Phase II Study of Dasatinib (BMS-354825) in Patients With Metastatic Adenocarcinoma of the Pancreas

Abstract

Background. Src, EphA2, and platelet-derived growth factor receptors ␣ and ␤ are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, plateletderived growth factor receptor ␤, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. Methods. Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. Results. Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2months).In34evaluablepatients,thebestresponseachieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. Conclusion. Single-agent dasatinib does not have clinical activity in metastatic PDAC.

CCR7 regulates Twist to induce the epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma

“…However, the general 5-year survival rate is still less than 6 %, which cause some difficulties for surgeons. In the clinical practice, PDAC is usually defined at an advanced stage, when the tumor is very hard to resect, and the PDAC patients after operation have a high possibility of tumor recurrence and distant metastasis, including liver and peritoneal invasion [4][5][6][7]. Thus, it is necessary to throw light on the molecular mechanisms underlying PDAC progression, through which we can develop some new and useful targets agents.…”

Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer

“…Similarly, vatalanib and sorafenib that target VEGFR and Raf protein kinases respectively, as well as lestaurtinib that is a multitarget kinase inhibitor, failed to show promising benefits in phase I and phase II trials on human pancreatic cancer 3,4 . Src tyrosine kinase inhibitors saracatinib 5 and dasatinib 6 were not promising in clinical trials. Thus there is a critical need to identify new therapeutic targets for treating this lethal cancer.…”

Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis

“…In clinical trials using dasatinib, which targets the ATP binding pocket of Src and other kinases, the compound did not show promising antitumor effects in solid tumor patients as a monotherapeutic agent [6,28]. Unlike previous Src inhibitors, KX-01 targets the non-ATP binding region.…”