Ru Jia

S-1 as Monotherapy or in Combination With Leucovorin as Second-Line Treatment in Gemcitabine-Refractory Advanced Pancreatic Cancer: A Randomized, Open-Label, Multicenter, Phase II Study

BACKGROUND In this study, we compared the efficacy and safety of the oral fluoropyrimidine S-1 as monotherapy or in combination with leucovorin as the second-line treatment for patients with metastatic pancreatic cancer whose disease had progressed on gemcitabine treatment. METHODS The study was a randomized, open-label, controlled study. Patients randomly received S-1 or S-1 in combination with leucovorin (SL arm) in 21-day cycles. The primary endpoint was the 6-month survival rate. RESULTS A total of 92 patients were randomized to S-1 (n = 47) and SL (n = 45). No statistically significant differences were observed between the two arms with regard to 6-month survival rates (40% vs. 49%), median overall survival (5.5 vs. 6.3 months), median progression-free survival (1.9 vs. 3.0 months), and overall response rate (4.7% vs. 8.3%). The rate of major grade 3-4 adverse events of digestive toxicity was significantly higher in the SL arm than in the S-1 arm. CONCLUSION Compared with S-1, SL did not improve the survival of patients with metastatic pancreatic cancer who had failed to benefit from prior gemcitabine treatment, but SL had a higher adverse event rate.

PIK3CA mutations contribute to acquired cetuximab resistance in metastatic colorectal cancer patients

Purpose: Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential role of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated. Experimental Design: Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells. Results: We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, seven (22%) carried five novel PIK3CA mutations, whereas eight (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in two patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation. Conclusions: The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. Clin Cancer Res; 23(16); 4602–16. ©2017 AACR.

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.

Phase II Study of Recombinant Antitumor and Antivirus Protein Injection Compared With Placebo in Metastatic Colorectal Cancer After Failure of Standard Treatment

LESSONS LEARNED Novaferon showed moderate efficacy and was well-tolerated in patients with metastatic colorectal cancer (mCRC), especially with the 20 μg injected 3 times a week strategy.Although Novaferon did not provide a survival benefit for mCRC patients who have failed standard treatment, it may play a role in improvement of immune function. BACKGROUND To observe the efficacy, safety, and optimal dosage of recombinant antitumor and antivirus protein (Novaferon) in treating patients with metastatic colorectal cancer (mCRC) who failed at least two prior palliative regimens. METHODS We enrolled 108 patients from May 2011 to December 2012. According to different treatment modalities and therapeutic dosages, the participants were randomly divided into four cohorts at a 2:2:2:1 ratio: (a) 20 μg Novaferon (Genova Biotech, Beijing, Peoples Republic of China, http://www.genovabiotech.net) injected twice per week, (b) 20 μg Novaferon injected 3 times per week, (c) 40 μg Novaferon injected 3 times per week, or (d) saline injected 3 times per week. The primary endpoint was overall survival. RESULTS There was no significant difference in overall survival among the four cohorts. The 20-μg dose of Novaferon injected 3 times per week had the highest disease control rate (44.0%) at 6 weeks but without significant differences when compared with placebo (p = .159). Major adverse events with Novaferon were influenza-like symptoms, bone marrow suppression, liver dysfunction, and gastrointestinal discomfort. The level of natural killer cells increased and regulatory T cells decreased significantly after treatment with Novaferon, whereas levels in the placebo group remained the same. CONCLUSION Novaferon showed moderate efficacy and was well tolerated in patients with mCRC, especially with the 20-μg dose injected 3 times per week. Furthermore, Novaferon might improve immune function of these patients.

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.