy.
   • SD as best response after at least 4 cycles of first line therapy.
   • PR as best response after at least 6 cycles of first line therapy.
   • CR and disease recurrence within < 6 months from the completion of first-line therapy.

4. Patients must have received adequate first-line therapy including at a minimum: an anti-CD20 monoclonal antibody (rituximab or obinutuzumab), and CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone) or CHOP-like chemotherapy.

5. At the investigator's discretion, the patient should not be a candidate for 1st relapse CAR-T therapy or unwilling to receive CAR-T therapy.

6. Patients must be autologous stem cell transplantation (ASCT)-ineligible: Age ≥65 and/or HTC-CI ≥3 or or unwilling to receive transplant.

7. PET positive disease.

8. Performance status according to Eastern Cooperative Oncology Group (ECOG) 0 to 2.

9. Patients meeting with the following hematology values:

   • Hemoglobin ≥8 g/dl (transfusion support permitted but not within 7 days of screening lab collection)
   • Absolute neutrophil count (ANC) ≥ 1/109/L (growth factor support allowed in case of bone marrow involvement).
   • Absolute lymphocyte count ≥ 0.1/109/L,
   • Platelet count ≥ 70/109/L (unless secondary to bone marrow involvement, OR ≥50x/109/L if documented bone marrow involvement). Platelet transfusions permitted but not within 7 days of screening lab collection.

10. Female patients of child-bearing potential must have a negative urine or serum pregnancy test at screening and agree to use highly effective methods of contraception (e.g., established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS) upon enrollment according to the recommendations provided by Clinical Trial Facilitation Group (CTFG), during the treatment period and for 4 months after the last dose of study medication. Moreover, the patient must agree to ongoing pregnancy testing during the course of the study, and after study therapy has ended. This applies even if the patient practices complete and continued sexual abstinence.

    Women not of childbearing potential are defined as: premenarchal; postmenopausal (greater than 50 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 greater than 40 IU per L or milli-International unit (mIU) per mL); permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy.

11. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential) upon enrollment according to the recommendations provided by CTFG, during the treatment period, and for 4 months following the last dose of investigational drug or agreement to remain abstinent. Agreement to refrain from donating blood or sperm during the study participation and for 4 months after the last dose of study medication.

12. Women must agree not to donate blood or oocytes during the course of the study and for 4 months after the last dose of study medication. Restrictions concerning blood donation apply as well to females who are not of childbearing potential. Men must also not donate sperm during the trial and for 4 months after receiving the last dose of study drug.

13. Females of childbearing potential must refrain from breastfeeding during the course of the study and for 4 months after the last dose of study medication.

14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

15. Not included in other clinical trial or treated with an experimental drug.

Exclusion Criteria

1. Patients who received more than one prior line of systemic therapy

2. Patients with detectable Central Nervous System (CNS) lymphoma

3. Significant organ function impairment:

   • creatinine clearance calculated by Cockcroft-Gault ≤ 45 ml/min
   • direct bilirubin level < 2 x ULN (except in patients with Gilbert's syndrome),
   • alanine transaminase (ALT) and aspartate aminotransferase (AST) >3 × ULN or >5 × ULN in cases of documented liver involvement.
   • clinically relevant pleural effusion,
   • left ventricular ejection fraction (LVEF) ≤ 45%

4. Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months.

5. Have a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or are at a high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period

6. Known clinically significant cardiac disease, including:

   • Onset of unstable angina pectoris within 6 months of signing the patient informed consent form.
   • Acute myocardial infarction within 6 months of signing the patient informed consent form.
   • Congestive heart failure (grade III or IV as classified by the New York Heart Association.
   • Left ventricular ejection fraction ≤45%.

7. Known past or current malignancy other than inclusion diagnosis, except for: Cervical carcinoma of Stage 1B or less; Non-invasive basal cell or squamous cell skin carcinoma; Non-invasive, superficial bladder cancer; Localized low grade prostate cancer (up to Gleason score 6); DCIS of the breast; Other malignancy that has been treated with curative intent and has remained in remission for 3 years.

8. Previous ASCT.

9. Prior anti-CD3 and CD20 bispecific antibodies therapy or prior treatment with tafasitamab.

10. Presence of severe infection that is uncontrolled or requiring IV antimicrobials for management.

11. History of HIV infection or acute or chronic active hepatitis B or C infection.

    • Individuals with positive HIV serology may be included if negative viral load and CD4 >200/mm3. For being included, patients should have controlled disease and been on treatment for at least 1 year
    • Individuals with history of hepatitis infection with positive antibodies (anti-HB and anti-HV) might be included if negative viral load (negative hepatitis B PCR). Patients who are HBcAb positive must receive HBV prophylaxis while on treatment. Patients with positive HbsAg are excluded. Patients who are hepatitis B PCR positive will be excluded. Patients who are hepatitis C RNA positive will be excluded.

12. Females who are pregnant or breastfeeding.

13. Richter's transformation or prior chronic lymphocytic leukemia (CLL).

14. Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 4 weeks prior to Cycle 1 Day 1.

15. Recent major surgery (within 4 weeks before the start of Cycle 1 Day 1) other than for diagnosis.

16. Vaccination with a live vaccine or COVID-19 vaccination within 4 weeks prior to treatment.

17. History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure. History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies.

18. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EPCO monotherapy	Epcoritamab	Epcoritamab in monotherapy will be administred until cycle 12.
Combination therapy	Epcoritamab, tafasitamab and lenalidomide	3 cycles of Epcoritamab in monotherapy will be administred and then Epcoritamab will be administred with Tafasitamab and Lenalidomide from cycle 4 until cycle 15.

Primary Outcome Measures

Name	Time	Method
Efficacy of Epcoritamab monotherapy	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days.	The efficacy of Epcoritamab monotherapy will be centrally evaluated by the best CRR at any moment since initiation. The CRR will be assessed by PET-CT according to Lugano Classification and is defined as the proportion of patients who achieve a best response of complete response (CR) at any moment since initiation of Epcoritamab first administration.

Secondary Outcome Measures

Name	Time	Method
Efficacy of Epcoritamab monotherapy after 3 cycles	At the end of cycle 3 (each cycle is 28 days)	The efficacy of Epcoritamab monotherapy will be centrally evaluated by the best CRR, defined as the proportion of patients who achieve a best response of CR after 3 cycles of Epcoritamab administration.
Efficacy of Epcoritamab monotherapy and combination therapy by CRR	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days.	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per CRR (locally evaluated for Epcoritamab monotherapy; local and central evaluation for combination therapy).
Evaluation of MRD	Cycles 3, 4, 7, 10, 12, 13, 15 (each cycle is 28 days), EoT (28 days after last administration of Study drug) and cycles 18 and 24 (epcoritamab monotherapy) or cycles 21 and 27 (combination therapy) visits (each cycle is 28 days).	The efficacy of Epcoritamab monotherapy and combination therapy will be evaluated by MRD (positive or negative) from ctDNA samples immediately before initiation of C3, C4, C7, C10, C12, C13, C15, End of Treatment (EoT) and cycles 18/24 (epcoritamab monotherapy) or cycles 21/27 (combination therapy).
Evaluation of patients with negative MRD by PFS	At cycle 3 visit (each cycle is 28 days).	The PFS of patients with negative MRD at Visit 3 (V3) (immediately before administrating C3 of Epcoritamab monotherapy).
Safety and tolerability	Baseline, during all the cycles day 1 visit (each cycle is 28 days) and at EoT (28 days afert las administration of Study drug).	The safety and tolerability of Epcoritamab monotherapy and combination therapy are evaluated as follows: * Type, frequency, and severity of adverse events (AEs).; * Type, frequency, and severity of Adverse events of special interest (AESIs): Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), clinical tumor lysis syndrome (CTLS) and other safety topics of interest (tumour flare reaction, prolonged cytopenia, serious infections and second primary malignancies).; * Incidence, severity, and treatment.
Efficacy of Epcoritamab Monotherapy and Combination therapy by ORR	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per ORR at any time.
Efficacy of Epcoritamab Monotherapy and combination therapy by DoR	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per DoR at any time.
Efficacy of Epcoritamab monotherapy and combination therapy by DoCR	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per DoCR at any time.
Efficacy of Epcoritamab monotherapy and combination therapy by EFS	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per Event-free survival (EFS) at any time.
Efficacy of Epcoritamab monotherapy and combination therapy by PFS	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per PFS at any time.
Efficacy of Epcoritamab montherapy and combination therapy by OS	Cycle 3, cycle 4, cycle 7, cycle 10, cycle 13 (for combination therapy) and EoT (28 days after last administration of investigational product) visits. Each cycle is 28 days	The efficacy of Epcoritamab monotherapy and combination therapy with tafasitamab-lenalidomide will be evaluated by local investigators and central evaluation as per OS at any time.
Evaluation of patients with negative MRD by OS	At cycle 3 visit (each cycle is 28 days).	The OS of patients with negative MRD at Visit 3 (V3) (immediately before administrating C3 of Epcoritamab monotherapy).
Evaluation of patients with negative MRD by DoR	At cycle 3 visit (each cycle is 28 days).	The DoR of patients with negative MRD at Visit 3 (V3) (immediately before administrating C3 of Epcoritamab monotherapy).

Trial Locations

Locations (15)

Hospital Universitario Miguel Servet; 🇪🇸 Zaragoza, Aragón, Spain

Hospital Universitario de Burgos; 🇪🇸 Burgos, Castilla y León, Spain

ICO Badalona; 🇪🇸 Badalona, Cataluña, Spain

Hospital Universitari Vall d'Hebrón; 🇪🇸 Barcelona, Cataluña, Spain

Hospital General Universitario Gregorio Marañón; 🇪🇸 Madrid, Comunidad de Madrid, Spain

Hospital Universitario Infanta Leonor; 🇪🇸 Madrid, Comunidad de Madrid, Spain

Hospital Universitario Fundación Jiménez Díaz; 🇪🇸 Madrid, Comunidad de Madrid, Spain

Hospital Universitario Dr. Peset; 🇪🇸 Valencia, Comunidad Valenciana, Spain

Hospital Universitario y Politécnico La Fe; 🇪🇸 Valencia, Comunidad Valenciana, Spain

Hospital San Pedro de Alcántara; 🇪🇸 Cáceres, Extremadura, Spain

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