A Study of BI-1206 in Combination With Rituximab in Subjects With Indolent B-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcyRIIB), in Combination with Rituximab in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That has Relapsed or is Refractory to Rituximab

Detailed Description
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This is a Phase 1/2a, dose escalation, consecutive-cohort, open-label trial of BI-1206 in combination with rituximab in subjects with indolent relapsed or refractory B-cell NHL, subtypes FL (except FL grade 3B), MZL, and MCL. The trial consists of 2 main parts: Phase 1 with two different Arms assessing IV or SC dosing of BI-1206,with dose escalation cohorts and selection of the RP2D of IV dosing (ivRP2D)and the RP2D of SC dosing (scRP2D) of BI-1206 in combination with rituximab (administered IV). Phase 2a with two expansion cohorts evaluating the ivRP2D and scRP2D of BI-1206 in combination with rituximab (administered IV). Subjects in each phase (Phase 1 and 2a) and dosing Arms will receive 1 cycle of induction therapy with BI-1206 in combination with rituximab. Subjects who show clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) at Week 6 will continue onto maintenance therapy and receive BI-1206 ( using the same dose and route of administration as induction therapy) and rituximab once every 8 weeks (relative to previous maintenance dose) for up to 6 maintenance cycles, or up to 1 year from first dose of BI-1206 (whichever occurs first).

Official Title
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Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcYRIIB), in Combination With Rituximab in Subjects With Indolent B-Cell Non-Hodgkin Lymphoma That Has Relapsed or is Refractory to Rituximab

Conditions
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Indolent B-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: BI-1206


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are ≥ 18 years of age by initiation of study treatment. Have B-cell NHL proven by histology, with histological subtypes limited to follicular lymphoma (FL) (except FL grade 3B), MCL and marginal zone lymphoma (MZL). Have measurable nodal disease Are willing to undergo lymph node biopsies or biopsies of other involved tissue Have relapsed disease or disease refractory to conventional treatment or for which no standard therapy exists. Have received at least one line of conventional previous therapy which must include at least one rituximab-based regimen. Have a life expectancy of at least 12 weeks Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Have CD20+ malignancy Have hematological and biochemical indices within prespecified ranges Exclusion Criteria: Have had an allogenic bone marrow or stem cell transplant within 12 months Have presence of active chronic graft versus host disease Have current leptomeningeal lymphoma or compromise of the central nervous system. Have transformed lymphoma from a pre-existing indolent lymphoma. Have Waldenstrom's Macroglobulinemia or FL3B, Need systemic doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the study trial other than as pre-medication. Have known or suspected hypersensitivity to rituximab or BI-1206. Have cardiac or renal amyloid light-chain amyloidosis. Have received any of the following: Chemotherapy or small molecule products with 2 weeks of first dose of BI-1206 Radiotherapy (except for focal symptomatic control of lymphadenopathy) within 4 weeks Immunotherapy within 8 weeks Have ongoing toxic manifestations of previous treatments. Have the ability to become pregnant (or already pregnant or lactating/breastfeeding). Have had major surgery from which the subject has not yet recovered. Are at high medical risk because of non-malignant systemic disease including active infection on treatment with antibiotics, antifungals or antivirals. Are serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Have an active, known or suspected autoimmune disease. Have concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), Have current malignancies of other types

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: Single Group Assignment
Interventional Model Description: Phase 1/2a, dose escalation, consecutive-cohort, open-label study trial of BI-1206 in combination with rituximab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI-1206 IV<br>BI-1206 IV Standard 3+3 Dose-Escalation Design | Biological: BI-1206<br>* 375 mg/m2, as per SmPC<br>* Other names: Rituximab;|
| Experimental: BI-1206 SC<br>BI-1206 SC Adaptive Dose Escalation Design (Bayesian logistic regression model (BLRM) | Biological: BI-1206<br>* 375 mg/m2, as per SmPC<br>* Other names: Rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Documenting AEs and SAEs and determining causality in relation to BI-1206 and/or rituximab | Assess the safety and tolerability profile of BI-1206 when administered intravenously (IV) or subcutaneously (SC) in combination with rituximab in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL),subtypes follicular lymphoma (FL)(except FLgrade 3B), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL). | During the 28-day treatment period on induction therapy | 
| Determining the MTD of BI-1206 at the same dose level experiencing a BI-1206 or Rituximab-related or possibly related dose-limiting toxicity (DLT) | Select the recommended Phase 2 dose (RP2D) by establishing the maximum tolerated dose (MTD) of BI-1206 given once weekly for 4 weeks, via IV infusion or SC injection in combination with rituximab. | During the 28-day treatment period on induction therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of PK parameters for BI-1206. | Study the PK profile of BI-1206 when administered IV or SC in combination with rituximab in subjects with relapsed or refractory B-cell NHL, subtypes FL (except FL grade 3B), MZL and MCL. | Up to 1 year | 
| Evaluation of PK parameters for rituximab during the BI-1206 treatment period. | Study the PK profile of rituximab when administered in combination with BI-1206 (IV or SC). | Up to 1 year | 
| Evaluation of ADA response to BI 1206. | Assess the immunogenicity of BI-1206 when administered IV or SC in combination with rituximab. | Up to 1 year | 
| Measurement of B cell depletion. | Evaluate the effect of BI-1206 administered IV or SC in combination with rituximab on the depletion of B-cells. | Up to 1 year | 
| Assessment of overall response rate (ORR) according to the response criteria for malignant lymphoma (Cheson, 2014). | Assess possible anti-tumor activity of BI-1206 administered IV or SC in combination with rituximab at Week 6 after first dose of BI-1206 and for subjects who continue during maintenance therapy. | Up to 1 year | 
| CD32b protein expression levels | Investigate CD32b protein expression levels; evaluate any potential correlation with clinical responses. | Up to 1 year |