Abstract 3481: Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study
Authors: Raskin Grigory , Kazey Vasily , Gorbacheva Svetlana , Nikiforova Aiyyna , Statsenko Galina , Artamonova Elena , Vladimirova Liubov , Besova Natalia , Mochalova Anastasia , Rykov Ivan , Moiseyenko Vladimir , Utyashev Igor , Iugai Sergei , Dragun Nadezhda , Reznikov Dmitry , Gavrilova Evgenia , Tjulandin Sergei , Tsimafeyeu Ilya 
Published: June 2022

Abstract
Alofanib is a potent, small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms. Phase 1b clinical study (RPT835GC1B) met its primary endpoints and recommended phase 2 dose was described early. Here, we present pharmacokinetics (PK) and results of biomarker analysis.
Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels using a 3 + 3 design. 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver (43%) and bone (14.3%) metastases, 19% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). The PK and biomarker analysis set included 18 patients. FGFR2 amplification was accessed by FISH with ZytoLight SPEC FGFR2/CEN 10 Dual Color Probe and FGFR2 expression was accessed by IHC with antibody 1G3 (Abcam (ab 5820).
Table summarizes PK data. The geometric mean values of Cmax, AUC0-t, T1/2, Vd increased and CL, Kel decreased approximately dose-proportionally after single dosing, similar to previous preclinical studies. The decrease in the mean value of the Vd for a dose of 350 mg/m2 may be associated with a significant increase in AUC0-t. No correlations between PK values and objective response rate (n=2; 9.5%), progression-free (median 3.63 months (95% CI, 1.58 - 5.68) and overall (median 7.0 months (3.82 - 10.18) survival as well as in patients with liver metastases were found (all P&gt;0.1). A positive FGFR2 IHC expression was observed in all tumor cells and a weak positive reaction in normal epithelium. FGFR2 amplification was confirmed by FISH in 1 (5.6%) patient.Alofanib PK in a gastric patient population is well characterized, supporting the use of a once-daily 350 mg/m2 dose. In further studies, the evaluation of FGFR2 amplification seems to be important.
Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 50 mg/m2 100 mg/m2 165 mg/m2 250 mg/m2 350 mg/m2 Cmax, mcg/ml (CV%) 21.4 (32.3) 23.7 (18.4) 44.7 (15.5) 72.8 (64.3) 145.9 (42.7) AUC0-t, mcg*h/ml (CV%) 2.3 (31.9) 6.6 (14.2) 13.3 (49.9) 23.8 (8.7) 74.0 (57.5) Vd, ml/m2 (CV%) 4006.1 (28.3) 4907.5 (14.7) 5676.8 (26.6) 6686.7 (11) 3823.0 (63.8) CL, ml/h/m2 (SD) 19609.5 (7740) 14028.2 (1990) 11910.5 (8740) 10011.0 (827) 4183.0 (2420) Kel, 1/h (CV%) 4.9 (15.3) 2.9 (2.8) 2.1 (41.2) 1.5 (3.8) 1.1 (47.0) T1/2, h (SD) 0.1 (0.024) 0.2 (0.01) 0.3 (0.118) 0.5 (0.0171) 0.6 (0.293)
Citation Format: Grigory Raskin, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, Natalia Besova, Anastasia Mochalova, Ivan Rykov, Vladimir Moiseyenko, Igor Utyashev, Sergei Iugai, Nadezhda Dragun, Dmitry Reznikov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu. Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3481.