Abstract 4642: Model-based alternative clinical trial designs and evaluations for SGN-CD19A, a novel antibody-drug conjugate
Authors: Zhao Baiteng , Albertson Tina M. , Law Che-Leung , O'Meara Megan M. , Kostic Ana , Han Tae H. 
Published: May 2015

Abstract
Background
SGN-CD19A is a novel antibody-drug conjugate (ADC) 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. CD19 is a B-cell specific marker that is found on B cells as early as the pro-B cell stage and is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma (NHL). The objectives of this evaluation were to develop a semi-mechanistic PK-PD model based on the pharmacokinetics (PK) and pharmacodynamics (PD) of SGN-CD19A in patients with leukemia or NHL and to simulate alternative clinical trial designs using this model for the design of future clinical trials.
Methods
A semi-mechanistic integrated PK-PD model was developed based on the mechanism of action of SGN-CD19A and the clinical PK and PD data from the ongoing first-in-human dose-escalation study in adult and pediatric patients with relapsed or refractory B-cell leukemia or highly aggressive B-cell lymphoma (CT.gov NCT01786096). Plasma SGN-CD19A ADC concentration-time profiles were described by a two-compartment PK model with both linear and nonlinear clearance pathways. The nonlinear clearance was modeled as target-mediated disposition through binding to cell membrane CD19 and internalization of the complex. Anti-tumor effects in the form of reduced bone marrow disease burden were modeled using a cell-kill PK-PD model driven by the internalized cys-mcMMAF concentrations. Both PK and PD data were fitted simultaneously using NONMEM® version 7.1.2. Model simulations were conducted for alternative doses and schedules, including loading dose regimens, and for patients with different baseline disease characteristics.
Results
The integrated PK-PD model accurately described the SGN-CD19A PK and PD profiles in patients with either leukemia or NHL at multiple dose levels. Intra-patient adjustments in doses, disease status changes over time, and CD19 occupancy on tumor blast cells were well described based on goodness-of-fit evaluations. Using CD19 occupancy as the target engagement biomarker, multiple dosing schedules were evaluated using simulations for patients with different levels of baseline disease burden. Simulations suggested that various schedules can achieve and maintain target saturation, which may result in comparable anti-tumor activity.
Conclusions
The clinical PK, PD, and PK/PD of SGN-CD19A are well-characterized by a semi-mechanistic integrated model. Multiple dosing schedules were predicted to achieve target saturation.
Citation Format: Baiteng Zhao, Tina M. Albertson, Che-Leung Law, Megan M. O'Meara, Ana Kostic, Tae H. Han. Model-based alternative clinical trial designs and evaluations for SGN-CD19A, a novel antibody-drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4642. doi:10.1158/1538-7445.AM2014-4642