Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome

Small Lymphocytic Lymphoma Clinical Trial

— EPCORE™ CLL-1  

Official title:

A Phase 1b/2, Open-Label, Safety and Efficacy Study of Epcoritamab (GEN3013; DuoBody®-CD3xCD20) in Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04623541
• Other study ID #: GCT3013-03
• Secondary ID: 2020-000848-57NL
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 25, 2020
• Est. completion date: August 2029

Study information

• Verified date: June 2024
• Source: Genmab
• Contact: Genmab Trial Information
• Phone: +4570202728
• Email: clinicaltrials[@]genmab.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study is a global, multi-center safety and efficacy trial of epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20). Epcoritamab will either be studied as: - Monotherapy, or - Combination therapy: - epcoritamab + venetoclax - epcoritamab + lenalidomide - epcoritamab + R-CHOP (i.e., rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone). The study includes patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL)/small lymphocytic lymphoma (SLL) and patients with Richter's Syndrome (RS). Study participants with R/R CLL/SLL are treated either with epcoritamab as monotherapy or epcoritamab + venetoclax. Study participants with RS are treated either with epcoritamab as monotherapy or epcoritamab + lenalidomide or epcoritamab + R-CHOP. The trial consists of two parts, a dose-escalation phase (phase Ib) and an expansion phase (phase II). Patients with RS are only included in the expansion phase.

Description:

The purpose of the dose-escalation phase of the trial is to determine the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD; if reached) as well as establish the safety profile of epcoritamab monotherapy and epcoritamab + venetoclax in participants with R/R CLL. The purpose of the expansion phase is to assess and evaluate the preliminary efficacy, safety and tolerability profiles of epcoritamab monotherapy and epcoritamab + venetoclax at the RP2D for patients with R/R CLL/SLL. Along with this, epcoritamab monotherapy, epcoritamab + lenalidomide and epcoritamab + R-CHOP will be evaluated in patients with RS to assess their efficacy, safety and tolerability profiles.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 184
• Est. completion date: August 2029
• Est. primary completion date: June 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria

1. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

2. Evidence of CD20 positivity in a sample representative of the disease at Screening.

3. Acceptable hematology parameters and organ function based on baseline bloodwork.

4. For R/R CLL arms - Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.

5. For R/R CLL arms - Received at least 2 prior lines of systemic anti-neoplastic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.

6. For all RS arms - Have tumor biopsy-proven CD20+ Diffuse large B-cell Lymphoma (DLBCL) and a clinical history of CLL/SLL.

7. For all RS arms - Must have measurable disease by fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) or magnetic resonance imaging (MRI) scan.

8. For all RS arms - Must provide mandatory formalin-fixed, paraffin-embedded (FFPE) tumor biopsy sample.

9. Life expectancy >3 months on standard of care (SOC).

10. For RS - monotherapy arm: Deemed as ineligible for chemoimmunotherapy at investigator's discretion or participant who refuses to receive intensive chemotherapy

11. For RS - lenalidomide combination therapy arm

• Deemed as ineligible for chemoimmunotherapy at the investigator's discretion, or participant who refuses to receive intensive chemotherapy.
• Eligible for treatment with lenalidomide.
• Must be willing to use contraception and adhere to the Lenalidomide Pregnancy Risk Minimization Plan

12. For RS - R-CHOP combination Therapy Arm -

• Eligible for treatment with R-CHOP.

13. For R/R CLL - venetoclax combination Therapy arm - after receiving at least 1 prior line of systemic antineoplastic therapy. Key Exclusion Criteria

1. Received prior treatment with a CD3×CD20 bispecific antibody.

2. Received any prior allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation.

3. Received (CAR) T-cell therapy within 100 days or an investigational drug within 4 weeks, prior to first dose of epcoritamab.

4. Autoimmune disease or other diseases that require permanent or high-dose immunosuppressive therapy.

5. Received vaccination with live vaccines within 28 days.

6. Clinically significant cardiac disease.

7. Known current malignancy other than inclusion diagnosis.

8. Has had major surgery within 4 weeks.

9. Active hepatitis B virus or active hepatitis C.

10. Known history of HIV.

11. For R/R CLL arms - Any history of RS or evidence indicating a potential Richter's transformation.

12. Received venetoclax within 24 months prior to beginning venetoclax ramp-up for this trial and progressed on treatment.

13. For all RS arms - Diagnosis of Richter's syndrome not of the DLBCL subtype such as Hodgkin's lymphoma, prolymphocytic leukemia.

14. RS - Lenalidomide Combination Therapy and RS Monotherapy Arms - received more than 2 prior lines of therapy for RS. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Relapsed/Refractory Chronic Lymphocytic Leukemia
• Richter's Syndrome
• Small Lymphocytic Lymphoma
• Syndrome

Intervention

Biological:
• Epcoritamab
Epcoritamab will be administered subcutaneously in cycles of 28 days (except Cycle 1 for high-dose cohorts = 35 days).
• Epcoritamab
Epcoritamab will be administered subcutaneously in cycles of 21 days (Cycle 1-6) and 28 days for Cycle 7 and beyond.

Drug:
• rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone
R-CHOP will be administered intravenously in cycles of 21 days for the first 6 cycles.
• Venetoclax
Venetoclax tablets will be administered orally once daily during the 5-week ramp up period and during Cycle 1-26 of 28 or 35 days each.

Biological:
• Epcoritamab
Epcoritamab will be administered subcutaneously in cycles of 28 days.

Drug:
• Lenalidomide
Lenalidomide capsules will be administered once daily for 21 days in each cycle of 28 days up to 12 cycles.

Locations

Country	Name	City	State
Australia	Barwon Health	Geelong	Victoria
Australia	St. George Hospital	Kogarah	New South Wales
Australia	Alfred Health	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Belgium	AZ Sint-Jan	Bruges
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UZ Leuven	Leuven
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Králové	Nový Hradec Králové
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni Nemocnice Ostrava	Ostrava	Poruba
Czechia	Vseobecna Fakultni Nemocnice	Praha	Nové Mesto
Denmark	Aalborg University Hospital	Aalborg
Denmark	Århus University Hospital	Århus
Denmark	Rigshospitalet	København	Hovedstaden
Denmark	Odense University Hospital	Odense
Denmark	Roskilde Sygehus	Roskilde
Denmark	Vejle Sygehus	Vejle
France	CHU Clermont Ferrand	Clermont Ferrand cedex	Puy De Dome
France	CHU de Montpellier Hôpital Saint Eloi	Montpellier	Cedex 5
France	Hôpital Privé du Confluent	Nantes	Pays De La Loire
France	Hôpital Saint-Louis	Paris
France	Hôpital Universitaire Pitié-Salpêtrière	Paris
France	CHU Hôpital Haut-Lévêque Bordeaux	Pessac	Gironde
France	CHU Hôpital de Brabois Nancy	Vandœuvre-lès-Nancy	Meurthe Et Moselle
Germany	Universitaetsklinikum Schleswig-Holstein- Karl-Lennart-Krebscentrum	Kiel
Germany	Universitaetsklinikum Koeln	Koeln
Israel	Bnai Zion Medical Center	Haifa
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Rabin Medical Center-Beilinson Campus	Petah Tikva
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv-Yafo
Italy	AOU Policlinico Sant'Orsola Malpighi IRCCS	Bologna
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civili)	Brescia
Italy	IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori IRST	Meldola	Forli - Cesena
Italy	Ospedale San Raffaele	Milano
Italy	Ospedale Maggiore di Novara	Novara
Italy	AOU Policlinico Umberto I	Roma
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Italy	IRCCS Policlinico Universitario Agostino Gemelli	Roma	Lazio
Netherlands	Amsterdam UMC	Amsterdam
Netherlands	Albert Schweitzer Ziekenhuis, Dordwijk	Dordrecht	South Holland
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Spain	ICO Badalona - Hospital Universitario Germans Trias Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	AOC Arcispedale Saint'Anna	Coaña	Ferarra
Spain	Hospital Universitario Fundacion Jiménez Díaz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia	València
United Kingdom	St. James s University Hospital	Leeds	West Yorkshire
United Kingdom	Barts Hospital	London
United Kingdom	Nottingham University Hospitals City Campus	Nottingham	Nottinghamshire
United Kingdom	Royal Cornwall Hospital	Truro	Cornwall
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	O'Neal Comprehensive Cancer Center at University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	James Cancer Hospital	Columbus	Ohio
United States	The University of Texas Southwestern Medical Centre	Dallas	Texas
United States	Henry Ford Medical Group	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Hackensack Meridian Hospital	Hackensack	New Jersey
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Northwell Health Cancer Institute	Lake Success	New York
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	David Geffen School of Medicine	Los Angeles	California
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Columbia University Hervert Irving Comprehensive Cancer Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Stanford Cancer Center	Palo Alto	California
United States	Memorial Healthcare System	Pembroke Pines	Florida
United States	University of Pennsylvania School of medicine	Philadelphia	Pennsylvania
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Genmab	AbbVie

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Czechia,  Denmark,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation Phase (R/R CLL arm): Number of Participants with Dose Limiting Toxicities (DLTs)	DLT events were defined as clinically significant adverse events (AEs) or abnormal laboratory values assessed as unrelated to disease progression, underlying disease, intercurrent illness, or concomitant medications as assessed per Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria version 5.0.	During the first cycle for low dose cohorts (Cycle length = 28 days) and for high dose cohorts (Cycle length = 35 days)
Primary	Dose Escalation Phase: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		From first dose until the end of the safety follow-up period (60 days after last dose)
Primary	Dose Escalation Phase: Number of Participants with Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and Clinical Tumor Lysis Syndrome (CTLS)	CRS and ICANS will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. CTLS will be graded according to Cairo-Bishop criteria.	From first dose until the end of the safety follow-up period (60 days after last dose)
Primary	Expansion Phase: Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieve a response of partial response or complete response, prior to initiation of subsequent therapy. R/R CLL participants will be assessed according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and the RS participants according to Lugano criteria.	Up to 5 years
Secondary	Expansion Phase: Number of Participants with TEAEs and SAEs		From first dose until the end of the safety follow-up period (60 days after last dose)
Secondary	Dose Escalation Phase: ORR	ORR is defined as percentage of participants who achieve a response of partial response or complete response, prior to initiation of subsequent therapy as assessed by iwCLL criteria.	Up to 5 years
Secondary	Both Phases: Duration of Response (DOR)	DOR is defined among responders, as the time from the initial documentation of response to the date of disease progression or death, whichever occurs earlier.	Up to 5 years
Secondary	Both Phases: Number of Participants with Complete Remission (CR) / CR with Incomplete Bone Marrow Recovery (CRi)	CR and CRi for R/R CLL participants will be assessed according to iwCLL criteria and CR for the RS participants, according to Lugano criteria.	Up to 5 years
Secondary	Both Phases: Time to Response (TTR)	TTR is defined among responders, as the time between first dose of epcoritamab and the initial documentation of response.	Up to 5 years
Secondary	Both Phases: Progression Free Survival (PFS)	PFS is defined as the time from the first dosing date of epcoritamab and the date of disease progression or death, whichever occurs earlier.	Up to 5 years
Secondary	Both Phases: Overall Survival (OS)	OS is defined as the time from the first dosing date of epcoritamab and the date of death due to any cause.	Up to 5 years
Secondary	Both Phases: Time to Next Systemic Anti-cancer Therapy (TTNT)	TTNT is defined as the time from the first dosing date of epcoritamab to the first documented administration of subsequent systemic anticancer therapy.	Up to 5 years
Secondary	Both Phases: Area Under the Concentration-time Curve (AUC) From Time Zero to Last Quantifiable Sample (AUClast) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: AUC From Time Zero to Infinity (AUCinf) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Maximum (Peak) Plasma Concentration (Cmax) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Pre-dose (Trough) Concentrations (Cthrough) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Time to Reach Cmax (Tmax) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Elimination Half-life (T1/2) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Total Body Clearance of Drug From Plasma (CL) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Volume of distribution (Vd) in Epcoritamab		Predose and post dose at multiple timepoints at end of each cycle for low dose and high dose cohorts (Cycle length = 28 days, except Cycle 1 for high dose cohorts = 35 Days)
Secondary	Both Phases: Lymphoid Cells for Immunophenotyping	Evaluation of B cells, T cells and their activation	Up to 5 years
Secondary	Expansion Phase: Number of Participants with CRS, ICANS and CTLS	CRS and ICANS will be graded based on ASTCT criteria. CTLS will be graded according to Cairo-Bishop criteria.	From first dose until the end of the safety follow-up period (60 days after last dose)
Secondary	Expansion Phase: Percentage of Participants with Minimal Residual Disease (MRD) Negativity	MRD negativity rate, is defined as the proportion of participants with at least 1 undetectable MRD result according to the specific threshold, prior to initiation of subsequent therapy.	Up to 5 years
Secondary	Both Phases: Number of Participants with Anti-drug Antibodies (ADA) to Epcoritamab		Up to end of treatment period (Up to 2 years)
Secondary	Expansion Phase: Number of Participants with Partial Remission (PR)/Nodular Partial Remission (nPR)	nPR is defined as PR with residual nodules or suspicious lymphocytic infiltrates in participants who are in remission. nPR is only calculated for R/R CLL.	Up to 5 years
Secondary	Both Phases: Duration of MRD Negativity	The time from first achieving MRD negativity after start of treatment to the MRD conversion to positive.	Up to 5 years