A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma

Purpose: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyo-matosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) with-out KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleo-tide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. Patients and Methods: Phase II study of guadecitabine (subcu-taneously, 45 mg/m(2)/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/ paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. Results: Nine patients (7 with dSDH GIST, 1 each with para-ganglioma and HLRCC-RCC, 6 females and 3 males, age range 18- 57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demeth-ylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. Conclusions: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.