Phase II trial of sunitinib in patients with relapsed or refractory germ cell tumors

Abstract

Vascular endothelial growth factor (VEGF) overexpression and increased angiogenesis have been proposed as having biologic importance in germ cell tumors (GCT). We conducted a single-institution phase II trial of sunitinib, an oral inhibitor of the VEGF receptor, in patients with relapsed or refractory GCT. A Simon's two-stage design was used to determine the number of patients for enrollment. Responses were assessed using a modified version of Response Evaluation Criteria in Solid Tumors (RECIST), taking into account tumor marker changes. Dose modifications were made according to a nomogram for adverse events. Ten patients were enrolled. The first five received sunitinib 50 mg for four consecutive weeks, followed by a two-week break (4/2). Since four of five treated on this schedule had some tumor marker decline during the four-week "on" period, with subsequent rise during the two-week break, the dose was changed to 37.5 mg continuously for patients six to ten. However, only marker stabilization (no declines) was seen. Overall, there were no objective responses: Five had stable disease and five progressive disease (PD). Sunitinib was well tolerated; only one patient required a dose reduction due to grade 3 mucositis. Two patients experienced tumor-related hemorrhage (grade 3 and grade 1). All patients developed PD within three cycles. Sunitinib is well tolerated, but at standard doses, does not demonstrate significant activity in highly refractory GCT. Correlation between sunitinib treatment and tumor marker changes on the 50 mg 4/2 schedule suggest some pathways targeted by sunitinib (ie, angiogenesis) may be important to GCT biology.

The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

“…These results indicate that compounds such as sunitinib or pazopanib, in addition to their antiangiogenic response, also directly affect testicular tumor cells by blocking these PDGFRs. Sunitinib as a single agent was tested in three clinical trials of refractory TGT (29)(30)(31), giving modest results, with only a few cases of short-duration disease stabilization followed by rapid progressive disease in two studies (29,31), but with three temporary partial responses (9%) and 41% of cases of stable disease in the other (30). Moreover, there was a decrease in the frequency of tumor markers following sunitinib treatment, suggesting that the targets of sunitinib may still be important in TGT biology (29,31).…”

Sunitinib in Patients with Cisplatin-Refractory Germ Cell Tumors

“…It was reported previously that monotherapy with sunitinib has limited efficacy in patients with heavily pretreated, unselected,refractorygermcelltumors [1,2].Howeveritisof great interest to explore the molecular characteristics of respondingpatientsasitmayallowidentificationofamolecular profilesuitableforsunitinibtherapyortreatmentwithother targetedagents [1].…”

Will Testicular Germ Cell Tumors Remain Untargetable?

“…These dismal survival rates urge the need of more effective drugs and opened the door to investigate targeted therapy in patients with relapsed or refractory TGCTs. Sunitib, an oral TKI, was tested in different phase II trials with limited efficacy with a short lived response rate not exceeding 13 % in a study of 33 patients [70,71]. Despite these results, Reckova et al hypothesize that there might be some efficacy of sunitinib in GCTs with teratoma components that is in concordance with reported overexpression of VEGF in teratomas [72].…”