A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.

Abstract

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.