Guadecitabine Clinically Active Against AML and MDS

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The novel investigational DNA methylation-inhibiting agent guadecitabine (SGI-110) is “well-tolerated, easily administered, and biologically and clinically active” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

The novel investigational DNA methylation-inhibiting agent guadecitabine (SGI-110) is “well-tolerated, easily administered, and biologically and clinically active” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), according to authors of a newly published multicenter phase I clinical trial. Results were published August 19, 2015 in The Lancet Oncology.1

The randomized, open-label, dose-escalation clinical safety and tolerability trial was conducted at 13 US and Canadian cancer centers. A total of 93 patients were enrolled in the study; 74 with AML and 19 with MDS.

Abnormal methylation of DNA alters gene expression and can contribute to disease progression and drug resistance. Guadecitabine is a small molecule that reverses aberrant DNA methylation.

Among study participants with AML and MDS, clinical response was associated with the extent of DNA demethylation.

“This means that the drug is safe and those patients who had more changes of their epigenome responded more to the drug,” said lead study author Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research and Molecular Biology at Temple University and co-Leader of the Cancer Epigenetics Program at the Fox Chase Cancer Center in Philadelphia.2

The most common grade ≥3 adverse events included febrile neutropenia (41% of all participants), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%), the study authors reported.

Prior treatment with the DNA methyltransferase inhibitors azacitidine or decitabine “did not seem to limit the activity of guadecitabine, at least anecdotally,” noted Mohamed A Kharfan-Dabaja, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., in a commentary published with the new study.3

Guadecitabine is manufactured by Astex Pharmaceuticals. It is a dinucleotide of decitabine, a commercially available nucleoside analogue used in MDS treatment, and deoxyguanosine. Decitabine is guadecitabine’s active metabolite, but guadecitabine better resists decitabine degradation by enzymes like cytidine deaminase, extending decitabine’s half-life.

 “The increased half-life of decitabine makes guadecitabine an attractive drug to assess in other settings and in combination with chemotherapy,” notes Dr. Kharfan-Dabaja. “One must remain cautious, however, about the potential risk of serious toxicities, especially when combining guadecitabine with cytotoxic therapies.”

“This study has led to a large phase II study that has not yet been published,” Dr. Issa noted. “The most exciting outcome of these studies is that this drug also started a new phase III clinical trial, and if successful, it can lead to FDA approval to treat leukemia patients.”

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