Abstract CT094: Phase I study of fibroblast growth factor receptor 2 antibody-drug conjugate (FGFR2-ADC) BAY 1187982 in patients with advanced cancer
Authors: Kim Sung-Bae , Meric-Bernstam Funda , Berlin Jordan , Wittemer-Rump Sabine , Osada Motonobu , Valencia Ray , Babich Aleksei , Liu Rong , Hwang Andy , Tanigawa Takahiko , Reetz Frank , Laurent Dirk , Kalyan Aparna 
Published: July 2017

Abstract
Background: FGFR2-ADC (BAY 1187982) consists of an anti-FGFR2 antibody (BAY 1179470) and a stably linked, highly potent and non-cell permeable microtubule-binding auristatin toxophore. A phase I study was conducted in patients (pts) with advanced solid tumors focusing on tumor types with a described expression of FGFR2.
Methods: Eligible pts with solid tumors, known to express FGFR2 and refractory to standard treatment, adequate organ function, and ECOG performance status (PS) ≤ 1 were enrolled. BAY 1187982 was administered by an one hour intravenous infusion on an every 21 days (q3w) schedule in 20 pts (5 cholangiocarcinoma, 5 colon, 2 gastric, 2 breast cancer and 6 others) at doses ranging from 0.1 to 1.3 mg/kg. Dose escalation followed the continous reassessment design treating 3-4 pts per cohort. Pts were assessed for AEs weekly in C1-C3 and on D1 in subsequent cycles. Tumor response was assessed every 6 weeks. Blood samples for a full pharmacokinetic profile were collected after dosing on D1 of C1 and C3 and thereafter every second cycle pre-dose and at the end of infusion.
Results: A total of 20 pts were evaluable: 55% female, mean age 52 yrs (range 24-76), PS 0/1 75% / 25%. No drug-related serious adverse events were reported at dose levels 0.1 and 0.2 mg/kg. At 0.4 mg/kg drug-related serious adverse events were similar to other ADCs, including reversible asymptomatic liver function test increases, and gastrointestinal disorders. Dose limiting toxicities (DLTs) were observed at dose level 0.8 and 1.3 mg/kg, respectively: 0.8 mg/kg cohort grade 3 thrombocytopenia (N=1); 1.3 mg/kg cohort grade 3 corneal epitheliopathy (N=1), grade 4 thrombocytopenia (N=1) and proteinuria progressing to nephrotic syndrome after treatment in C2 or C3 (N=2) with signs of reversibility after discontinuation. In dose level 0.4 and 0.8 mg/kg the majority of pts discontinued study drug treatment already in C1 or C2 due to disease progression and data on proteinuria at these dose levels were absent or spare. As a consequence only doses below 0.4 mg/kg were considered safe. Exposures of BAY 1187982 increased in a dose-proportional manner in the investigated dose range from 0.1 to 1.3 mg/kg.
Conclusion: While this drug was tolerated well at lower dose levels, dose-limiting toxicities occurred below the expected therapeutic dose level. As the predicted human efficacious dose level based on the majority of animal models was above 0.4 mg/kg (Wittemer-Rump et al. AACR; Cancer Res 2015;75, 15 Suppl: Abstract nr 1683) a Phase II dose cannot be recommended and a successful clinical development of the compound was regarded as unlikely. The data from the preclinical safety analysis in monkey and rat will be submitted as abstract to AACR 2017.
Citation Format: Sung-Bae Kim, Funda Meric-Bernstam, Jordan Berlin, Sabine Wittemer-Rump, Motonobu Osada, Ray Valencia, Aleksei Babich, Rong Liu, Andy Hwang, Takahiko Tanigawa, Frank Reetz, Dirk Laurent, Aparna Kalyan. Phase I study of fibroblast growth factor receptor 2 antibody-drug conjugate (FGFR2-ADC) BAY 1187982 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT094. doi:10.1158/1538-7445.AM2017-CT094