Clinical trial NCT04623541: Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Richter&#39;s Syndrome
Treatment-naïve High Risk Chronic Lymphocytic Leukemia
Keywords: DuoBody®
Bispecific antibodies
Anti-CD3
Anti-CD20
Lead sponsor: Genmab
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
name: Eli Lilly and Company
First posted: 2020-11-10
Enrollment: 424
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 be tested either in

Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as:

* Monotherapy, or
* Combination therapy:

  * epcoritamab + venetoclax
  * epcoritamab + pirtobrutinib

Treatment-naïve (TN) high risk (HR) (CLL):

• epcoritamab + pirtobrutinib

Combination therapy for Richter's Syndrome (RS):

* epcoritamab + lenalidomide
* epcoritamab + R-CHOP (i.e., rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine \[Oncovin®\] and prednisone).

The study includes participants with R/R or TN HR CLL/small lymphocytic lymphoma (SLL) and participants with RS.

The trial consists of two parts, a dose-escalation phase (phase Ib) and an expansion phase (phase II). Participants with RS are only included in the expansion phase.

Epcoritamab will be injected subcutaneously (under the skin). Standard-of-care and combination treatments (venetoclax, pirtobrutinib, lenalidomide, and R-CHOP) will be given either orally (by mouth) or intravenously (in a vein).

Study details include:

* Study duration will be up to 5 years after the last participant's first treatment in the trial.
* The treatment duration for each participant will be between 12 months (1 year) and 24 months (2 years), depending upon the treatment arm assigned.
* The visit frequency will be either weekly, every other week, or monthly, depending upon the part of the study.

All participants will receive active drug; no one will be given placebo.

Detailed 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, epcoritamab + venetoclax and epcoritamab + pirtobrutinib at the RP2D for participants with R/R CLL, TN HR CLL and SLL. Along with this, epcoritamab monotherapy, epcoritamab + lenalidomide and epcoritamab + R-CHOP will be evaluated in participants with RS to assess their efficacy, safety and tolerability profiles.

The purpose of safety run-in phase for pirtobrutinib combination therapy is to evaluate the safety and tolerability profiles of pirtobrutinib in combination with epcoritamab.

Eligibility criteria: 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. Life expectancy \>3 months on standard of care (SOC) for CLL, \>3 months for RS.
5. For R/R CLL arms - Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
6. For R/R CLL monotherapy arms - Received at least 2 prior lines of systemic anti-neoplastic therapy including a Bruton's tyrosine kinase (BTK) inhibitor or at least 1 prior line of systemic antineoplastic therapy, including treatment with (or intolerance of) a covalent BTK inhibitor (cBTKi) and a B-cell lymphoma 2 (BCL-2) inhibitor.
7. For all RS arms - Have tumor biopsy-proven CD20+ Diffuse large B-cell Lymphoma (DLBCL) and a clinical history of CLL/SLL.
8. 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.
9. For all RS arms - Must provide mandatory formalin-fixed, paraffin-embedded (FFPE) tumor biopsy sample.
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
    * A woman must agree not to breastfeed a child during treatment and for at least 28 days after discontinuation from study.
12. For RS - R-CHOP combination Therapy Arm -

    * Eligible for treatment with R-CHOP.
    * Females of childbearing potential must use highly effective contraceptive measures while taking R-CHOP and for 12 months after stopping treatment.
    * A woman must agree not to breastfeed a child during treatment or until 12 months after last treatment.
13. For R/R CLL - venetoclax combination Therapy arm - after receiving at least 1 prior line of systemic antineoplastic therapy.

    * Presence of measurable disease.
    * Must take prophylaxis for tumor lysis syndrome (TLS).
14. For R/R CLL pirtobrutinib combination Therapy arm:

    * Must have active CLL/SLL disease requiring treatment per iwCLL 2018 criteria.
    * Presence of measurable disease.
    * Previous treatment with at least one and a maximum 3 prior lines of therapy including a cBTKi.
    * Diagnosis of CLL/SLL that met published iwCLL criteria.
15. Participants with TN HR CLL - Pirtobrutinib Combination Therapy Expansion:

    * Diagnosis of CLL/SLL that met published iwCLL criteria 2018.
    * Must have active CLL/SLL disease that needs treatment per iwCLL
    * Must take prophylaxis for TLS based on their TLS risk evaluation upon initiation of trial drug.
    * Must have one or more high-risk features.
    * Presence of measurable disease.

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 chimeric antigen receptor (CAR) T-cell therapy within 100 days or an investigational drug within 4 weeks, prior to first dose of trial drug.
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. Known history of human immunodeficiency virus (HIV).
10. For R/R CLL arms - Any history of RS or evidence indicating a potential Richter's transformation.
11. For R/R CLL - Venetoclax Combination Therapy arm: received venetoclax within 24 months prior to beginning venetoclax ramp-up for this trial or has progressed on venetoclax treatment.
12. For all RS arms - Diagnosis of Richter's syndrome not of the DLBCL subtype such as Hodgkin's lymphoma, prolymphocytic leukemia.
13. RS - Lenalidomide Combination Therapy and RS Monotherapy Arms - received more than 2 prior lines of therapy for RS.
14. R/R CLL - Pirtobrutinib Combination Therapy Arm - Prior exposure to a non-covalent (reversible) BTK inhibitor or a BTK degrader.
15. Pirtobrutinib Combination Therapy Expansion Arms:

    * History of bleeding disorders or participants requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist
    * Require continuous treatment with or have received strong cytochrome P450 (CYP) 3A inhibitors or strong/moderate CYP3A inducers within 4 to 5 half-lives or 14 days prior to the first dose of pirtobrutinib.

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

Primary outcomes:
measure: Dose Escalation Phase and Safety Run-in (R/R CLL arm): Number of Participants with Dose Limiting Toxicities (DLTs)
timeFrame: During the first cycle for low dose cohorts (Cycle length = 28 days) and for high dose cohorts (Cycle length = 35 days)
measure: Dose Escalation Phase and Safety Run-in: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 5 years
measure: Dose Escalation Phase: Number of Participants with Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and Clinical Tumor Lysis Syndrome (CTLS)
timeFrame: Up to 5 years
measure: Expansion Phase: Overall Response Rate (ORR)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Expansion Phase: Number of Participants with TEAEs and SAEs
timeFrame: Up to 5 years
measure: Dose Escalation Phase and Safety Run-in: ORR (for R/R CLL Participants)
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Duration of Response (DOR)
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Number of Participants with CR/CRi
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Time to Response (TTR)
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Progression Free Survival (PFS)
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Overall Survival (OS)
timeFrame: Up to 5 years
measure: Both Phase and Safety Run-in: Time to Next Systemic Anti-cancer Therapy (TTNT)
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Area Under the Concentration-time Curve (AUC) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases and Safety Run-in: Maximum (Peak) Plasma Concentration (Cmax) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases: Pre-dose (Trough) Concentrations (Cthrough) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases and Safety Run-in: Time to Reach Cmax (Tmax) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases and Safety Run-in: Elimination Half-life (T1/2) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases and Safety Run-in: Total Body Clearance of Drug From Plasma (CL) in Epcoritamab
timeFrame: 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), up to 5 years
measure: Both Phases: Lymphoid Cells for Immunophenotyping
timeFrame: Up to 5 years
measure: Expansion Phase: Number of Participants with CRS, ICANS and CTLS
timeFrame: Up to 5 years
measure: Expansion Phase and Safety Run-in : Percentage of Participants with Minimal Residual Disease (MRD) Negativity
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Number of Participants with Anti-drug Antibodies (ADA) to Epcoritamab
timeFrame: Up to 5 years
measure: Expansion Phase: Number of Participants with PR
timeFrame: Up to 5 years
measure: Both Phases and Safety Run-in: Duration of MRD Negativity
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: O'Neal Comprehensive Cancer Center at University of Alabama at Birmingham
state: Alabama
city: California
country: United States
facility: University of California Davis Medical Center Sacramento
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Healthcare System
state: Florida
city: Bethesda
country: United States
facility: National Institutes of Health
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Medical Group
state: Michigan
city: Hackensack
country: United States
facility: Hackensack Meridian Hospital
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center
state: New York
city: Lake Success
country: United States
facility: Northwell Health Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania School of medicine
state: Pennsylvania
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Centre
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Kogarah
country: Australia
facility: St. George Hospital
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Geelong
country: Australia
facility: Barwon Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Bruges
country: Belgium
facility: AZ Sint-Jan
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice
state: Nové Město
city: Hradec Králové
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
state: Nový Hradec Králové
city: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava
state: Poruba
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: København
country: Denmark
facility: Rigshospitalet
state: Hovedstaden
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Roskilde
country: Denmark
facility: Roskilde Sygehus
city: Vejle
country: Denmark
facility: Vejle Sygehus
city: Århus
country: Denmark
facility: Århus University Hospital
city: Montpellier
country: France
facility: CHU de Montpellier Hôpital Saint Eloi
state: Cedex 5
city: Pessac
country: France
facility: CHU Hôpital Haut-Lévêque Bordeaux
state: Gironde
city: Vandœuvre-lès-Nancy
country: France
facility: CHU Hôpital de Brabois Nancy
state: Meurthe et Moselle
city: Nantes
country: France
facility: Hôpital Privé du Confluent
state: Pays de la Loire
city: Clermont Ferrand cedex
country: France
facility: CHU Clermont Ferrand
state: Puy de Dome
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Hôpital Universitaire Pitié-Salpêtrière
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
state: Baden Wuerttemberg
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein- Karl-Lennart-Krebscentrum
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Petah Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv-Yafo
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Torino
country: Italy
facility: Istituto di Candiolo
state: Candiolo
city: Ferrara
country: Italy
facility: AOU Arcispedale Sant'Anna
state: Cona
city: Meldola
country: Italy
facility: IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori IRST
state: Forli - Cesena
city: Roma
country: Italy
facility: IRCCS Policlinico Universitario Agostino Gemelli
state: Lazio
city: Bologna
country: Italy
facility: AOU Policlinico Sant'Orsola Malpighi IRCCS
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (Presidio Spedali Civili)
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Novara
country: Italy
facility: Ospedale Maggiore di Novara
city: Roma
country: Italy
facility: AOU Policlinico Umberto I
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis, Dordwijk
state: South Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Katowice
country: Poland
facility: Pratia Medical Center Katowice (Centrum Medyczne Pratia Katowice)
city: Kraków
country: Poland
facility: Pratia Malopolskie Medical Center Krakow (Pratia Małopolskie Centrum Medyczne Krakow)
city: Skorzewo
country: Poland
facility: Aidport sp z o.o.
city: Badalona
country: Spain
facility: ICO Badalona - Hospital Universitario Germans Trias Pujol
state: Barcelona
city: Coaña
country: Spain
facility: AOC Arcispedale Saint'Anna
state: Ferarra
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
state: València
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jiménez Díaz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals City Campus
state: Nottinghamshire
city: Leeds
country: United Kingdom
facility: St. James s University Hospital
state: West Yorkshire
city: London
country: United Kingdom
facility: Barts Hospital
Study officials:
References: