Abstract 2412: Phase 1, open-label, dose-escalation studies of SGN-CD19A in patients with relapsed or refractory B-lineage acute leukemia and non-Hodgkin lymphoma.
Authors: Albertson Tina M. , Sandalic Lali , Law Che-Leung , Broglio Kristine , Berry Scott 
Published: August 2014

Abstract
Background. CD19 is a member of the immunoglobulin superfamily that regulates B-lineage cell development and differentiation. It is not known to be expressed by any cell outside of the B-lineage and expression is maintained upon malignant transformation. Due to its restricted normal tissue expression profile, CD19 is an attractive target for antibody-based therapeutics for the treatment of B-lineage malignancies. SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. We describe two first-in-human, dose-escalation studies of SGN-CD19A.
Methods. The objectives of both studies include evaluation of safety, tolerability, the pharmacokinetic (PK) profile, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-lineage malignancies. SGN19A-001 will evaluate a weekly (days 1 and 8 of 21-day cycles) and an every 3 week (q3wk) IV dosing schedule in adult and pediatric patient populations with B-lineage acute lymphoblastic leukemia and aggressive lymphoma. SGN19A-002 will enroll adult patients with B-lineage non-Hodgkin lymphoma and will test a q3wk IV dosing schedule. Both trials will employ a modified continual reassessment method (CRM) to estimate the dose-toxicity relationship, estimate the maximum tolerated dose (MTD), and allocate patients to dose levels. Each trial has an additional dose-finding expansion phase that can be initiated to further evaluate multiple doses and schedules to help identify a recommended phase 2 dose based on a utility score that weighs both toxicity and efficacy in different patient populations. The CRM algorithm estimates the efficacy and toxicity of each patient population and disease subgroup by borrowing information across groups (age and disease). Exploratory analyses will include correlation of target (CD19) expression, target saturation, and apoptotic cellular markers with clinical response and clearance of leukemic blasts; dose and PK of SGN-CD19A will also be correlated with target saturation and intracellular levels of cys-mcMMAF. These studies are scheduled to be initiated by late 2012.
Expected Results. The CRM design will allow the MTDs to be identified with high probability. As designed, we expect 10 pediatric and/or 20 adult patients to be treated at or around the estimated MTDs during dose escalation. During the dose-finding expansion portions, refined estimates of the MTDs and estimates of antitumor activity at multiple dose levels will provide rationale for the best dosing regimen for future phase 2 trials.
Citation Format: Tina M. Albertson, Lali Sandalic, Che-Leung Law, Kristine Broglio, Scott Berry. Phase 1, open-label, dose-escalation studies of SGN-CD19A in patients with relapsed or refractory B-lineage acute leukemia and non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2013-2412