Background: Sarcomas are a heterogeneous group of tumors and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes. Restoration of normal methylation patterns using DNA hypomethylating agent when combined with chemotherapy has shown to slow tumor growth in preclinical studies. Low continuous dosing of hypomethylating agent has epigenetic modulating effect with less toxicity. We conducted a Phase 1b study evaluating safety & tolerability and identifying the recommended phase 2 dose (RP2D) of subcutaneous (SQ) decitabine (DEC) given with fixed dose infusion gemcitabine (GEM) in patients with advanced soft tissue sarcomas (STS) and bone sarcomas. Methods: Eligible patients at least age 18 yrs with metastatic histologically confirmed STS or bone sarcoma after progression on one line or if refused adriamycin for STS were included. Prior GEM use was permitted. A modified 3+3 dose escalation design was used exploring two dose cohorts of DEC, 0.1 and 0.2 mg/kg SQ administered on a twice weekly schedule for three weeks and GEM given as 900 mg/m², IV over 90 min on days 1, 8 & 15 of a 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined as any drug related non-hematological grade 3 or 4 toxicity per CTCAE v4.0. Disease assessment was performed every 8 weeks using RECIST v1.1. Results: 31 patients (25 STS & 6 bone sarcomas) were enrolled of which 7 were non-evaluable. There were 12 evaluable patients in each dosing cohort. Of the total 744 adverse events (AE) 17.2% were grade 3/4 and most were neutropenia without neutropenic fever. 45.7% AEs were possibly (44.6%) or probably (1.1%) attributed to DEC use. The toxicities were not significantly different between DEC doses. No DLTs were observed. One patient died due to progressive disease. Conclusions: Combination of fixed dose infusion GEM with low dose subcutaneous DEC is moderately toxic. Most toxicities were hematological. While there were few responses, the RP2D of DEC selected was 0.1 mg/kg as it showed prolonged disease stabilization. Clinical trial information: NCT02959164.

Partial responses were noted in leiomyosarcoma, chondrosarcoma, adenosarcoma and carcinosarcoma. A clinical benefit rate of 58% was noted. Eleven patients had previously received and progressed on GEM based therapy.