First-in-Human (FIH) Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma (EPCORE™ NHL-1)

• ClinicalTrials.gov Identifier: NCT03625037
• Recruitment Status: Recruiting
• First Posted: August 10, 2018
• Last Update Posted: May 31, 2023
• Sponsor: Genmab
• Collaborator: AbbVie
• Information provided by (Responsible Party): Genmab

Tracking Information

• First Submitted Date: June 7, 2018
• First Posted Date: August 10, 2018
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: June 26, 2018
• Estimated Primary Completion Date: January 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2023)

• Escalation part: Incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: During the first cycle (28 days) in each cohort. ]
  To determine the RP2D and the MTD, if reached.
• Escalation part: Incidence and severity of Adverse Events (AEs) [ Time Frame: From first dose until the end of the safety follow-up period (4 weeks after last dose) ]
  Treatment-emergent AEs (TEAEs) as assessed by CTCAE v5.0. Abnormal laboratory values are reported as AEs per protocol.
• Expansion part: Objective Response Rate (ORR) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as proportion of participants who have a partial or complete response (PR or CR) following treatment with epcoritamab. Determined by the Lugano response criteria, assessed by the Independent Review Committee (IRC).
• Optimization part: Number of participants with cytokine release syndrome (CRS) events [ Time Frame: From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) ]
• Optimization part: Percentage of participants with =>Grade 2 CRS events [ Time Frame: From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) ]

Original Primary Outcome Measures (submitted: August 9, 2018)

• Dose Limiting Toxicities (DLTs) [ Time Frame: DLTs are assessed during the first cycle (28 days) in each cohort ]
  To determine recommended phase 2 dose of GEN3013
• Adverse Events (AEs) [ Time Frame: AEs are collected throughout the study and up to 5 years after last patient first visit ]
  Number of participants with treatment-related adverse events as assessed by CTCAE v4.03

Current Secondary Outcome Measures (submitted: March 27, 2023)

• Escalation & Optimization parts: ORR [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as proportion of participants who have a PR or CR following treatment with epcoritamab. Determined by the Lugano response criteria.
• Escalation phase: PR rate [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Determined by the Lugano response criteria.
• All parts: CR rate [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as proportion of participants with CR. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in expansion part is reviewed by the IRC.
• Expansion part: Time to Response (TTR) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as time to first documentation of objective tumor response (PR or better). Determined by the Lugano and LYRIC response criteria, assessed by the IRC.
• All parts: Duration of Response (DOR) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as time from first documentation of response (CR or PR) to the date of progression of disease (PD) or death, whichever occurs earlier. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in the expansion part is reviewed by the IRC.
• Expansion & Optimization parts: Duration of CR (DoCR) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as time from first documentation of CR to the date of PD or death, whichever occurs earlier. Determined by the Lugano and LYRIC response criteria, assessed by the IRC.
• All parts: Time to next anti-lymphoma therapy (TTNT) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Calculated as time to date of initiation of new anti-lymphoma therapy.
• All parts: Progression Free Survival (PFS) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as time to first documented PD or death due to any cause. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in the expansion part is reviewed by the IRC.
• All parts: Overall survival (OS) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as time to death.
• Optimization part: Incidence of DLTs [ Time Frame: From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) ]
• Optimization part: Number of participants with CRS events [ Time Frame: From Day 15 (DLBCL/MCL) or Day 22 (FL) until up to 1 year after the last participant's first dose ]
• Optimization part: Percentage of participants with =>Grade 2 CRS events [ Time Frame: From Day 15 (DLBCL/MCL) or Day 22 (FL) until up to 1 year after the last participant's first dose ]
• Optimization part: Number of participants with CRS events [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
• Optimization part: Percentage of participants with =>Grade 2 CRS events [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
• Expansion & Optimization parts: Incidence and severity of AEs [ Time Frame: From first dose until the end of the safety follow-up period (60 days after last dose) ]
  TEAEs as assessed by CTCAE v5.0. Abnormal laboratory values are reported as AEs per protocol.
• All parts: Area-under-the-concentration-time curve from Time 0 to Time of last dose (AUClast) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: AUC from Time 0 to Infinity (AUCinf) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year. ]
• All parts: Maximum (peak) plasma concentration (Cmax) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Time to reach Cmax (Tmax) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Pre-dose (trough) concentrations (Cthrough) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Elimination half-life (t 1/2) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Total body clearance of drug from the plasma (CL) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Volume of distribution (Vd) [ Time Frame: From first dose until treatment discontinuation, expected average of 1 year ]
• All parts: Incidence of anti-drug antibodies (ADA) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
• Expansion & Optimization parts: Percentage of participants with Minimal Residual Disease (MRD) negativity status [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as proportion of participants with at least one MRD negative result.
• Expansion & Optimization parts: Duration of MRD negative status [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Defined as the number of days from the first documentation of MRD negative status to the date of MRD status change (not MRD negative).
• Expansion part: Changes in lymphoma symptoms as measured by the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) [ Time Frame: From first dose until up to 1 year after the last participant's first dose ]
  Monitor change from baseline in health-related quality of life over time and in relation to treatment.

Original Secondary Outcome Measures (submitted: August 9, 2018)

• Cytokine measures [ Time Frame: During the first two cycles of treatment (1 cycle is 28 days), at unscheduled visits and up to 5 years after last patient first visit ]
  To establish tolerability of GEN3013 using an array-based ligand binding assay
• Area-under-the-concentration-time curve (AUC0-C last) [ Time Frame: Through study completion and up to 5 years after last patient first visit ]
  To establish the PK profile of GEN3013 after single and multiple doses
• Maximum Plasma Concentration (Cmax) of GEN3013 [ Time Frame: Through study completion and up to 5 years after last patient first visit ]
  To establish the PK profile of GEN3013 after single and multiple doses
• Presence of neutralizing anti-drug antibodies (ADAs) in blood (positive/negative). [ Time Frame: Through study completion and up to 5 years after last patient first visit ]
  To evaluate immunogenicity of GEN3013
• Reduction in tumor size [ Time Frame: Through study completion and up to 5 years after last patient first visit ]
  To evaluate the anti-lymphoma activity of GEN3013 as evaluated by Lugano classification (Cheson et al., 2014)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: First-in-Human (FIH) Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma
• Official Title: A Phase 1/2, Open-label Safety Trial of GEN3013 in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

Brief Summary

The trial is a global, multi-center safety and efficacy trial of epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20). The trial consists of 3 parts:

• a dose-escalation part (Phase 1, first-in-human (FIH))
• an expansion part (Phase 2a)
• a dose-optimization part (Phase 2a)

Detailed Description

The purpose of the dose-escalation part of the trial is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), as well as to establish the safety profile of epcoritamab in patients with relapsed, progressive or refractory B-cell lymphoma.

In the expansion part, additional patients will be treated with epcoritamab, at the RP2D and the purpose is to further explore and determine the safety and efficacy of epcoritamab.

The dose-optimization part will evaluate alternative priming and intermediate dose regimens of epcoritamab. All patients will receive epcoritamab at the RP2D.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diffuse Large B-cell Lymphoma (DLBCL)
• High-grade B-cell Lymphoma (HGBCL)
• Primary Mediastinal Large B-cell Lymphoma (PMBCL)
• Follicular Lymphoma (FL)
• Mantle Cell Lymphoma (MCL)
• Small Lymphocytic Lymphoma (SLL)
• Marginal Zone Lymphoma (MZL)

Intervention

Biological: Epcoritamab

Administered as specified in the treatment arm.

Other Names:

• GEN3013
• DuoBody®-CD3xCD20
• EPKINLY™

Study Arms

Experimental: Epcoritamab

Epcoritamab will be administered by subcutaneous injections in cycles of 28 days

Intervention: Biological: Epcoritamab

Publications *

• Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, Do YR, Feldman T, Gasiorowski R, Jurczak W, Kim TM, Lewis DJ, van der Poel M, Poon ML, Cota Stirner M, Kilavuz N, Chiu C, Chen M, Sacchi M, Elliott B, Ahmadi T, Hutchings M, Lugtenburg PJ. Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol. 2023 Apr 20;41(12):2238-2247. doi: 10.1200/JCO.22.01725. Epub 2022 Dec 22.
• Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, Lewis DJ, Sureda Balari A, Cunningham D, Oliveri RS, Elliott B, DeMarco D, Azaryan A, Chiu C, Li T, Chen KM, Ahmadi T, Lugtenburg PJ. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021 Sep 25;398(10306):1157-1169. doi: 10.1016/S0140-6736(21)00889-8. Epub 2021 Sep 8.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 18, 2022): 700
• Original Estimated Enrollment (submitted: August 9, 2018): 110
• Estimated Study Completion Date: April 2029
• Estimated Primary Completion Date: January 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Main Inclusion Criteria - Escalation Part (recruitment completed)

• Documented CD20+ mature B-cell neoplasm

  1. DLBCL - de novo or transformed
  2. HGBCL
  3. PMBCL
  4. FL
  5. MCL
  6. SLL
  7. MZL (nodal, extranodal or mucosa associated)
• Relapsed, progressive 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.
• ECOG performance status 0,1 or 2
• Patients must have measurable disease by CT, MRI or PET-CT scan
• Acceptable renal function
• Acceptable liver function

Main Inclusion Criteria - Expansion & Optimization 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 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 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

Main Exclusion Criteria - All Parts

• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening
• Known past or current malignancy other than inclusion diagnosis
• AST, and/or 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 CrCl <45 mL/min
• Known clinically significant cardiovascular disease
• Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment). Past 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 (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection). Subjects with evidence of prior 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 ICF
• Pregnancy or breast feeding
• Patient 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 patient
• Contraindication to all uric acid lowering agents

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Genmab Trial Information; +45 70202728; clinicaltrials@genmab.com

• Listed Location Countries: Australia, Canada, Denmark, Finland, France, Germany, Italy, Korea, Republic of, Netherlands, Poland, Singapore, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT03625037
• Other Study ID Numbers: GCT3013-01; 2017-001748-36 ( EudraCT Number ); NL64317.078.17 ( Registry Identifier: CCMO ); 241053 ( Other Identifier: IRAS ID; Research Summary Database )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Genmab
• Original Responsible Party: Same as current
• Current Study Sponsor: Genmab
• Original Study Sponsor: Same as current
• Collaborators: AbbVie

Investigators

• Principal Investigator: Pieternella Lugtenburg, MD, PhD; Erasmus MC University Medical Center Rotterdam

• PRS Account: Genmab
• Verification Date: May 2023