Abstract LB-291: First-in-human phase I dose escalation study of a novel anti-mesothelin antibody drug conjugate (ADC), BAY 94-9343, in patients with advanced solid tumors.
Authors: Bendell Johanna , Blumenschein George , Zinner Ralph , Hong David , Jones Suzanne , Infante Jeffrey , Burris Howard , Rajagopalan Prabhu , Kornacker Martin , Henderson David , Kelly Andrea , Hassan Raffit 
Published: August 2014

Abstract
Background: BAY 94-9343 (BAY, Mesothelin-ADC) is a novel ADC consisting of a fully human monoclonal antibody directed against mesothelin, conjugated to a maytansine derivative DM4. Mesothelin is an internalizing antigen overexpressed by a number of solid tumors, including a majority of mesotheliomas and pancreatic and ovarian adenocarcinomas. BAY demonstrates mesothelin-specific antitumor activity in relevant xenografts. Objectives of this study were evaluation of safety, PK, immunogenicity, biomarkers, antitumor activity, and determination of Maximum Tolerated Dose (MTD) of BAY in patients (pts) with advanced solid tumors.
Methods: BAY doses ranged from 0.15 to 5.5 mg/kg IV every 21 days. PK samples were collected in Cycles (C) 1 and 3; biomarker and immunogenicity samples were also collected. Tumor assessments were planned every 6 weeks.
Results: 32 pts (16 mesothelioma, 9 pancreatic, 3 ovarian and 4 other) received BAY. No dose limiting toxicities (DLT) have been observed up to 5.5 mg/kg. One pt had possibly study drug related SAE of Grade 3 chest pain in C2. There were no other related Grade 3/4 AEs. One pt had a Grade 2 infusion reaction and one pt had possibly related Grade 2 pericardial effusion (PE). Two other pts had PE not related to BAY but to underlying cancer. The most common possibly related Grade 1/2 AEs were fatigue (10 pts), nausea (7), anorexia (4), vomiting (4), and weakness (3). PK of ADC and Total Antibody increased in a generally dose proportional manner; half-life was 4 to 5 days. DM4 Cmax increased in a dose proportional manner and DM4 metabolite exposure increased in a more than dose proportional manner; half-lives were approx. 2 and 6 days, respectively. Anti-BAY antibodies were observed in 3 pts at dose levels ≤ 2.4 mg/kg which was associated with decreased ADC exposure in C3. Exploratory analysis of cytokeratins (CK18 M30 and M65) and serum mesothelin as biomarkers will be discussed. One mesothelioma pt in 5.5 mg/kg cohort has confirmed partial response and is currently ongoing. Durable stable disease has been observed in 2 mesothelioma pts (6 and 10 cycles, respectively).
Conclusions: BAY has been tolerated at doses of up to 5.5 mg/kg and dose escalation continues. There are no prohibitive findings with regards to PK and antidrug antibodies at higher dose levels. Initial signals of clinical activity are seen. Updated results will be presented.
Citation Format: Johanna Bendell, George Blumenschein, Ralph Zinner, David Hong, Suzanne Jones, Jeffrey Infante, Howard Burris, Prabhu Rajagopalan, Martin Kornacker, David Henderson, Andrea Kelly, Raffit Hassan. First-in-human phase I dose escalation study of a novel anti-mesothelin antibody drug conjugate (ADC), BAY 94-9343, in patients with advanced solid tumors. [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 LB-291. doi:10.1158/1538-7445.AM2013-LB-291