Ye Hua

Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial

Importance Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. Objective To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. Design, Setting, and Participants FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. Interventions Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. Main Outcomes and Measures The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. Results Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. Conclusions and Relevance Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. Trial Registration ClinicalTrials.gov Identifier: NCT02314819

Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: results from a phase I study

Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included 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.

Abstract A1: First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors

Background : Sulfatinib is a highly selective oral small molecule inhibitor targeting both vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR). A phase I dose-escalation study was carried out to determine sulfatinib maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), pharmacokinetic (PK) profiles, and preliminary antitumor activity in patients with advanced solid tumors. Methods: Sulfatinib was administered orally in 28-day treatment cycles until disease progression or unacceptable toxicity. The study utilized 3+3 dose escalation method, with ascending dose cohorts from 50mg to 350mg daily. During the study, a milled formulation was developed to reduce the inter-patient PK variations and optimize drug absorption. The milled formulation was used in 200mg once daily (QD) to 350mg QD dose cohorts. Results: As of July 6, 2015, a total of 77 patients had been enrolled. Forty-three of the 77 patients received original formulation in dose cohorts from 50mg to 300mg daily. The data of patients treated with original formulation dosing from 50 to 300mg once daily, or 125mg and 150mg twice daily were reported in ASCO 2012(#3040). Thirty-four of the 77 patients received milled formulation. Among the 34 patients, 23 were enrolled in the dose-escalation phase, receiving sulfatinib 200mg to 350mg QD whereas 11 patients were enrolled in the dose-expansion phase receiving sulfatinib 300mg or 350 mg QD. Among the 34 patients, there were 24 male patients (70.6%) and 10 female patients (29.4%). The median age was 55.97 (23.35-73.17) years. The most common adverse events of 34 patients were hypertension, proteinuria, diarrhea, elevated AST/ALT and decreased blood albumin, mostly grade1/2. One DLT (grade 3 ALT/AST increase) was observed in the 200 mg QD dose group. MTD was not reached up to 350mg QD. Among the 34 subjects treated with milled formulation, 22 subjects were diagnosed with neuroendocrine tumors (NETs). Eight NET patients (5 in 300mg QD and 3 in 350mg QD cohort) had confirmed partial response (PR) with median duration of response (DoR) of 60 weeks. The tumor origins of the 8 NET patients include pancreas (3 patients), duodenum (1 patient), rectum (1 patient), thymus (1 patient) and unknown origin (2 patients). Objective response rate among the 18 efficacy evaluable NET patients was 44.4% and disease control rate was 100%. Sulfatinib half-life (t 1/2 ) in plasma averaged 14-20 hours at the test dose levels, which supported sulfatinib QD dosing frequency. Following QD multiple dosing, sulfatinib achieved steady state on Day 14. The drug exposure increased when the dose increased from 200 mg to 300 mg, and then plateaued from 300 mg to 350 mg. Based on the clinical safety, efficacy, and PK data, the recommended Phase II dose is determined to be 300 mg QD. Conclusions: Sulfatinib was well tolerated with an acceptable safety profile. Promising anti-tumor activity was observed in NET patients. Further clinical studies with sulfatinib are warranted. Citation Format: Jian-Ming Xu, Lin Sheng, Yan Wang, Yu-Ling Chen, Ru Jia, Jian Wang, Ke Li, Yang Sai, Jing Li, Chuan Qi, Ye Hua, Wei-Guo Su. First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A1.

Abstract CT305: Phase I studies of a selective cMet inhibitor AZD6094 (HMPL504/volitinib) in patients with advanced solid tumors

Background: Volitinib is a selective oral small molecule inhibitor of cMet kinase, which has demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: Two phase I dose-escalation studies have been conducted in Australia (AU) and China (CN) in parallel to determine the maximum tolerated dose (MTD) or phase II Recommended Dose (P2RD), to evaluate pharmacokinetics (PK) profile, and to assess antitumor activity of Volitinib. Treatment was given orally in 21-day cycles until disease progression or unacceptable toxicity. Results: By July 2014 both studies completed dose-escalation phase. A total of 61 patients were enrolled (40 in AU and 21 in CN). Patients were treated with daily (QD) volitinib from 100mg to 1000mg or twice daily (BID) from 300 mg to 600mg. Median age at baseline was 63 years, and 60% patients were male in the AU study; whereas median age was 53 years, and 57% patients were male in the CN study. In both studies, the most common treatment related adverse events included nausea, vomiting, fatigue, peripheral edema and decreased appetite, mostly of grade (G) 1/2. Four patients experienced 5 dose limiting toxicities (DLTs) in the AU study: 1 G3 abnormal liver function test at 600mg QD, 1 G3 fatigue at 800mg QD, and 2 G3 fatigues and 1 G3 headache at 1000mg QD. One DLT of G3 fatigue at 600mg BID was reported in the CN study. The MTD for the QD regimen was identified as 800mg whereas the MTD for the BID regimen had not been reached in either study. 500mg BID was determined to be the P2RD as monotherapy based on the favorable benefit/risk profile demonstrated in both studies. In the AU study, 2 patients in the 600mg QD cohort and 1 patient in 1000mg QD cohort achieved partial response (PR). All 3 responders were papillary renal cell carcinoma patients. Two of the 3 responders remain PR with volitinib treatment of approximately 10 and 18 months respectively by July 2014. One CRC patient at 600mg QD achieved a 29% tumor reduction. Tumor sample analysis showed that all responders had both MET gene copy number increase (Chr7 gains or Met gene amplification) and high MET protein expression. Volitinib was rapidly absorbed with Tmax around 2∼4 hours and rapidly eliminated with half-life around 3∼7 hours in both studies. Both Cmax and AUC were roughly dose-proportional up to 800 mg QD and 500 mg BID. No obvious accumulation was found after 21-day of continuous QD or BID dosing. Drug exposure did not show racial difference between Caucasian and Asian patients. Conclusions: Volitinib was well tolerated up to 800 mg QD and 600 BID with acceptable safety profile. 500mg BID was determined to be the P2RD as monotherapy. Preliminary efficacy data demonstrated promising anti-tumor activity in patients with Met gene copy number increase or high protein expression. Volitinib demonstrated linear PK profile without marked drug accumulation. Further clinical studies are warranted. Citation Format: Ye Hua, Lin Shen, Hui Gan, Jason Lickliter, Michael Millward, Jianming Xu, Jian Wang, Yang Sai, Weiguo Su, Melanie M. Frigault, Chuan Qi. Phase I studies of a selective cMet inhibitor AZD6094 (HMPL504/volitinib) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT305. doi:10.1158/1538-7445.AM2015-CT305