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 In Non-United States (US) Participants Only: 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 (non-US participants only)/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.
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 (in non-US participants only) 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
195
Epcoritamab will be administered subcutaneously in cycles of 28 days, (except Cycle 1 for high-dose cohorts = 35 days).
Epcoritamab will be administered subcutaneously in cycles of 21 days and 28 days.
R-CHOP will be administered intravenously (prednisone may be administered orally) in cycles of 21 days.
Venetoclax tablets will be administered orally once daily during the 5-week ramp up period in cycles of 28 or 35 days each.
Epcoritamab will be administered subcutaneously in cycles of 28 days.
Lenalidomide capsules will be administered once daily for 21 days in each cycle of 28 days.
Epcoritamab will be administered subcutaneously in cycles of 28 days.
Pirtobrutinib tablets will be administered in cycles of 28 days.
Epcoritamab will be administered subcutaneously in cycles of 28 days.
O'Neal Comprehensive Cancer Center at University of Alabama at Birmingham
Birmingham, Alabama, United States
University of California Davis Medical Center Sacramento
California City, California, United States
City of Hope National Medical Center
Duarte, California, United States
Cedars-Sinai Medical Center
Los Angeles, California, United States
David Geffen School of Medicine
Los Angeles, California, United States
Dose Escalation Phase and Safety Run-in (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.
Time frame: During the first cycle for low dose cohorts (Cycle length = 28 days) and for high dose cohorts (Cycle length = 35 days)
Dose Escalation Phase and Safety Run-in: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Up to 5 years
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.
Time frame: Up to 5 years
Expansion Phase: Overall Response Rate (ORR)
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. ORR based on the Lugano criteria is defined as the percentage of participants who achieve a response of PR or complete remission (CR), prior to initiation of subsequent therapy. The ORR based on the iwCLL criteria is defined as the percentage of participants who achieve a response of PR, CR with incomplete bone marrow recovery (CRi), or CR, prior to the initiation of subsequent therapy.
Time frame: Up to 5 years
Expansion Phase: Number of Participants with TEAEs and SAEs
Time frame: Up to 5 years
Dose Escalation Phase and Safety Run-in: ORR (for R/R CLL Participants)
The ORR is defined as the percentage of participants who achieve a response of PR, CRi, or CR, prior to the initiation of subsequent therapy as assessed by iwCLL criteria.
Time frame: Up to 5 years
Both Phases and Safety Run-in: 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.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Number of Participants with CR/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.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Time to Response (TTR)
TTR is defined among responders, as the time between first dose of any study drug and the initial documentation of response.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Progression Free Survival (PFS)
PFS is defined as the time from the first dosing date of any study drug and the date of disease progression or death, whichever occurs earlier.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Overall Survival (OS)
OS is defined as the time from the first dosing date of any study drug and the date of death due to any cause.
Time frame: Up to 5 years
Both Phase and Safety Run-in: Time to Next Systemic Anti-cancer Therapy (TTNT)
TTNT is defined as the time from the first dosing date of any study drug to the first documented administration of subsequent systemic anticancer therapy.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Area Under the Concentration-time Curve (AUC) in Epcoritamab
Time frame: 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
Both Phases and Safety Run-in: Maximum (Peak) Plasma Concentration (Cmax) in Epcoritamab
Time frame: 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
Both Phases: Pre-dose (Trough) Concentrations (Cthrough) in Epcoritamab
Time frame: 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
Both Phases and Safety Run-in: Time to Reach Cmax (Tmax) in Epcoritamab
Time frame: 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
Both Phases and Safety Run-in: Elimination Half-life (T1/2) in Epcoritamab
Time frame: 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
Both Phases and Safety Run-in: Total Body Clearance of Drug From Plasma (CL) in Epcoritamab
Time frame: 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
Both Phases: Lymphoid Cells for Immunophenotyping
Evaluation of B cells, T cells and their activation
Time frame: Up to 5 years
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.
Time frame: Up to 5 years
Expansion Phase and Safety Run-in : 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.
Time frame: Up to 5 years
Both Phases and Safety Run-in: Number of Participants with Anti-drug Antibodies (ADA) to Epcoritamab
Time frame: Up to 5 years
Expansion Phase: Number of Participants with PR
Time frame: Up to 5 years
Both Phases and Safety Run-in: Duration of MRD Negativity
The time from first achieving MRD negativity after start of treatment to the MRD conversion to positive.
Time frame: Up to 5 years
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Stanford Cancer Center
Palo Alto, California, United States
Mount Sinai Comprehensive Cancer Center
Miami Beach, Florida, United States
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Pembroke Pines, Florida, United States
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Bethesda, Maryland, United States
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Boston, Massachusetts, United States
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