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

DLBCL Clinical Trial

— EPCORE™ NHL-1  

Official title:

A Phase 1/2, Open-label Safety Trial of GEN3013 in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03625037
• Other study ID #: GCT3013-01
• Secondary ID: 2017-001748-36NL
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 26, 2018
• Est. completion date: January 2029

Study information

• Verified date: June 2024
• Source: Genmab
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to measure the following in participants with relapsed and/or refractory B-cell lymphoma who receive epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20):

• The dose schedule for epcoritamab

• The side effects seen with epcoritamab

• What the body does with epcoritamab once it is administered

• What epcoritamab does to the body once it is administered

• How well epcoritamab works against relapsed and/or refractory B-cell lymphoma

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 (OPT) (Phase 2a)

The trial time for each participant depends on which trial part the participant enters:

• For the dose-escalation part, each participant will be in the trial for approximately 1 year, which is made up of 21 days of screening, 6 months of treatment (the total time of treatment may be different for each participant), and 6 months of follow-up (the total time of follow-up may be different for each participant).

• For the expansion and dose-OPT parts, each participant will be in the trial for approximately 1.5 years, which is made up of 21 days of screening, 1 year of treatment (the total time of treatment may be different for each participant), and 6 months of follow-up (the total time of follow-up may be different for each participant).

Participation in the study will require visits to the sites. During the first month, participants must visit every day or every few days, depending on which trial part the participant enters. After that, participants must visit weekly, every other week, once a month, and once every 2 months, as trial participation ends.

All participants will receive active drug, and no participants will be given placebo.

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 participants with relapsed or refractory B-cell lymphoma.

In the expansion part, additional participants 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-OPT part will evaluate alternative priming and intermediate dose regimens of epcoritamab in participants with:

• Diffuse large B-cell lymphoma (DLBCL)

• Follicular lymphoma (FL)

• Mantle cell lymphoma (MCL)

All participants will receive epcoritamab at the RP2D.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 666
• Est. completion date: January 2029
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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 CT, 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 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.

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 Creatinine clearance (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). Participants 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 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.

Related Conditions & MeSH terms

• DLBCL
• High-grade B-cell Lymphoma (HGBCL)
• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Marginal Zone Lymphoma (MZL)
• MCL
• Primary Mediastinal Large B-cell Lymphoma (PMBCL)
• Small Lymphocytic Lymphoma (SLL)

Intervention

Biological:
• Epcoritamab
Administered as specified in the treatment arm.

Locations

Country	Name	City	State
Australia	Monash Health	Clayton
Australia	Concord Hospital	Concord
Australia	St. Vincent Hospital	Fitzroy
Australia	Royal Brisbane and Women's Hospital	Herston
Australia	Royal Hobart Hospital RHH	Hobart
Australia	St. George Hospital	Kogarah
Australia	Cabrini Hospital	Malvern
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Gold Coast Hospital	Southport
Australia	Westmead Hospital	Sydney
Canada	Tom Baker Cancer Care	Calgary
Canada	Toronto-Sunnybrook Regional Cancer Ctr	Toronto
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense University Hospital	Odense
Denmark	Vejle Hospital	Vejle
Finland	Helsinki University Hospital	Helsinki
Finland	Kuopio University Hospital	Kuopio
Finland	Tampere University Hospital	Tampere
France	Hopital Henri Mondor	Créteil
France	CHU Montpellier	Montpellier
France	Hospital Saint-Louis	Paris
France	Hospices Civils de Lyon Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Centre Henri Becquerel	Rouen cedex
France	CHU de Tours-Hopital Bretonneau	Tours
Germany	Charite - Universitaetsmedizin Berlin	Berlin
Germany	Klinik fur Innere Medizin Hamatologie and Onkologie	Berlin
Germany	Universitaetsklinikum Koeln	Cologne
Germany	Universitaetsklinikum Essen	Essen
Germany	Johannes Gutenberg University	Mainz
Germany	Der Universität Munchen Medizinische Klinik III LMU	München
Italy	Ao Ss Antonio E Biagio Alessandria	Alessandria
Italy	Policlinico S. Orsola-Ematologia LA Seragnoli	Bologna
Italy	Istituto di Candiolo- Fondazione del Piemonte per l'Oncologia	Candiolo
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	IRCCS Ospedale San Raffaele	Milan
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Keimyung University Dongsan Medical Center	Daegu
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Chonbuk National University Hospital	Jeonju
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University	Seoul
Netherlands	VU University Medical Center	Amsterdam
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Erasmus MC Cancer Institute	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Poland	Szpital Uniwersytecki nr 2 im dr. Jana Biziela	Bydgoszcz
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Pratia-McM	Kraków
Poland	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka	Slupsk
Poland	Maria Sklodowska-Curie Memorial Cancer Center and Institute	Warszawa
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego	Wroclaw
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Universitario Vall dHebron	Barcelona
Spain	Institut Catala de Oncologia	Barcelona
Spain	Hospital Universitario Fundacin Jimnez Daz	Madrid
Spain	Clinica Universidad de Navarra	Pamplona	Navarra
Sweden	Skåne University Hospital	Lund
Sweden	Karolinska University Hospital Huddinge	Stockholm
Sweden	Akademiska sjukhuset Uppsala University Hospital	Uppsala
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Plymouth University School of Medicine- Derriford Hospital	Plymouth
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	University of Michigan	Ann Arbor	Michigan
United States	Medical University of South Carolina	Charleston	South Carolina
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	UT Southwestern	Dallas	Texas
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Hackensack Meridian Health	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa Hospital and Clinics	Iowa City	Iowa
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Arizona Mayo Clinic	Phoenix	Arizona
United States	Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	OHSU Knight Cancer Institute	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of California at San Francisco	San Francisco	California
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Genmab	AbbVie

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  Finland,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Singapore,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

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, Lug — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-Escalation: Dose Limiting Toxicity (DLT)	To determine the MTD and/or RP2D to be studied in the Expansion part. DLT will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.	During the first cycle (28 days) in each Dose-OPT Part DLBCL, FL and MCL
Primary	Dose-Escalation: Number of Participants with Adverse Events (AEs)	An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.	From first dose until the end of the safety follow-up period (Up to 1 year)
Primary	Expansion and Dose-OPT MCL: Overall Response Rate (ORR)	ORR is defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on Lugano criteria as assessed by independent review committee (IRC).	Up to 1.5 years
Primary	Dose-OPT DLBCL, FL and MCL: Percentage of Participants with =>Grade 2 Cytokine Release Syndrome (CRS) Events and All Grade CRS Events	CRS will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria.	From first dose until 7 days after second full dose (Day 28 for DLBCL; Day 35 for FL; Day 28-35 for MCL)
Secondary	Dose-Escalation: Number of Participants with Anti-lymphoma Activity of Epcoritamab	Anti-lymphoma activity will be evaluated as number of participants with resolution of constitutional symptoms, reduction in tumor size, objective, and best response (ORR, CR and PR).	Up to 1 year
Secondary	Dose-Escalation: DOR	DOR is defined as the time from the first documentation of response (CR or PR) to the date of PD or death, whichever occurs earlier as assessed by the investigator.	Up to 1 year
Secondary	Expansion: DOR	DOR is defined as the time from the first documentation of response (CR or PR) to the date of PD or death, whichever occurs earlier based on Lugano criteria assessed by IRC.	Up to 1.5 years
Secondary	Expansion Part: Changes in Lymphoma Symptoms as Measured by the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)	Change from baseline in health-related quality of life over time and in relation to treatment will be evaluated using FACT-Lym scale.	Up to 1.5 year
Secondary	Dose-OPT DLBCL and FL: Percentage of Participants with >=Grade 2 CRS Events and All Grade CRS Events Following First Full Dose	CRS will be graded based on ASTCT criteria.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: Percentage of Participants with >=Grade 2 CRS Events and All Grade CRS Events Overall	CRS will be graded based on ASTCT criteria.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: ORR	ORR is defined as the percentage of participants achieving CR or PR assessed by investigator.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: CR Rate	CR rate is defined as the percentage of participants with CR assessed by investigator.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: Duration of CR (DoCR)	DoCR is defined as the time from the first documentation of CR to the date of PD or death, whichever occurs earlier assessed by investigator.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: Progression-Free Survival (PFS)	PFS is defined as the time from Day 1 of Cycle 1 to first documented PD or death due to any cause, whichever occurs earlier assessed by investigator.	Up to 1.5 years
Secondary	Dose-OPT DLBCL and FL: DLT	To determine the MTD and/or RP2D to be studied in the expansion part. DLT will be graded according to NCI-CTCAE version 5.0.	During the first cycle (28 days) in each Dose-OPT Part (DLBCL, FL and MCL)
Secondary	Dose-OPT MCL: Time to Complete Response (TTCR)	TTCR is defined as the time from Day 1 of Cycle 1 to first documentation of complete response based on Lugano criteria and LYRIC as assessed by IRC.	Up to 1.5 years
Secondary	Dose-OPT DLBCL, FL and MCL: DOR	DOR is defined as the time from the first documentation of response (CR or PR) to the date of PD or death, whichever occurs earlier based on Lugano criteria assessed by investigator.	Up to 1.5 years
Secondary	Dose-Escalation and Dose-OPT DLBCL, FL and MCL: Pre-dose Values of Epcoritamab		Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days)
Secondary	Dose-Escalation, Expansion Part and Dose-OPT MCL: PFS	PFS is defined as the time from Day 1 of Cycle 1 to first documented PD or death due to any cause, whichever occurs earlier based on Lugano criteria assessed by IRC.	Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part (MCL): 1.5 years
Secondary	Expansion and Dose-OPT MCL: CR Rate	CR rate is defined as the percentage of participants with CR based on Lugano criteria as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: DoCR	DoCR is defined as the time from the first documentation of CR to the date of PD or death, whichever occurs earlier based on Lugano criteria as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: ORR	ORR is defined as the percentage of participants achieving CR or PR based on lymphoma response to immunomodulatory therapy criteria (LYRIC) as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: Time to Response (TTR)	TTR is defined as the time from Day 1 of Cycle 1 to first documentation of objective tumor response (PR or better) earlier based on Lugano criteria as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: CR Rate	CR rate is defined as the percentage of participants with CR based on LYRIC as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: PFS	PFS is defined as the time from Day 1 of Cycle 1 to first documented PD or death due to any cause, whichever occurs earlier based on LYRIC assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: DOR	DOR is defined as the time from the first documentation of response (CR or PR) to the date of PD or death, whichever occurs earlier based on LYRIC assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: DoCR	DoCR is defined as the time from the first documentation of CR to the date of PD or death, whichever occurs earlier based on LYRIC as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT MCL: TTR	TTR is defined as the time from Day 1 of Cycle 1 to first documentation of objective tumor response (PR or better) earlier based on LYRIC as assessed by IRC.	Up to 1.5 years
Secondary	Expansion and Dose-OPT DLBCL, FL and MCL: Number of Participants with AEs	An AE is any untoward medical occurrence in a clinical trial participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.	Up to 7 years and 6 months
Secondary	Expansion and Dose-OPT DLBCL, FL and MCL: Rate of Minimal Residual Disease (MRD) Negativity	MRD is defined as percentage of participants with at least 1 MRD negative result.	Up to 1.5 years
Secondary	All Parts: Number of Participants with CRS Events	CRS will be graded based on ASTCT criteria.	Up to Day 1 of Cycle 12 (Cycle length=28 days)
Secondary	All Parts: Immunophenotyping for Absolute T-cell and B-cell	Number of cells will be reported for absolute T-cells and B-cells.	Up to Day 1 of Cycle 12 (Cycle length=28 days)
Secondary	All Parts: T-Cell Activation and Exhaustion Marker	T-Cell Activation and Exhaustion Marker (CD69, CD25, and PD-1) will be measured using flow cytometry.	Up to 7 years and 6 months
Secondary	All Parts: Total Body Clearance of Epcoritamab from the Plasma (CL)		Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days)
Secondary	All Parts: Area under Curve (AUC) of Epcoritamab		Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days)
Secondary	All Parts: Maximum (peak) Plasma Concentration (Cmax) of Epcoritamab		Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days)
Secondary	All Parts: Time to Reach Cmax of Epcoritamab		Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days)
Secondary	All Parts: Half Life of Epcoritamab (t1/2)		Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days)
Secondary	All Parts: Number of Participants with Anti-drug Antibody (ADA)	Plasma samples will be screened for antibodies binding to epcoritamab, and for confirmed positive samples, the titer against the two specific arms of epcoritamab will be reported.	Up to 7 years and 6 months
Secondary	All Parts: Time to Next Anti-lymphoma Therapy (TTNT)	TTNT is defined as the time from Day 1 of Cycle 1 to first recorded administration of subsequent anti-lymphoma therapy or death due to any cause, whichever occurs earlier.	Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part (DLBCL, FL and MCL): Up to 1.5 years
Secondary	All Parts: Overall survival (OS)	OS is defined as the time from Day 1 of Cycle 1 to death.	Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part DLBCL, FL and MCL: Up to 1.5 years