Study of VAY736 as Single Agent and in Combination With Select Antineoplastic Agents in Patients With Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), immunogenicity and preliminary efficacy of VAY736 alone or in combination with other therapies in patients with NHL in a platform trial.

Detailed Description
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The primary objective of the study is to evaluate the safety and tolerability in patients with NHL and identify a maximum tolerated dose (MTD) and/or recommended dose (RD) of VAY736 single agent and in combination with other anti-cancer therapies. This is a phase I/Ib, multi-center, open-label study with multiple treatment arms in an adaptive study design. The study is comprised of a dose escalation part and dose expansion part. In dose escalation, the investigational drug VAY736 will be explored alone or in combination with partner therapies. Increasing doses of VAY736 alone or in combination will be given to small groups of patients to identify the MTD/RD in patients with NHL. In dose expansion, some or all the treatments from dose escalation will be tested at the recommended doses in patients with NHL. The combination partners include lenalidomide and CC-99282. Other combination partners may be added in the future by protocol amendment. The study is expected to be approximately 4 years in duration (from enrollment of first patient to discontinuation of last patient).

Official Title
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A Phase Ib, Multi-center, Open-label Dose Escalation and Expansion Platform Study of VAY736 as Single Agent and in Combination With Select Antineoplastic Agents in Patients With Non-Hodgkin Lymphoma (NHL)

Conditions
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Non-Hodgkin Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma

Intervention / Treatment
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* Drug: VAY736
* Drug: lenalidomide
* Drug: CC-99282


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with confirmed diagnosis of relapsed/refractory B-cell NHL with all subtypes of DLBCL, follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL) per WHO 2016 criteria. Patients in subtype arm e.g. DLBCL must have confirmed diagnosis of relapsed/refractory DLBCL. Received and failed or be intolerant to standard of care therapy (at least two prior lines, including an anti-CD20 therapy for NHL) Must have measurable disease and ECOG of 0 to 2 Exclusion Criteria: Baseline laboratory results outside of protocol defined ranges Patients with primary CNS lymphoma History of hypersensitivity to VAY736 or any drugs in similar chemical classes (e.g. monoclonal antibodies) Impaired cardiac function or clinically significant cardiac disease History of or current interstitial lung disease or pneumonitis grade 2 or higher HIV infection Active hepatitis C infection and/or hepatitis B infection Pregnant or nursing (lactating) women Women of child-bearing potential unless they are using highly effective methods of contraception Other 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1A<br>VAY736 single agent dose escalation in patients with NHL subtypes of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;|
| Experimental: Arm 1B<br>VAY736 single agent dose expansion in patients with DLBCL | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;|
| Experimental: Arm 2A<br>VAY736 + lenalidomide dose escalation in patients with DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;Drug: lenalidomide<br>* Immune-modulatory agent that enhances activation of NK cells.<br>|
| Experimental: Arm 2B<br>VAY736 + lenalidomide dose expansion in patients with DLBCL | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;Drug: lenalidomide<br>* Immune-modulatory agent that enhances activation of NK cells.<br>|
| Experimental: Arm 3A<br>VAY736 + CC-99282 dose escalation in patients with NHL subtypes of DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;Drug: CC-99282<br>* Cereblon (CRBN) E3 Ligase Modulator that induces the recruitment, ubiquitination and destruction of key target substrates (e.g. Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3)<br>* Other names: BMS-986369, golcadomide;|
| Experimental: Arm 3B<br>VAY736 + CC-99282 dose expansion in patients with DLBCL | Drug: VAY736<br>* VAY736 is a fully human IgG1 monoclonal antibody (mAb) which targets the B cell activating factor receptor (BAFF-R) expressed on the surface of differentiated B cells and modulates their function.<br>* Other names: ianalumab;Drug: CC-99282<br>* Cereblon (CRBN) E3 Ligase Modulator that induces the recruitment, ubiquitination and destruction of key target substrates (e.g. Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3)<br>* Other names: BMS-986369, golcadomide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and nature of dose limiting toxicities (DLTs) | Safety and tolerability | 28 days (first cycle of treatment) | 
| Incidence of Adverse events (AEs) and serious adverse events (SAEs) | Incidence of AEs and SAEs is defined as number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs. | 4 years | 
| Number of patients with dose interruptions and dose reductions | Safety and tolerability | 4 years | 
| Dose intensity | Safety and tolerability | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Efficacy will be assessed by Lugano Classification (FDG-PET/CT scans) | 4 years | 
| Best overall response (BOR) rate | Efficacy will be assessed by Lugano Classification (FDG-PET/CT scans) | 4 years | 
| Area under curve (AUC) for VAY736 | PK parameters will be derived from serum concentrations | 4 years | 
| Maximum observed drug concentration after single dose administration (Cmax) for VAY736 | PK parameters will be derived from serum concentrations | 4 years | 
| AUC for lenalidomide | PK parameters will be derived from plasma concentrations | 4 years | 
| Cmax for lenalidomide | PK parameters will be derived from plasma concentrations | 4 years | 
| Change from baseline in anti-drug antibodies (ADA) | Blood samples will be collected to detect change in levels of antibodies to VAY736 | Baseline, 4 years | 
| AUC for CC-99282 | PK parameters will be derived from plasma concentrations | 4 years | 
| Cmax for CC-99282 | PK parameters will be derived from plasma concentrations | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VAY736, ianalumab, lenalidomide, CC-99282, golcadomide, BMS-986369, non-Hodgkin lymphoma, NHL, Diffuse large B cell lymphoma, DLBCL, Follicular lymphoma, FL, Mantle cell lymphoma, MCL, Marginal zone lymphoma, MZL