BACKGROUND: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Germ cell tumor including platinum-resistant embryonal carcinoma cells lines are extremely sensitive to hypomethylating agents and low dose decitabine can restore cisplatin sensitivity 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 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 guadecitabine in combination with cisplatin, determine the maximum tolerated and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT02429466.

FINDINGS: Between 2015 and 2017, we enrolled and treated 10 patients. Grade 3 or 4 adverse events were febrile neutropenia, thrombocytopenia, anemia, and diarrhea. The most common serious adverse events were febrile neutropenia and thrombocytopenia. Guadecitabine 45 mg/m2 was associated with prolonged SAE and felt to be unsafe to continue. The maximum tolerated dose was 30 mg/m2 daily × 5. Two patients achieved a complete response to treatment lasting more than 6 months.

INTERPRETATION: Guadecitabine SQ at 30 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with platinum-refractory GCT. The study is still ongoing.

Citation Format: Costantine Albany, Neda S. Hashemi, Fang Fang, James Lowder, Lawrence Einhorn, Kenneth Nephew. Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1386.