A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

Abstract

Purpose Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next‐generation HMA guadecitabine (SGI‐110) with cisplatin in recurrent, cisplatin‐resistant GCT patients. Methods Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28‐day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD). Results The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

“…This data provided the rationale to combine cisplatin and guadecitabine in a phase Ib study of heavily pretreated cisplatin-resistant TGCT patients [NCT02429466]. This combination was tolerable and showed two major responses and an overall clinical benefit rate of 46% from 14 patients [ 127 ].…”

Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

“…Both proof-of-concept studies constitute an argument in favor of using hypomethylating targeted treatments for these resistant patients, which was one of the main research questions investigated in our discovery work. In fact, the same group and others have already shown the benefit of agents such as 5-AZA, DAC and guadecitabine in treating resistant patients and in rescuing sensitivity to cisplatin, both in vitro and including in a recent clinical trial [ 34 – 38 ].…”

Recent advances in testicular germ cell tumours

“…In pre-clinical studies, TGCTs were extremely sensitive to low-dose decitabine, a DNA methyltransferase inhibitor, which restored sensitivity to cisplatin in cell lines 73 . A phase I study of guadecitabine and cisplatin in 14 patients with TGCTs showed an overall response rate of 23% 61 ; excellent responses were also reported in two patients with platinum-refractory disease treated in a phase 1 study of cisplatin, gemcitabine and guadecitabine 62 .…”