Although sample size was small, the two dose cohorts demonstrated comparable anti-tumor activity. abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors. strong class=”kwd-title” Keywords: phase I clinical trial, neuroendocrine tumor, solid tumor, sulfatinib, tyrosine kinase inhibitor INTRODUCTION Vascular endothelial growth factor (VEGF)- and fibroblast growth factor (FGF)-mediated pathways play key roles in tumor angiogenesis [1, 2]. VEGF and FGF secretion by tumor cells promotes rapid proliferation and packing of endothelial cells, which leads to the formation of excessive, coarsely packed blood vessels . These blood vessels supply oxygen and nutrients to the tumor and promote tumor cell leakage into the circulation, resulting in increased tumor growth and a risk of metastasis . While VEGF receptor (VEGFR)-targeted therapies are important in the management of several cancer types, many patients exhibit no or limited respond to treatment, due in part to tumor cell resistance through alternative molecular pathways . In response to anti-VEGF therapies, some tumors can increase FGF secretion to stimulate endothelial cell proliferation, promote tumor angiogenesis, and bypass VEGF signaling pathways [4, 5]. Evidence also suggests that VEGFR, FGF receptors (FGFRs), and colony stimulating factor 1 receptor (CSF1R) promote tumor immune evasion. VEGF secreted by tumors can activate VEGFR signaling pathways in T cells; this leads to programmed cell death protein 1 (PD-1) receptor overexpression, which decreases T cell anti-tumor activity . FGFR and CSF1R also appear to induce tumor-associated macrophage proliferation and differentiation, thereby promoting tumor immune evasion . Targeting multiple kinases to simultaneously block VEGFR-, FGFR-, and CSF1R-mediated pathways may be a more effective method of preventing tumor angiogenesis and tumor immune evasion, and therefore represents an attractive anti-cancer therapy approach. Sulfatinib (HMPL012) is a potent small molecule tyrosine kinase inhibitor of VEGFR 1, 2, and 3, FGFR 1, and CSF1R , and has demonstrated selectivity in a broad kinase screening (Table ?(Table1).1). The aims of this phase I clinical CUDC-101 study in patients with advanced solid tumors were to determine the sulfatinib maximum tolerated dose (MTD) and recommended dose for further phase II investigations. The study was designed to investigate the safety, pharmacokinetics (PK), and tumor response of sulfatinib. Table 1 Sulfatinib kinase selectivity profile thead th align=”left” valign=”middle” rowspan=”1″ colspan=”1″ Kinase /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ IC50 (M) /th /thead VEGFR Rabbit polyclonal to Dcp1a 10.002VEGFR 20.024VEGFR 30.001FGFR10.015CSF1R0.004TrkB0.041FLT30.067278 other kinases 0.150 Open in a separate window FLT3: fms-related tyrosine kinase 3; IC50: half maximal inhibitory concentration; TrkB: tropomyosin receptor kinase B. RESULTS Patient baseline characteristics Seventy-seven Chinese patients were enrolled in 12 dose cohorts between April 2010 and September 2014, and followed up until July 2015 (Figure ?(Figure1).1). The first 43 patients received sulfatinib formulation 1 and the remaining 34 received formulation 2 (Figure ?(Figure2).2). Patient baseline demographic and clinical characteristics are summarized in Table ?Table22. Open in a separate window Figure 1 Study designaSulfatinib dose was escalated (until MTD was met) according to a modified Fibonacci 3+3 protocol. Each patient received the assigned dose for the study duration. CUDC-101 bThe tumor expansion phase was initiated following determination of the recommended phase II dose based on the results of the dose-escalation phase. Open in a separate window Figure 2 Patient configurationaAt enrolment, patients were assigned a dose sequentially according to the Fibonacci 3+3 dose-escalation design. Patients received that dose for the study duration. bPatients who completed the DLT observation phase could remain on treatment at their original dose until disease progression or any other withdrawal criteria were met. Table 2 Patient baseline demographic and clinical characteristics thead th align=”left” valign=”top” rowspan=”1″ colspan=”1″ Characteristic /th th align=”center” valign=”top” rowspan=”1″ colspan=”1″ Formulation 1 (N=43) /th th align=”center” valign=”top” rowspan=”1″ colspan=”1″ Formulation 2 (N=34) /th /thead CUDC-101 Median (range) age, years52.7 (23.5C69.9)56.0 (23.4C73.2)Gender, n (%)?Male27 (62.8)24 (70.6)?Female16 (37.2)10 (29.4)Tumor type, n (%)?Colorectal carcinoma9 (20.9)0?Hepatocellular carcinoma8 (18.6)9 (26.5)?Stromal tumor8 (18.6)1 (2.9)?NET (grade 1/2)a7 (16.3)21 (61.8)?Non-small cell lung cancer2 (4.7)0?Renal cell carcinoma2 (4.7)0?Other7 (16.3)3 (8.8)ECOG performance status, n (%)?010 (23.3)4 (11.8)?129 (67.4)30 (88.2)?24 (9.3)0Median (range) time since diagnosis,.