Safety and Efficacy Trial of Epcoritamab Combinations in Subjects With B-cell Non-Hodgkin Lymphoma (B-NHL)

Study Overview
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Brief Summary
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A phase 1b/2, open-label, multinational, interventional trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab (EPKINLY™) in combination with other standard of care (SOC) agents in participants with B-cell Non-Hodgkin Lymphoma (B-NHL).

Detailed Description
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All participants in the trial will receive epcoritamab, as monotherapy or in combination. The following regimens will be investigated: Arm 1: epcoritamab + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in participants with previously untreated diffuse large B-cell lymphoma (DLBCL) Arm 2: epcoritamab + rituximab and lenalidomide (R2) in participants with relapsed/refractory (R/R) follicular lymphoma (FL) Arm 3: epcoritamab + rituximab and bendamustine (BR) in participants with previously untreated FL Arm 4: epcoritamab + rituximab, cytarabine, dexamethasone, and oxaliplatin/ carboplatin (R-DHAX/C) in participants with R/R DLBCL eligible for autologous stem cell transplant (ASCT) Arm 5: epcoritamab + gemcitabine and oxaliplatin (GemOx) in participants with R/R DLBCL ineligible for ASCT due to age, performance status (PS), or comorbidity Arm 6: epcoritamab + R2 in participants with previously untreated FL Arm 7: epcoritamab maintenance in participants with FL who achieve a complete response (CR) or a partial response (PR) with SOC treatment Arm 8: epcoritamab + reduced dose of R-CHOP (R mini-CHOP) in participants with previously untreated DLBCL who are ineligible to receive full-dose anthracycline Arm 9: epcoritamab + lenalidomide for second-line treatment in participants with FL who progressed within 24 months of initiation of first-line anti-CD20-containing immunochemotherapy Arm 10: epcoritamab + rituximab, ifosfamide, carboplatin, and etoposide phosphate (R-ICE) in participants with R/R DLBCL eligible for ASCT The trial consists of two parts: Part 1 ('Dose Escalation') and Part 2 ('Dose Expansion'). The primary objective of Part 1 is safety, and it includes Arm 1-5 and Arm 10. Part 2 includes all 10 arms (Arm 1-10) and the primary goal of all arms, except Arm 7, is preliminary efficacy. For Arm 7, the primary goal is safety. Patients in Arm 1-5 and Arm 10 can only participate in either Part 1 or Part 2. Dose Limiting Toxicities (DLTs) will be assessed in Part 1 and for a selected number of patients in Arm 8 during a 28-day period ('safety-run phase'). The arms are conducted in parallel.

Official Title
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A Phase 1b/2, Open-Label Trial to Assess the Safety and Preliminary Efficacy of Epcoritamab (GEN3013; DuoBody®-CD3xCD20) in Combination With Other Agents in Subjects With B-cell Non-Hodgkin Lymphoma (B-NHL)

Conditions
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Diffuse Large B-Cell Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
* Drug: rituximab and lenalidomide
* Drug: rituximab and bendamustine
* Drug: rituximab, cytarabine, dexamethasone, and oxaliplatin/carboplatin
* Drug: gemcitabine and oxaliplatin
* Biological: Epcoritamab
* Drug: rituximab, cyclophosphamide, reduced dose of doxorubicin, vincristine, and prednisone
* Drug: Lenalidomide
* Drug: rituximab, ifosfamide, carboplatin, and etoposide phosphate
* Biological: Epcoritamab
* Biological: Epcoritamab
* Biological: Epcoritamab
* Biological: Epcoritamab
* Biological: Epcoritamab
* Biological: Epcoritamab
* Biological: Epcoritamab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Measurable disease defined as ≥1 measurable nodal lesion (long axis >1.5 cm and short axis >1.0 cm) or ≥1 measurable extra-nodal lesion (long axis >1.0 cm) on computed tomography (CT) or magnetic resonance imaging (MRI) Eastern Cooperative Oncology Group (ECOG) PS score of 0, 1 or 2 Acceptable organ function at screening CD20-positive non-Hodgkin lymphoma (NHL) at most recent representative tumor biopsy If of childbearing potential subject must practicing a highly effective method of birth control A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control Arm 1: Newly Diagnosed Documented diffuse large B-cell lymphoma (DLBCL) DLBCL, NOS double-hit or triple-hit DLBCL FL Grade 3B Arm 2: R/R FL Arm 3: Newly diagnosed, previously untreated FL grade 1-3A Arm 4: Documented DLBCL and eligible for HDT-ASCT DLBCL, NOS double-hit or triple-hit DLBCL FL Grade 3B Arm 5: Relapsed or refractory documented DLBCL and ineligible for HDT-ASCT DLBCL, NOS double-hit or triple-hit DLBCL FL Grade 3B Arm 6: Newly diagnosed, previously untreated FL grade 1-3A Arm 7: FL Grade 1-3A If PR or CR per Lugano criteria following first-line or second-line treatment with SOC regimen, and last dose of SOC within 6 months prior to enrollment. Arm 8: DLBCL, NOS T-cell/histiocyte rich DLBCL double-hit or triple-hit DLBCL FL Grade 3B Arm 9: R/R FL Progressed within 24 months of initiating first-line treatment Arm 10: Documented DLBCL and eligible for HDT-ASCT DLBCL, NOS double-hit or triple-hit DLBCL FL Grade 3B Key Exclusion Criteria Chemotherapy, radiation therapy, or major surgery within 4 weeks prior to the first dose of epcoritamab Any prior treatment with a bispecific antibody targeting CD3 and CD20. Treatment with CAR-T therapy within 30 days prior to first dose of epcoritamab Clinically significant cardiovascular disease Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results CNS lymphoma or known CNS involvement by lymphoma at screening as confirmed by MRI/CT scan of the brain and, if clinically indicated, by lumbar puncture Active positive tests for hepatitis B virus or hepatitis C virus indicating acute or chronic infection Known history of seropositivity of human immunodeficiency virus (HIV) Active tuberculosis or history of completed treatment for active tuberculosis within the past 12 months Neuropathy > grade 1 Receiving immunostimulatory agent Prior allogeneic HSCT Current seizure disorder requiring anti-epileptic therapy NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Epcoritamab + R-CHOP<br>In participants with previously untreated DLBCL. | Drug: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone<br>* 21-day cycles<br>* Other names: R-CHOP;Biological: Epcoritamab<br>* Every week in cycle 1-4, every 3 weeks in cycle 5 and 6, followed by every 4 weeks in cycle 7 for a total of 1 year.<br>* Other names: EPKINLY™;|
| Experimental: Arm 2 - Epcoritamab + R2<br>In participants with R/R FL. | Drug: rituximab and lenalidomide<br>* 28-day cycles<br>* Other names: R2;Biological: Epcoritamab<br>* Every week in cycle 1-3, every 2 weeks in cycle 4-9, followed by every 4 weeks for a total of 2 years.<br>* Other names: EPKINLY™;|
| Experimental: Arm 3 - Epcoritamab + BR<br>In participants with previously untreated FL. | Drug: rituximab and bendamustine<br>* 28-day cycles<br>* Other names: BR;Biological: Epcoritamab<br>* Every week in cycle 1-3, every 2 weeks in cycle 4-9, followed by every 4 weeks for a total of 2 years.<br>* Other names: EPKINLY™;|
| Experimental: Arm 4 - Epcoritamab + R-DHAX/C<br>In participants with R/R DLBCL eligible for ASCT. | Drug: rituximab, cytarabine, dexamethasone, and oxaliplatin/carboplatin<br>* 21-day cycles<br>* Other names: R-DHAX/C;Biological: Epcoritamab<br>* Every week in cycle 1-4, every 2 weeks in cycle 5-9 followed by every 4 weeks until disease progression or unacceptable toxicity.<br>* Other names: EPKINLY™;|
| Experimental: Arm 5 - Epcoritamab + GemOx<br>In participants with R/R DLBCL ineligible ASCT. | Drug: gemcitabine and oxaliplatin<br>* 28-day cycles<br>* Other names: GemOx;Biological: Epcoritamab<br>* Every week in cycle 1-4, every 2 weeks in cycle 5-9 followed by every 4 weeks until disease progression or unacceptable toxicity.<br>* Other names: EPKINLY™;|
| Experimental: Arm 6 - Epcoritamab + R2<br>In participants with previously untreated FL. | Drug: rituximab and lenalidomide<br>* 28-day cycles<br>* Other names: R2;Biological: Epcoritamab<br>* Every week in cycle 1 and 2, followed by every 4 weeks for a total of 2 years.<br>* Other names: EPKINLY™;|
| Experimental: Arm 7 - Epcoritamab maintenance<br>In participants with FL who achieved a CR or PR after receiving SOC treatment in 1L or 2L. | Biological: Epcoritamab<br>* Every week in cycle 1 and then every 8 weeks for a total of 2 years.<br>* Other names: EPKINLY™;|
| Experimental: Arm 8 - Epcoritamab + R mini-CHOP<br>In participants with previously untreated DLBCL who are ineligible to receive full-dose anthracycline. | Drug: rituximab, cyclophosphamide, reduced dose of doxorubicin, vincristine, and prednisone<br>* 21-day cycles<br>* Other names: R mini-CHOP;Biological: Epcoritamab<br>* Every week in cycles 1 and 2, then every 3 weeks in cycles 3 to 6 and then every 4 weeks for cycles 7 and 8.<br>* Other names: EPKINLY™;|
| Experimental: Arm 9 - Epcoritamab + Lenalidomide<br>In participants with FL who progressed within 24 months of initiation of first-line anti-CD20-containing immunochemotherapy. | Drug: Lenalidomide<br>* 28-day cycles<br>Biological: Epcoritamab<br>* Every week in cycle 1-3 and then every 4 weeks for a total of 2 years.<br>* Other names: EPKINLY™;|
| Experimental: Arm 10 - Epcoritamab + R-ICE<br>In participants with R/R DLBCL eligible for ASCT. | Drug: rituximab, ifosfamide, carboplatin, and etoposide phosphate<br>* 21-day cycles<br>* Other names: R-ICE;Biological: Epcoritamab<br>* Every week in cycle 1-4, every 2 weeks in cycle 5-9 followed by every 4 weeks until transplant or disease progression.<br>* Other names: EPKINLY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Dose limiting Toxicities (DLTs) | DLT events are 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 (Cycle length= 28 days) in each cohort | 
| Part 1 and Part 2 (Arm 7): Number of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign. (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | From first dose of trial medication to the maximum of 60 days after last dose of epcoritamab or initiation of subsequent anti-lymphoma therapy. | 
| Part 2 (Except Arm 7): Overall Response Rate (ORR) | ORR is defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on Lugano criteria. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Clearance (CL) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Volume of Distribution (Vd) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Area Under the Concentration-Time Curve (AUC) from Time Zero to Last Quantifiable Dose (AUC0-last) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Area Under the Concentration-Time Curve (AUC) from Time Zero to Infinity (AUC0-inf) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Maximum (Peak) Plasma Concentration (Cmax) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Time to Reach Cmax (Tmax) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Terminal Elimination Half-Life (t 1/2) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Plasma Trough (Pre-dose) Concentrations (Ctrough) of Epcoritamab |  | Predose and postdose at multiple timepoints until treatment discontinuation (up to 3 years) | 
| Part 1 and 2: Number of Immune Cell Populations | Immune cell populations in peripheral blood and tumor biopsies will be assessed. | Up to 2 years | 
| Part 1 and 2: Percentage of Immune Cell Populations | Immune cell populations in peripheral blood and tumor biopsies will be assessed. | Up to 2 years | 
| Part 1 and 2: Change From Baseline in Cytokine Levels up to Cycle 3 | Change in cytokine levels in peripheral blood samples will be assessed. | Up to Cycle 3 (cycle length = 21 days for Arms 1, 4, 8 and 10; cycle length = 28 days for Arms 2, 3, 5, 6 and 9; cycle length = 28 days (Cycle 1) and 56 days (Cycles 2, 3) for Arm 7) | 
| Part 1 and 2: Change From Baseline in Circulating Tumor Deoxyribonucleic Acid (DNA) Level up to End of Treatment (up to 2 Years) | Change in circulating tumor DNA levels will be assessed. | Up to 2 years | 
| Part 1 and 2: Number of Participants With Anti-Drug Antibodies (ADAs) to Epcoritamab |  | Up to 3 years | 
| Part 1: ORR | ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria. | Up to 3 years | 
| Part 1 and 2: Duration of Response (DOR) | DOR: the time from the first documentation of objective tumor response (CR or PR) to the date of first PD or death based on Lugano criteria. | Up to 3 years | 
| Part 1 and 2: Time to Response (TTR) | TTR is defined as the time from Day 1 of Cycle 1 to first documentation of objective tumor response (CR or PR). | Up to 3 years | 
| Part 1 and 2: 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 based on Lugano criteria. | Up to 3 years | 
| Part 1 and 2: Overall Survival (OS) | OS is defined as the time from the date of first dose, to the date of death due to any cause. | Up to 3 years | 
| Part 1 and 2: Time to Next Anti-lymphoma Therapy (TTNT) | TTNT is defined as the time from Day 1 of Cycle 1 to first documented administration of subsequent anti-lymphoma therapy. | Up to 3 years | 
| Part 1 and 2: Percentage of Participants With Minimal Residual Disease (MRD) Negativity | It is defined as the percentage of participants with at least 1 MRD negative result. | Up to 3 years | 
| Part 1 and 2: Duration of minimal residual disease (MRD) negativity |  | Up to 3 years | 
| Part 2 (Arm 7): Percentage of Participants Who Converted From MRD Positivity to MRD Negativity |  | Up to 3 years | 
| Part 2 (Except Arm 7): Percentage of Participants with Complete Response (CR) in Arms 1 to 10 |  | Up to 3 years | 
| Part 2 (Arm 7): Percentage of Participants With CR | It is defined as the percentage of participants who remain in complete remission or converting to complete remission after first trial drug administration. | Week 24, Week 48, and Week 96 | 
| Part 1 and 2: Time to Complete Response (TTCR) | TTCR is defined as the time from first trial drug administration to the date of first documented complete response post-treatment. | Up to 3 years | 
| Part 1 and 2: Duration of Complete Response (DoCR) | DoCR is defined as the time from the first documentation of CR to the date of PD or death, whichever occurs first based on Lugano criteria. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DuoBody®, monoclonal antibodies, anti-CD3, anti-CD20