LAUSR

Background and Objectives: Metastatic pancreatic adenocarcinoma is the second leading cause of cancer related death in the US with limited therapeutic options. Preclinical data have shown that methylation alongside other epigenetic modifications play a role in carcinogenesis and development of chemotherapy resistance in that disease. Sarcomas are a heterogeneous group of tumors originating from mesenchyme and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes as well. Preclinical work suggested that Methylation plays a role in cellular reprogramming to a less differentiated, more invasive cell that is resistant to chemotherapy. Based on that, restoration of normal methylation patterns is a potential therapeutic target for these tumors. Experience from other disease settings showed that protracted intermittent low dosing of hypomethylating agents do have epigenetic modulating effect with less toxicity. The concept of this trial is to assess the feasibility of combining a standard of care chemotherapy with a protracted course of intermittent low dose DNMT inhibitor. Gemcitabine is a universally accepted therapy option for both pancreatic adenocarcinoma as well as Sarcomas while Decitabine is a potent DNMT inhibitor. Our primary objectives are to assess the safety and tolerability of protracted course of intermittent low dose Decitabine in combination with Gemcitabine in previously treated patients with advanced PADC and sarcomas, to identify the recommended phase 2 dosing (RP2D) and to describe the dose limiting toxicities (DLT). Methods: Patients with metastatic histologically or cytologically confirmed PADC or sarcoma (soft tissue or bone) after who meet inclusion criteria will be enrolled. Prior Gemcitabine exposure is allowed. A total of 18 patients (9 from each diagnostic group) will be enrolled. A modified 3+3 dose escalation design is employed for each diagnostic group. Two dose levels of Decitabine, 0.1 and 0.2 mg/kg subcutaneously administered on twice weekly schedule for three weeks of a 28-day cycle are being tested. Gemcitabine is given as 900 mg/m2, IV over 90 min on Days 1, 8 and 15 of a 28-day cycle. Treatment is continued until disease progression or unacceptable toxicity. DLT is defined as any drug related non-hematological grade 3 or 4 toxicities per CTCAE v 4.0. Disease assessment is performed every 8 weeks using RECIST v1.1. Patients will be monitored for tolerance and safety with routine clinical exams, laboratory studies, and periodic CT scans to assess response to therapy. The study is currently open to accrual with 5 PDAC patients and 9 Sarcoma patients already enrolled. Preliminary data has shown excellent tolerance for the regimen in the completed Sarcoma cohort and an expansion phase had been designed and is currently underway. Clinical trial identifier: NCT02959164. Citation Format: Laith Abushahin, Varum Monga, Daniel Berg, Chandrikha Chandrasekharan, Munir Tanas, Michael Henry, Mariel Mckay, Sarah Mott, Mohammed Milhem. Phase Ib study of Decitabine in combination with Gemcitabine in treatment of refractory pancreatic adenocarcinoma and advanced soft tissue or bone sarcomas [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 CT136.