A Study to Evaluate Adverse Events and Change in Disease Activity of Subcutaneous (SC) Epcoritamab in Combination With Oral and Intravenous Anti-Neoplastic Agents in Adult Participants With Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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B-cell Lymphoma is an aggressive and rare cancer of a type of immune cell (a white blood cell responsible for fighting infections). The purpose of this study is to assess the safety and tolerability of epcoritamab in combination with anti-neoplastic agents in adult participants with Non-Hodgkin lymphoma (NHL). Adverse events and change in disease activity will be assessed. Epcoritamab is an investigational drug being developed for the treatment of NHL. Study doctors put the participants in groups called treatment arms. The combination of epcoritamab with anti-neoplastic agents will be explored. Each treatment arm receives a different treatment combination depending on eligibility. Approximately 394 adult participants with NHL will be enrolled in 100 sites globally. In both the dose escalation and dose expansion arms participants will receive subcutaneous (SC) epcoritamab in 28-day or 21 day cycles dependent on the arm in combination with the anti-neoplastic agents described below: 1: Oral lenalidomide in participants with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL); 2: Oral ibrutinib and oral lenalidomide in participants with with R/R DLBCL; 3: Intravenous (IV) polatuzumab vedotin, IV rituximab, IV cyclophosphamide, IV doxorubicin hydrochloride (HCl), and oral prednisone (pola-R-CHP) in participants with newly diagnosed treatment-naïve DLBCL; 4: Oral CC-99282 in participants with R/R DLBCL; 5: Oral CC-99282 in participants with R/R follicular lymphoma (FL); 6A: Oral ibrutinib in participants with R/R mantle cell lymphoma (MCL); 6B: Oral ibrutinib, and oral venetoclax in participants with R/R MCL; 7: Oral ibrutinib, and oral venetoclax in participants with newly diagnosed treatment-naïve MCL. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.

Official Title
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Phase 1b/2, Open-Label Study to Evaluate Safety and Tolerability of Epcoritamab in Combination With Anti-Neoplastic Agents in Subjects With Non-Hodgkin Lymphoma

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Epcoritamab
* Drug: Lenalidomide
* Drug: Ibrutinib
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride [HCl]
* Drug: Prednisone
* Drug: Polatuzumab Vedotin
* Drug: Venetoclax
* Drug: CC-99282


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of: -- Diffuse large B-cell lymphoma (DLBCL) (de novo or histologically transformed from follicular lymphoma (FL) or nodal marginal zone lymphoma) with histologically confirmed CD20+ disease, inclusive of the following according to World Health Organization (WHO) 2016 classification and documented in pathology report: DLBCL, not otherwise specified (NOS). High-grade B cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations per WHO 2016 (double-hit or triple-hit) Note: High-grade B-cell lymphomas NOS or other double- /triple-hit lymphomas (with histologies not consistent with DLBCL) are not eligible. Follicular lymphoma (FL) Grade 3B. OR FL with histologically confirmed CD20+ Grade 1 to 3a and no evidence of histologic transformation to an aggressive lymphoma at most recent representative tumor biopsy, according to WHO 2016 classification. OR Mantle cell lymphoma (MCL) with histologically confirmed CD20+ disease at most recent representative tumor biopsy according to the WHO 2016 classification with evidence of overexpression of cyclin D1 in association with relevant markers or evidence of t(11;14) assessed by flow cytometry, FISH, or polymerase chain reaction (PCR). Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2, except for Arms 6 and 7 where ECOG performance status must be 0-1. Must have 1 or more measurable disease sites: A positron emission tomography (PET) /computed tomography (CT) scan demonstrating PET-positive lesion(s) AND At least 1 measurable nodal lesion (long axis > 1.5 cm) or >= 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or magnetic resonance imaging (MRI). Exclusion Criteria: Prior treatment with epcoritamab or any other bispecific antibody targeting CD3 and CD20. Toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Events (CTCAE, v 5.0), Grade 2 or below, with the exception of alopecia. Other eligibility criteria (e.g., laboratory, cardiac criteria) must also be met.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Dose Escalation<br>Participants with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) will receive escalating doses of subcutaneous (SC) epcoritamab in combination with oral lenalidomide in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Lenalidomide<br>* Oral; Capsule<br>|
| Experimental: Arm 2: Dose Escalation<br>Participants with R/R DLBCL will receive escalating doses of SC epcoritamab in combination with oral ibrutinib and oral lenalidomide in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Lenalidomide<br>* Oral; Capsule<br>Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;|
| Experimental: Arm 3: Dose Escalation<br>Participants with newly diagnosed treatment-naïve DLBCL will receive escalating doses of SC epcoritamab in combination with intravenous (IV) polatuzumab vedotin, IV rituximab, IV cyclophosphamide, IV doxorubicin hydrochloride (HCl), and oral prednisone (pola-R-CHP) in 21 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Rituximab<br>* Intravenous (IV); Injection<br>Drug: Cyclophosphamide<br>* IV; Injection<br>Drug: Doxorubicin Hydrochloride [HCl]<br>* IV; Injection<br>Drug: Prednisone<br>* Oral; Tablet<br>Drug: Polatuzumab Vedotin<br>* IV; Injection<br>|
| Experimental: Arm 4: Dose Escalation<br>Participants with R/R DLBCL will receive escalating doses of SC epcoritamab in combination with oral CC-99282 in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: CC-99282<br>* Oral; Capsule<br>|
| Experimental: Arm 5: Dose Escalation<br>Participants with R/R follicular lymphoma (FL) will receive escalating doses of SC epcoritamab in combination with oral CC-99282 in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: CC-99282<br>* Oral; Capsule<br>|
| Experimental: Arm 6A: Dose Escalation<br>Participants with R/R mantle cell lymphoma (MCL) will receive escalating doses of SC epcoritamab in combination with oral ibrutinib in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;|
| Experimental: Arm 6B: Dose Escalation<br>Participants with R/R MCL will receive escalating doses of SC epcoritamab in combination with oral ibrutinib, and oral venetoclax in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;Drug: Venetoclax<br>* Oral; Tablet<br>* Other names: GDC-0199;|
| Experimental: Arm 7: Dose Escalation<br>Participants with newly diagnosed treatment-naïve MCL will receive escalating doses of SC epcoritamab in combination with oral ibrutinib, and oral venetoclax in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;|
| Experimental: Arm 1: Dose Expansion<br>Participants with R/R DLBCL will receive the recommended dose of SC epcoritamab in combination with oral lenalidomide in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Lenalidomide<br>* Oral; Capsule<br>|
| Experimental: Arm 2: Dose Expansion<br>Participants with R/R DLBCL will receive the recommended dose of SC epcoritamab in combination with oral ibrutinib and oral lenalidomide in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Lenalidomide<br>* Oral; Capsule<br>Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;|
| Experimental: Arm 3: Dose Expansion<br>Participants newly diagnosed treatment-naïve DLBCL will receive the recommended dose of SC epcoritamab in combination with intravenous (IV) polatuzumab vedotin, IV rituximab, IV cyclophosphamide, IV doxorubicin hydrochloride (HCl), and oral prednisone (pola-R-CHP) in 21 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Rituximab<br>* Intravenous (IV); Injection<br>Drug: Cyclophosphamide<br>* IV; Injection<br>Drug: Doxorubicin Hydrochloride [HCl]<br>* IV; Injection<br>Drug: Prednisone<br>* Oral; Tablet<br>Drug: Polatuzumab Vedotin<br>* IV; Injection<br>|
| Experimental: Arm 4: Dose Expansion<br>Participants with R/R DLBCL will receive the recommended dose of SC epcoritamab in combination with oral CC-99282 in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;|
| Experimental: Arm 5: Dose Expansion<br>Participants with R/R FL will receive the recommended dose of SC epcoritamab in combination with oral CC-99282 in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;|
| Experimental: Arm 6: Dose Expansion<br>Participants with R/R MCL will receive the recommended dose of SC epcoritamab in combination with oral ibrutinib in 28 day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;;Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;|
| Experimental: Arm 7: Dose Expansion<br>Participants with newly diagnosed treatment-naïve MCL will receive the recommended dose of SC epcoritamab in combination with oral ibrutinib, and oral venetoclax in 28 day cycles. | Drug: Ibrutinib<br>* Oral; Capsule<br>* Other names: Imbruvica;Drug: Venetoclax<br>* Oral; Tablet<br>* Other names: GDC-0199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-Limiting Toxicities (DLT) | DLT events are defined as clinically significant adverse events or abnormal laboratory values assessed as unrelated to disease progression, underlying disease, intercurrent illness, or concomitant medications. | Up to Approximately 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) per Investigator | BOR is defined as the percentage of participants who achieved best overall response of CR or PR by Lugano 2014 criteria as assessed by the investigator. | Up to Approximately 5 Years | 
| Duration of response (DOR) per Investigator | DOR is defined for participants who achieved best overall response of CR or PR ('responders'), as the time in months from initial CR/PR to the earliest occurrence of radiographic progression determined by Lugano 2014 criteria as assessed by the investigator, or death from any cause. | Up to Approximately 5 Years | 
| Number of Participants with Progression-free survival (PFS) | PFS is defined as the time in months from the first dose of study drug to the earliest occurrence of disease progression determined by Lugano 2014 criteria as assessed by investigator, or death from any cause. | Up to Approximately 5 Years | 
| Percentage of Participants with Complete Response (CR) | CR is defined as the percentage of participantswho achieved best overall response of CR determined by Lugano 2014 criteria as assessed by investigator. | Up to Approximately 5 Years | 
| Time-to-response (TTR) | TTR is defined as the number of months from the date of first dose to the date of best overall response of CR or PR ('responders') determined by Lugano 2014 criteria as assessed by investigator. | Up to Approximately 5 Years | 
| Time to Next Antilymphoma Therapy (TTNT) | Time to next antilymphoma therapy. | Up to Approximately 5 Years | 
| Rate of Minimal Residual Disease (MRD) Negativity | MRD is defined as the percentage of participants with assessment of the minimal residual disease. | Up to Approximately 5 Years | 
| Overall Survival (OS) | (OS) is defined as the time in months from first dose of epcoritamab to death from any cause. | Up to Approximately 5 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin Lymphoma, Epcoritamab, Lenalidomide, Ibrutinib, Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride (HCl], Prednisone (pola-R-CHP), ABBV-GMAB-3013, Cancer, Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL), Venetoclax,, Venclexta, ABT-199, GDC-0199, CC-99282, EPCORE