A Phase I/II, Open-label Safety Trial of GEN3013 in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

Study Identifier:
GCT3013-01
CT.gov Identifier:
NCT03625037
EudraCT Identifier:
2017-001748-36
EU Trial (CTIS) Number:
2023-504802-12-00
Study Contact Information:
N/A
Recruitment Complete

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Study Summary

In the escalation part, the purpose is to determine the maximum tolerated dose and the recommended phase 2 dose as well as to establish the safety profile of epcoritamab GEN3013 (DuoBody-CD3xCD20) in patients with relapsed, progressive or refractory B-cell lymphoma. In the expansion part additional patients will be treated with epcoritamab with the RP2D and the purpose is to further explore and determine the safety and efficacy of epcoritamab. To evaluate the safety and efficacy of DuoBody-CD3xCD20 by subcutaneous administration in patients with B-cell malignancies. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). To evaluate subcutaneous epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-NHL, including LBCL and DLBCL. In the phase 2 expansion part, additional patients are treated with epcoritamab to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who had limited therapeutic options. To present updated results, including longer follow-up, in a challenging-to-treat population. To compare the efficacy of epcoritamab vs CAR T, pola-based regimens, and tafa-based regimens (including variations of pola-BR and tafa-len) in R/R DLBCL and LBCL. To compare the efficacy of epcoritamab versus chimeric antigen receptor T-cell (CAR T) therapy, polatuzumab-based (pola-based) regimens, and tafasitamab-based (tafa-based) regimens in R/R diffuse large B-cell lymphoma (DLBCL) and LBCL To present preliminary results from a DLBCL optimization cohort of the EPCORE NHL-1 trial that further investigates mitigating the risk of CRS in patients treated with epcoritamab SC monotherapy. Minimal residual disease (MRD) was assessed using NGS in peripheral blood. To report the first results from the fully enrolled EPCORE NHL-1 FL C1 OPT cohort investigating mitigation strategies for CRS with no mandatory hospitalization in pts with R/R FL receiving epcoritamab. Here we present long-term data, an additional efficacy analysis from the expansion cohort, and data from the cycle 1 optimization (C1 OPT) part. To evaluate subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL), including FL To further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who have limited therapeutic options To evaluate subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL), including FL. In the expansion part, additional patients were enrolled to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who have limited therapeutic options. To assess MRD, PK, and PD of a 2-step SUD regimen in cycle (C) 1 in comparison with a 3-step optimizationregimen in C1 (C1 OPT) in patients with R/R FL Cell phenotypes were assessed byvalidated flow cytometry assays and cytokines were tested with the Meso Scale Discovery platform. MRDanalysis was performed on peripheral blood mononuclear cells collected at prespecified time points(clonoSEQ® assay, Adaptive Biotechnologies). Screening tumor biopsies were used to identify trackable tumorclones; samples were quantified as tumor clones detected per 1 million nucleated cells. Overall response andprogression-free survival (PFS) were assessed by Lugano criteria per investigator assessmen To evaluate patient-reported outcomes (PROs) related to well-being and overall quality of life (QOL) based onchanges in the Functional Assessment of Cancer Therapy—Lymphoma (FACT-Lym) and EuroQol 5-Dimension-3L (EQ-5D-3L) among patients receiving epcoritamab for the treatment of R/R FL. Minimally important difference (MID) thresholds were calculated based on published literature (Carter et al. Blood. 2008;112:2376). Percentages of patients with meaningful improvement, stability, and deterioration for the FACT-Lym were calculated based on the upper-bound MID threshold to maximize HRQoL improvement and deterioration specificity. FACT-Lym mean change from BL scores were calculated for patients with any symptoms at BL and for patients with ≥3 symptoms at BL to assess HRQoL trajectory in patients with symptomatic disease at BL. Symptoms were identified through FACT-Lym items corresponding to body pain, fever, night sweats, lack of energy, tired easily, and losing weight. The analyses were performed for the study participants who completed PROs at BL and ≥1post-BL timepoint. Response was assessed per investigator for long-term outcomes.

To evaluate the durability of response of patients with R/R LBCL in CR who either paused or discontinued epcoritamab treatment.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Lymphoma
  • Hematological Cancer
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Epcoritamab Epcoritamab will be administered by subcutaneous injections in cycles of 28 days Biological: Epcoritamab Administered as specified in the treatment arm. ASH 2019: During dose escalation, patients received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. ASCO 2020: Patients received a single SC injection of flat-dose epcoritamab in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. EHA 2020: Patients received a single subcutaneous injection of flat-dose epcoritamab in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Per ASH 2020: Adults with R/R CD20+ B-NHL after prior therapy, including an anti-CD20 monoclonal antibody (mAb), receive a SC 1-mL injection of flat-dose epcoritamab in 28-day cycles (q1w: cycles 1-2; q2w: cycles 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk mitigation for cytokine release syndrome (CRS) includes starting with priming and intermediate doses and use of corticosteroids. ICML 2021: Patients received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1-2; q2w: cycles 3-6; q4w thereafter) until disease progression or unacceptable toxicity. EHA 2021: Patients received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1-2; q2w: cycles 3-6; q4w thereafter) until disease progression or unacceptable toxicity In the dose escalation phase, patients received subcutaneous epcoritamab (doses ranged from 0.0128-60mg) for 28 days. ICML 2023: Patients received subcutaneous epcoritamab (step-up priming and intermediate doses followed by 48-mg full doses) in 28-d cycles: QW, cycles 1-3; Q2W, cycles 4-9; Q4W, cycles ≥10 until PD or unacceptable toxicity. ASH 2023: Patients receive epcoritamab SC in 28-d cycles as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received 2 step-up doses (step-up dose 1, 0.16 mg, and step-up dose 2, 0.8 mg) followed by 48-mg full doses. ASTCT 2024: Patients received epcoritamab SC in 2 step-up doses in cycle (C) 1, followed by full 48-mg doses in 28-d Cs: QW, C1-3; Q2W, C4-9; and Q4W, C≥10 until disease progression or unacceptable toxicity. ASCO 2024: Pts received dexamethasone prophylaxis and hydration recommendations in C1. Hospitalization for CRS monitoring was not mandated. Pts received subcutaneous (SC) epcoritamab in 3 step-up doses (0.16, 0.8, and 3 mg) in C1, followed by 48-mg full doses in 28-d Cs (QW, C1-3; Q2W, C4-9; Q4W, C≥10) until disease progression or unacceptable toxicity. Pubmed: Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 016-mg priming dose on day 1 and a 080-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. EHA 2024: Patients with CD20+ R/R FL (grade 1-3A) with ≥2 prior tx lines received subcutaneous epcoritamab in 2-step(0.16 and 0.8 mg) or 3-step (0.16, 0.8, and 3 mg) SUD regimens in C1, followed by 48-mg full doses in 28-day(d) Cs (QW, C1-3; Q2W, C4-9; Q4W, C≥10) until disease progression. The C1 OPT cohort received recommendations for adequate hydration and dexamethasone as the preferred steroid for CRS prophylaxis. Hospitalization for monitoring was based on investigator discretion. EHA 2024: Adult patientswere enrolled and treated with subcutaneously administered epcoritamab over 28-day cycles until diseaseprogression or unacceptable toxicity Patients received subcutaneous epcor weekly in cycles 1a3, every 2 weeks in cycles 4a9, and every 4 weeks in cycle a10; each cycle was 28 days. Epcor was administered using two step-up dosing in cycle 1: priming (0.16 mg) and intermediate doses (0.8 mg) followed by 48-mg full doses. ASH 2024: Pts received SC epcor with 2 step-up doses: priming (0.16 mg) and intermediate (0.8 mg), followed by 48 mg full doses in 28-d Cycles (C): QW, C1-3; Q2W, C4-9; Q4W, C≥10 until progressive disease or unacceptable toxicity. Pts received CRS prophylaxis with steroids (predominantly prednisone), acetaminophen, and diphenhydramine in C1. ASCO 2025: Pts with R/R CD20+ LBCL and ≥2 prior LOT received epcor SC in 28-d cycles (C; 0.16- and 0.8-mg step-up doses in C1; 48-mg full dose thereafter; once weekly [QW], C1-3; Q2W, C4-9; Q4W, C≥10) until progressive disease (PD) or unacceptable toxicity.
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruitment Complete

    Requirements information
    Inclusion criteria
    • Main Inclusion Criteria - Escalation Part (recruitment completed)
    • Documented CD20+ mature B-cell neoplasm
    • DLBCL - de novo or transformed
    • HGBCL
    • PMBCL
    • FL
    • MCL
    • SLL
    • MZL (nodal, extranodal or mucosa associated)
    • Relapsed and/or refractory disease following treatment with an anti-CD20 monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy and/or relapsed after autologous stem cell rescue.
    • Eastern Cooperative Oncology Group (ECOG) performance status 0,1 or 2.
    • Participants must have measurable disease by computed tomography (CT), magnetic resonance imaging (MRI) or Positron emission tomography-Computed tomography (PET-CT) scan
    • Acceptable renal function.
    • Acceptable liver function.
    • Main Inclusion Criteria - Expansion & Dose-OPT Parts
    • Documented CD20 positive mature B cell neoplasm or CD20+ MCL.
    • DLBCL, de novo or transformed (including double hit or triple hit).
    • PMBCL
    • FL grade 3B
    • Histologic confirmed FL
    • MZL
    • SLL
    • MCL (prior Bruton's tyrosine kinase inhibitor [BTKi] or intolerant to BTKi)
    • At least 2 therapies including an anti-CD20 monoclonal antibody containing chemotherapy combination regimen.
    • Either failed prior autologous hematopoietic stem cell transplantation (HSCT) or ineligible for autologous stem cell transplantation due to age or comorbidities.
    • At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement of 2 or more clearly demarcated lesions and or nodes.
    Exclusion criteria
    • Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening.
    • Known past or current malignancy other than inclusion diagnosis.
    • Aspartate aminotransferase (AST), and/or alanine transaminase (ALT) >3 × upper limit of normal.
    • Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin.
    • Estimated Creatinine clearance (CrCl) <45 milliliters (mL)/min.
    • Known clinically significant cardiovascular disease.
    • Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment). Past coronavirus disease 2019 (COVID-19) infection may be a risk factor.
    • Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.
    • Seizure disorder requiring therapy (such as steroids or anti-epileptics).
    • Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20.
    • Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior to first epcoritamab administration.
    • Eligible for curative intensive salvage therapy followed by high dose chemotherapy with HSCT rescue.
    • Autologous HSCT within 100 days prior to first epcoritamab administration, or any prior allogeneic HSCT or solid organ transplantation.
    • Active hepatitis B (deoxyribonucleic acid [DNA] polymerase chain reaction [PCR]-positive) or hepatitis C (ribonucleic acid [RNA] PCR-positive infection). Participants with evidence of prior hepatitis B (HBV) but who are PCR-negative are permitted in
    • Known human immunodeficiency virus (HIV) infection.
    • Exposed to live or live attenuated vaccine within 4 weeks prior to signing Informed consent form (ICF).
    • Pregnancy or breast feeding.
    • Participant is known or suspected of not being able to comply with the study protocol or has any condition for which, participation would not be in the best interest of the participant.
    • Contraindication to all uric acid lowering agents.
    • NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Daniel Morillo Giles
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Lymphoma
    Hematological Cancer