Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Department of Pediatrics, Division of Hematology/Oncology, University of Florida, Gainesville, Florida.
Clin Cancer Res. 2023 Jan 17;29(2):341-348. doi: 10.1158/1078-0432.CCR-22-2168.
Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) 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.
Phase II study of guadecitabine (subcutaneously, 45 mg/m2/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.
Nine patients (7 with dSDH GIST, 1 each with paraganglioma 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 demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed.
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.
琥珀酸脱氢酶（SDH）缺陷型肿瘤，包括嗜铬细胞瘤/副神经节瘤、遗传性平滑肌瘤病和肾细胞癌相关肾细胞癌（HLRCC-RCC）以及无 KIT 或血小板衍生生长因子受体α突变的胃肠道间质瘤（GIST），通常对细胞毒性化疗、放疗和许多靶向治疗具有耐药性。我们评估了含有去甲基化药物地西他滨的二核苷酸药物 guadecitabine 在这些患者人群中的作用。
对 SDH 缺陷型 GIST、嗜铬细胞瘤/副神经节瘤或 HLRCC-RCC 患者进行 guadecitabine（皮下，每天 45mg/m2，连用 5 天，计划 28 天为一个周期）的 II 期研究，以评估临床活性（根据 RECISTv.1.1）。采用西蒙最优两阶段设计（目标缓解率 30%，排除率 5%）。分析外周血单核细胞（PBMC）、血清和尿液中的生物学标志物（甲基化和代谢物）。
共纳入 9 例患者（7 例 SDH 缺陷型 GIST，1 例副神经节瘤，1 例 HLRCC-RCC，6 例女性，3 例男性，年龄 18-57 岁）。2 例患者发生治疗相关的中性粒细胞减少。未观察到部分或完全缓解（治疗范围为 1-17 个周期）。观察到 PBMC 中整体去甲基化的生物学活性，但未观察到代谢物浓度的明显变化。
在 SDH 肿瘤患者中，guadecitabine 耐受良好，毒性可管理。尽管 9 例患者中有 4 例疾病稳定时间延长，但无客观缓解。因此，在该剂量下，guadecitabine 并未达到 SDH 肿瘤 30%缓解率的目标，尽管观察到了生物学活性的迹象。
