Zachary Bessette

GU Oncology Now

Guadecitabine&mdash;a dinucleotide containing the DNA methyltransferase inhibitor decitabine&mdash;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 <a href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-22-2168/711474/A-Phase-II-Trial-of-Guadecitabine-in-Children-and" target="_blank" rel="noopener">Clinical Cancer Research</a>.However, stable disease reported in the study did not translate to objective responses.dSDH-deficient tumors&mdash;including HLRCC-RCC, pheochromocytoma/paraganglioma, and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations&mdash;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.&ldquo;Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity,&rdquo; 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.

Guadecitabine Effectiveness in Patients With HLRCC-Associated RCC, Other Diseases

Localized Renal Cell Carcinoma

Guadecitabine may be well tolerated in patients with dSDH tumors, including HLRCC-RCC, according to results of a phase 2 trial.

Guadecitabine Efficacy in Patients With HLRCC-Associated RCC

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