Guadecitabine—a dinucleotide containing the DNA methyltransferase inhibitor decitabine—may be well tolerated in patients with succinate dehydrogenase-deficient (dSDH) tumors, including hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), according to results of a phase 2 trial published in Clinical Cancer Research.
However, stable disease reported in the study did not translate to objective responses.
dSDH-deficient tumors—including HLRCC-RCC, pheochromocytoma/paraganglioma, and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations—are often resistant to cytotoxic chemotherapy, radiotherapy, and targeted therapies.
John Glod, MD, PhD, of the National Cancer Institute, and colleagues designed a study to assess the clinical activity of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, 28-day cycle) across 7 patients with dSDH GIST and 1 each with paraganglioma and HLRCC-RCC. Within this patient sample, 6 were female, 3 were male, and the age range was 18 to 57 years.
Researchers utilized a Simon optimal 2-stage design, with a target response rate of 30%. Biologic correlates from peripheral blood mononuclear cells, serum, and urine were analyzed.
Researchers reported treatment-limiting neutropenia in 2 of the patients. No partial or complete responses were observed, though 4 of the patients had prolonged stable disease.
Additionally, researchers added that biologic activity assessed as global demethylation in peripheral blood mononuclear cells was observed, while no changes in metabolite concentrations were observed.
“Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity,” study authors concluded. However, they acknowledged that the drug did not meet the target 30% response rate at its current dose, implying that further study is needed.