A Study of BI-1206 in Combination With Rituximab With or Without Acalabrutinib in Subjects With Indolent B-Cell NHL

This is a Phase 1/2a, multicenter, dose escalation, consecutive-cohort, open-label trial of BI-1206 in combination with rituximab with or without acalabrutinib in subjects with indolent relapsed or refractory B-cell NHL, sub-types FL (except FL grade 3B), MZL, and MCL.

Phase 2a, consists of signal seeking cohorts followed by a randomized, parallel, two-arm dose optimization.

The trial consists of 2 main parts:

Phase 1

• Dose Escalation, with two different Arms assessing IV or SC dosing of BI-1206 in combination with rituximab, with dose escalation cohorts and selection of the IV and SC doses of BI-1206 for Phase 2a

Phase 2a

• Dose Expansion, with one expansion cohort evaluating the selected IV dose of BI-1206 in combination with rituximab
• Signal Seeking, assessing IV and SC dosing of BI-1206 in combination with rituximab and acalabrutinib. The Signal Seeking will consist of a Safety Run-in and an Expansion
• Dose Optimization to select the recommended dose of BI-1206 in combination with rituximab and acalabrutinib

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 FL grade 3B,
• 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
• Previous lines of treatment containing BTK inhibitors for Subjects receiving BI-1206 in combination with rituximab and acalabrutinib
• 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