Clinical trial NCT03625037: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: DLBCL
High-grade B-cell Lymphoma (HGBCL)
Primary Mediastinal Large B-cell Lymphoma (PMBCL)
FL
MCL
Small Lymphocytic Lymphoma (SLL)
Marginal Zone Lymphoma (MZL)
Indolent B-cell Non-Hodgkin Lymphoma (iNHL)
Aggressive B-cell Non-Hodgkin Lymphoma (aNHL)
Lead sponsor: Genmab
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
First posted: 2018-08-10
Enrollment: 666
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

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 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.

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 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.

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.
* 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.

Primary outcomes:
measure: Dose-Escalation: Dose Limiting Toxicity (DLT)
timeFrame: During the first cycle (28 days)
measure: Dose-Escalation: Number of Participants with Adverse Events (AEs)
timeFrame: From first dose until the end of the safety follow-up period (Up to 1 year)
measure: Expansion: Overall Response Rate (ORR)
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL, FL and MCL: Percentage of Participants with =>Grade 2 Cytokine Release Syndrome (CRS) Events and All Grade CRS Events
timeFrame: From first dose until 7 days after second full dose (Day 28 for DLBCL; Day 35 for FL; Day 28-35 for MCL)
Secondary outcomes:
measure: Dose-Escalation: Number of Participants with Anti-lymphoma Activity of Epcoritamab
timeFrame: Up to 1 year
measure: Dose-Escalation: Duration of Response (DOR)
timeFrame: Up to 1 year
measure: Expansion: DOR
timeFrame: Up to 1.5 years
measure: Expansion Part: Changes in Lymphoma Symptoms as Measured by the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)
timeFrame: Up to 1.5 year
measure: Dose-OPT DLBCL and FL: Percentage of Participants with >=Grade 2 CRS Events and All Grade CRS Events Following First Full Dose
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: Percentage of Participants with >=Grade 2 CRS Events and All Grade CRS Events Overall
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: ORR
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: CR Rate
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: Duration of CR (DoCR)
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: Progression-Free Survival (PFS)
timeFrame: Up to 1.5 years
measure: Dose-OPT DLBCL and FL: DLT
timeFrame: During the first cycle (28 days) in each Dose-OPT Part (DLBCL, FL and MCL)
measure: Dose-OPT DLBCL, FL and MCL: DOR
timeFrame: Up to 1.5 years
measure: Dose-Escalation and Dose-OPT DLBCL, FL and MCL: Pre-dose Values of Epcoritamab
timeFrame: Predose and postdose at multiple timepoints of each Cycle (Cycle length=28 days), up to approximately 1.5 years
measure: Dose-Escalation, Expansion Part and Dose-OPT MCL: PFS
timeFrame: Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part (MCL): 1.5 years
measure: Expansion and Dose-OPT MCL: CR Rate
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: DoCR
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: ORR
timeFrame: Up to 1.5 years
measure: Expansion: Time to Response (TTR)
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: CR Rate
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: PFS
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: DOR
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT MCL: DoCR
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT: TTR
timeFrame: Up to 1.5 years
measure: Expansion and Dose-OPT DLBCL, FL and MCL: Number of Participants with AEs
timeFrame: Up to 7 years and 6 months
measure: Expansion and Dose-OPT DLBCL, FL and MCL: Rate of Minimal Residual Disease (MRD) Negativity
timeFrame: Up to 1.5 years
measure: All Parts: Number of Participants with CRS Events
timeFrame: Up to Day 1 of Cycle 12 (Cycle length=28 days)
measure: All Parts: Total Body Clearance of Epcoritamab from the Plasma (CL)
timeFrame: Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days), Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part: Up to 1.5 years
measure: All Parts: Area under Curve (AUC) of Epcoritamab
timeFrame: Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days), Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part: Up to 1.5 years
measure: All Parts: Maximum (peak) Plasma Concentration (Cmax) of Epcoritamab
timeFrame: Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days), Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part: Up to 1.5 years
measure: All Parts: Time to Reach Cmax of Epcoritamab
timeFrame: Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days), Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part: Up to 1.5 years
measure: All Parts: Half Life of Epcoritamab (t1/2)
timeFrame: Predose and postdose at multiple timepoints of each cycle (Cycle length=28 days), Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part: Up to 1.5 years
measure: All Parts: Number of Participants with Anti-drug Antibody (ADA)
timeFrame: Up to 7 years and 6 months
measure: All Parts: Time to Next Anti-lymphoma Therapy (TTNT)
timeFrame: Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part (DLBCL, FL and MCL): Up to 1.5 years
measure: All Parts: Overall survival (OS)
timeFrame: Dose-Escalation: Up to 1 year; Expansion and Dose-OPT Part DLBCL, FL and MCL: Up to 1.5 years
measure: Expansion: Trough Concentration of Epcoritamab
timeFrame: Up to 1.5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Mayo Clinic
state: Arizona
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack Meridian Health
state: New Jersey
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Pittsburgh
country: United States
facility: Hillman Cancer Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Clayton
country: Australia
facility: Monash Health
city: Concord
country: Australia
facility: Concord Hospital
city: Fitzroy
country: Australia
facility: St. Vincent Hospital
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital RHH
city: Kogarah
country: Australia
facility: St. George Hospital
city: Malvern
country: Australia
facility: Cabrini Hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Southport
country: Australia
facility: Gold Coast Hospital
city: Sydney
country: Australia
facility: Westmead Hospital
city: Calgary
country: Canada
facility: Tom Baker Cancer Care
city: Toronto
country: Canada
facility: Toronto-Sunnybrook Regional Cancer Ctr
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Montpellier
country: France
facility: CHU Montpellier
city: Paris
country: France
facility: Hospital Saint-Louis
city: Pierre-Bénite
country: France
facility: Hospices Civils de Lyon Centre Hospitalier Lyon Sud
city: Rouen cedex
country: France
facility: Centre Henri Becquerel
city: Tours
country: France
facility: CHU de Tours-Hopital Bretonneau
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin
city: Berlin
country: Germany
facility: Klinik fur Innere Medizin Hamatologie and Onkologie
city: Cologne
country: Germany
facility: Universitaetsklinikum Koeln
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: München
country: Germany
facility: Der Universität Munchen Medizinische Klinik III LMU
city: Alessandria
country: Italy
facility: Ao Ss Antonio E Biagio Alessandria
city: Bologna
country: Italy
facility: Policlinico S. Orsola-Ematologia LA Seragnoli
city: Candiolo
country: Italy
facility: Istituto di Candiolo- Fondazione del Piemonte per l'Oncologia
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Jeonju
country: Korea, Republic of
facility: Chonbuk National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im dr. Jana Biziela
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: Pratia-McM
city: Słupsk
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka
city: Warszawa
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Universitario Vall dHebron
city: Barcelona
country: Spain
facility: Institut Catala de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Fundacin Jimnez Daz
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset Uppsala University Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Plymouth University School of Medicine- Derriford Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Genmab
name: Study Official
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Linton KM, Vitolo U, Jurczak W, Lugtenburg PJ, Gyan E, Sureda A, Christensen JH, Hess B, Tilly H, Cordoba R, Lewis DJ, Okada C, Hutchings M, Clausen MR, Sancho JM, Cochrane T, Leppa S, Chamuleau MED, Gernhardt D, Altintas I, Liu Y, Ahmadi T, Dinh MH, Hoehn D, Favaro E, Elliott B, Thieblemont C, Vose JM. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol. 2024 Aug;11(8):e593-e605. doi: 10.1016/S2352-3026(24)00166-2. Epub 2024 Jun 15.
citation: 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.