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

John A. Ligon, R. Taylor Sundby, Mary F. Wedekind, Fernanda I. Arnaldez, Jaydira Del Rivero, Lori Wiener, Ramaprasad Srinivasan, Melissa Spencer, Amanda Carbonell, Haiyan Lei, John Shern, Seth M. Steinberg, William D. Figg, Cody J. Peer, Sara Zimmerman, Josquin Moraly, Xia Xu, Stephen Fox, King Chan, Michael I. BarbatoThorkell Andresson, Naomi Taylor, Karel Pacak, J. Keith Killian, Eva Dombi, W. Marston Linehan, Markku Miettinen, Richard Piekarz, Lee J. Helman, Paul Meltzer, Brigitte Widemann, John Glod*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: 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. Patients and Methods: 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. Results: 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. Nopartial 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. 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.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalClinical Cancer Research
Volume29
Issue number2
DOIs
StatePublished - 15 Jan 2022
Externally publishedYes

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