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

Abstract

Purpose: Succinate dehydrogenase deficient (dSDH) tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GISTs) without KIT or platelet derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. Patients and Methods: Phase II study of guadecitabine (subcutaneously, 45mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to Response Evaluation Criteria in Solid Tumors v.1.1) across 3 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 (PBMCs), serum, and urine were analyzed. Results: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years-old) 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 demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. Conclusions: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. While 4/9 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, though signs of biologic activity were noted.

Succinate Dehydrogenase Defects Giant Renal Cell Carcinoma

“…This disease is rare, and no recommended radiotherapy or chemotherapy strategy is currently available. SDH-deficient tumors tend to be resistant to cytotoxic chemotherapy, radiation therapy, and many targeted therapies, as demonstrated in a clinical trial of guadecitabine in SDH-deficient tumors [ 9 ]. However, it has been suggested that pathological variant morphology of cancer cells, coagulative necrosis or sarcomatoid changes, and high ISUP-grade nucleolar features are associated with more aggressive behavior.…”