Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcyRIIB), in Combination with Rituximab with or without Acalabrutinib in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That has Relapsed or is Refractory to Rituximab
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 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
Single group
BI-1206
Biological/VaccineBI-1206 150 mg / 225 mg Subcutaneous injection BI-1206 50 mg /100 mg Intravenous infusion
Rituximab
Biological/VaccineRituximab 375 mg/m2, as per SmPC
Acalabrutinib
Biological/VaccineAcalabrutinib 100 mg orally as per SmPC
Documenting AEs and SAEs and determining causality in relation to BI-1206 and/or rituximab and/or acalabrutinib
Assess the safety and tolerability profile of BI-1206 when administered intravenously (IV) or subcutaneously (SC) in combination with rituximab or rituximab and acalabrutinib in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL), subtypes follicular lymphoma (FL)(except FL grade 3B), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL). Assessment will be done according to National Cancer Institute (NCI-CTCAE) criteria v. 5.0.
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)
Phase 1: 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.
Determine the recommended dose of BI-1206 in combination with rituximab and acalabrutinib
Phase 2a: Select the recommended dose of BI-1206 in combination with rituximab and acalabrutinib.
Evaluation of PK parameters for BI-1206
PK parameters assessed will include AUC, Cmax, time to Cmax and t1/2 of BI-1206 when administered IV or SC
Evaluation of ADA (immunogenicity) response to BI-1206
Assess the incidence and titre of antidrug antibodies of BI-1206 in serum when administered IV or SC in combination with rituximab or rituximab and acalabrutinib.
Measurement of peripheral blood B-lymphocytes depletion
Evaluate the effect of BI-1206 administered IV or SC in combination with rituximab or rituximab and acalabrutinib measuring B Lymphocytes CD19+ (absolute value) as part of hematology assessment to determine the level of peripheral blood B lymphocyte depletion.
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 or rituximab and acalabrutinib at Week 6 after first dose of BI-1206 and for subjects who continue during maintenance therapy.
Expression levels of CD32b protein
To investigate CD32b protein expression levels using flow cytometry to evaluate any potential correlation with clinical responses. Change from baseline expression levels will be summarized descriptively by dose cohort and/or response to treatment.
Assessment of Patient Reported Outcomes using the NCI PRO-CTCAE questionnaire
The NCI PRO-CTCAE will be used to evaluate symptomatic toxicities reported by patients. The questionnaire characterizes the frequency, severity, interference, and presence/absence of symptomatic toxicities, all toxicities that can be meaningfully reported from the patient perspective. Responses are scored from 0 to 4 (or 0/1 for absent/present). Scores for each attribute (frequency, severity and/or interference) will be presented descriptively (e.g. summary statistics or graphical presentations).
Expression levels of CD32b and/or other immunological markers
Perform whole-transcriptome, quantitative polymerase chain reaction (qPCR) and/or IHC analysis of lymph node biopsies to evaluate potential correlation with clinical responses.
Measurement of serum cytokines levels and/or soluble CD32b.
Study the potential cause of infusion related reactions (IRRs), such as cytokine release signs, C-reactive protein (CRP) and/or soluble CD32b.
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