Phase I trial of metronomic cyclophosphamide (CTX), bevacizumab (BV) and imatinib (IM) in patients (pts) with advanced solid tumors

Abstract

15026 Background: Low-dose chemotherapy without scheduled breaks (metronomic chemotherapy) is thought to be anti-angiogenic. Inhibitors of the VEGF and the PDGF signaling pathways may augment this effect. We initiated a prospective, phase I pharmacokinetic (PK) and biomarker study to assess the safety of a rationally designed combination anti-angiogenesis strategy consisting of metronomic CTX, BV (an anti-VEGF antibody), and IM (a PDGF-receptor inhibitor). Methods: Cycle length was 28 days. Doses: BV 5 mg/kg IV q 14 d, CTX 25–50 mg PO QD, IM 400–800 mg PO QD. DLT was defined as any treatment-related grade 4 hematologic event or grade 3/4 non-hematologic event during cycles 1 and 2. Quantification of circulating tumor cells (CTC), endothelial cells (CEC, aEC) and endothelial progenitor cells (EPC) was performed. Treatment-related effects on parameters measured by CT perfusion were assessed. Results: 10 pts with metastatic colorectal cancer have been enrolled: M/ F= 5/5; ECOG PS 0/1= 9/1; median age=55 (range 33–63). All pts had received prior BV and had disease refractory to standard chemotherapy (oxaliplatin, irinotecan, and a fluoropyrimidine). Pts have received treatment for a median of 56 days (range 21–222 days). Dose level 0 (DL 0) (BV 5 mg/kg, CTX 25 mg/d, IM 400 mg/d) was expanded to 6 pts after 1/3 initial pts was removed from the study for a Gr 2 gastrointestinal fistula (after cycle 1). DL+1 (BV 5 mg/kg, CTX 50 mg/d, IM 400 mg/d) had no DLT’s. 1 pt has been enrolled on DL+2 (BV 5 mg/kg, CTX 50 mg/d, I 300 mg/BID). The MTD has not been reached. Treatment has been well tolerated; there have been no treatment-related Gr 3/4 toxicities. The most common possible treatment-related AE’s have been Gr 1/2 fatigue, lymphopenia, nausea, and rash. Two pts (DL 0, DL+1) demonstrated SD lasting > 6 months; 1 of whom had a 19% decrease in target lesions by RECIST. Conclusions: The combination of metronomic CTX, IM, and BV can be safely administered. Class related side effects have been seen. Preliminary clinical activity has been observed in a heavily-pretreated patient population. Enrollment to this study continues, with CTX and IM PK to be performed at the MTD. Updated clinical and biomarker data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, Johnson & Johnson, sanofi-aventis Genentech™ BioOncology, Johnson & Johnson, Novartis