A Phase 2 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody (Ab), in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Background

NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 Abs in combination with chemotherapy are the standard of care for the treatment of B-NHLs; however, despite initial responses, many patients relapse, often with progressively shorter response durations in subsequent lines of therapy and poor outcome.

REGN1979 is a CD20 x CD3 bispecific IgG4 Ab that binds to CD3+ T-cells and CD20+ B-cells, targeting CD20+ tumor cells via T-cell-mediated cytotoxicity. An ongoing Phase 1 study in patients with B-cell malignancies is evaluating the safety, tolerability, and efficacy of REGN1979 as monotherapy (NCT02290951). Preliminary data from the Phase 1 study showed broad antitumor activity with REGN1979 in heavily pretreated R/R B-NHL patients, including some with progression after prior chimeric antigen receptor T (CAR T)-cell therapy. REGN1979 has been tolerated at doses up to 320 mg weekly, with no observed dose limiting toxicities. These data informed the dosage regimen of the current Phase 2 study.

Methods

This open-label, multi-center, Phase 2 study (NCT03888105) is evaluating the efficacy and safety of REGN1979 in six disease-specific cohorts, each comprising a single arm with independent parallel enrollment: patients with R/R FL Grade 1-3a after ≥2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; patients with R/R DLBCL after ≥2 prior lines of systemic therapy (patients in this cohort may not have received prior CAR T-cell therapy); patients with R/R DLBCL after CAR T-cell therapy failure; patients with MCL that have relapsed after or are refractory to Bruton's tyrosine kinase (BTK) inhibitor therapy (patients with R/R MCL who have demonstrated intolerance to BTK inhibitor therapy may also be enrolled); patients with R/R MZL that have relapsed after or are refractory to ≥1 prior line of systemic therapy; patients with R/R other B-NHL subtypes, excluding Waldenström macroglobulinemia, after ≥1 prior line of systemic therapy including an anti-CD20 antibody. The initial screening period of up to 28 days is followed by a weekly dosing period where REGN1979 is administered in gradually increasing doses to achieve target nominal dose by Week 4 and continued through Week 12. Patients then receive REGN1979 every two weeks for up to 86 weeks (total treatment period of 98 weeks). The post-treatment follow-up period will continue for up to 96 weeks after the last dose of study treatment.

Approximately 481 patients will be enrolled at sites across the US, Canada, Europe, and the Asia-Pacific region. Key eligibility criteria are: age ≥18 years; ≥1 bi-dimensionally measurable nodal lesion of ≥1.5 cm; Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate bone marrow and hepatic functions. Key exclusion criteria include primary central nervous system (CNS) lymphoma or involvement by non-primary CNS NHL; treatment with systemic anti-lymphoma therapy within five half-lives or 28 days prior to first administration of REGN1979; and history of allogeneic hematopoietic stem cell transplantation.

The primary endpoint for each disease-specific cohort is objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma by independent central review.

Secondary endpoints include complete response (CR) rate, progression-free survival, duration of response, disease control rate (DCR), duration of disease control, overall survival; incidence and severity of treatment-emergent adverse events; patient-reported outcomes; pharmacokinetics; and immunogenicity responses.

The primary endpoint, ORR, will be summarized along with a two-sided 95% confidence interval (CI). Other efficacy endpoints, such as CR rate and DCR, will be summarized using the same approach as for ORR. The time to event endpoints will be summarized, where appropriate, by median and the corresponding 95% CI using the Kaplan-Meier method.

The study is recruiting in FL grade 1-3a cohort and recruitment in other disease-specific cohorts is planned.

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