A Phase I Study of IMGN529, an Antibody-Drug Conjugate (ADC) Targeting CD37, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma (NHL)
Authors: Stathis Anastasios , Freedman Arnold S. , Flinn Ian W. , Maddocks Kami J. , Weitman Steven , Berdeja Jesus G. , Mejia Alex V. , Zucca Emanuele , Green Rebecca , Romanelli Angela , Zildjian Sybil H , Ruiz-Soto Rodrigo , Palomba Lia 
Published: October 2019

Abstract
Background: While CD37 is widely expressed on malignant B cells in NHL and chronic lymphocytic leukemia (CLL), few therapies are in development exploiting this target. In normal tissues, high CD37 expression is restricted to blood cells and lymphoid tissues, making CD37 well suited to an ADC approach. IMGN529 is a CD37-targeting ADC consisting of a CD37-binding antibody with intrinsic pro-apoptotic and immune effector activities conjugated to the maytansinoid anti-mitotic, DM1. Its unique profile enables IMGN529 to potentially kill CD37-positive B cells via multiple mechanisms of action. In preclinical studies, IMGN529 exhibits targeted, potent activity against NHL cells via direct inhibition of cell survival and effector function by its antibody and tubulin-disruption by DM1.
Methods: A Phase I study is being conducted to evaluate safety, pharmacokinetics, pharmacodynamics, exploratory biomarkers and preliminary evidence of activity of IMGN529 and to determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Efficacy is evaluated based on Cheson response criteria. CD37 is being evaluated by IHC in available tumor samples to assess expression of CD37 among different NHL subtypes.
Results: To date, 31 pts have been enrolled (66% male), median age of 65 years: Diffuse large B-cell (DLBCL, n = 14), Follicular lymphoma (FL, n = 10), MCL (n = 5), MZL (n = 2). Dose escalation began at 0.1 mg/kg. Early onset, transient grade 3-4 neutropenia was reported in 6 patients receiving doses at or below 0.8 mg/kg, potentially attributed to cytokine release. Peri-infusional steroid administration was added to the study protocol, and the incidence and severity of this neutropenia was significantly reduced. Additional patients have been enrolled and increasingly higher dose levels evaluated. To date the highest dose evaluated is 1.0 mg/kg. Cytokine levels are currently being evaluated in trial patients to gain a better understanding of the mechanisms underlying the early onset neutropenia. At the 1.0 mg/kg dose cohort grade 3-4 neutropenia was reported (1 DLT of febrile neutropenia among 6 patients) around d10 of the cycle and granulocyte colony stimulating factor (G-CSF) was added as primary prophylaxis. The most common treatment-emergent adverse events (AEs) occurring in ≥ 20% of the 31 pts enrolled were neutropenia (30%), fever (27%), asthenia (20%) and fatigue (20%). A reduction in lymphocyte count seen early after dosing (d2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes, consistent with the mechanism of action of a CD37-targeted therapy. Four objective responses have been reported in patients who had received multiple lines of prior therapy. At the 1.0 mg/kg dose level, two patients with DLBCL who were heavily pretreated and who relapsed following autologous transplant have achieved an objective response that is ongoing. One pt has achieved a PR and one patient has achieved a CR. As previously reported, at doses of 0.2 mg/kg and 0.4 mg/kg one pt with transformed FL, who progressed following an autologous transplant, and one pt with DLBCL achieved a PR. The maximum tolerated dose has not yet been achieved and dose escalation is ongoing with additional data expected.
Conclusions: IMGN529, a CD37-targeting ADC, demonstrates clinical activity in patients with NHL and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies.

Disclosures
Stathis: ImmunoGen, Inc: Travel assistance Other; Pfizer: Research Funding; Oncoethix SA: Research Funding. Flinn:ImmunoGen, Inc: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding, travel assistance Other. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Zildjian:ImmunoGen, Inc: Employment. Ruiz-Soto:ImmunoGen, Inc: Employment; Sanofi: Past employment within 1 year, Past employment within 1 year Other.