Mechanism of Action: DNA methyltransferase (DNMT) inhibition
Indication: Relapsed/Refractory Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukaemia (CMML)
How this therapy can help
Guadecitabine was rationally designed to prolong the exposure of tumor cells to the active metabolite, decitabine, ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.
As a next-generation DNA hypomethylating agent, guadecitabine inhibits DNMT to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells, restoring the expression of silenced tumor suppressor genes and tumor-associated antigens. Guadecitabine-mediated inhibition of DNA methylation upregulates tumor-associated antigens and may sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as resensitize resistant cancer cells to chemotherapeutics.
Astex is conducting ASTRAL-3 (Relapsed/Refractory MDS or CMML): 408-patient multicenter, randomized, open-label study in Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) after failure of prior azacitidine, decitabine, or both.
LDAC – low-dose cytarabine; IC (7+3) – intensive chemotherapy (cytarabine/anthracycline); BSC – best supportive care
The ASTRAL-3 clinical studies are based on data from a completed 400-patient Phase 1/2 study of guadecitabine in patients with AML or MDS (www.clinicaltrials.gov).
Other active clinical programs
Astex also has an active program evaluating the combination of guadecitabine with checkpoint inhibitors in the treatment of both hematological malignancies and solid tumors, and as a single agent and in combination with chemotherapy for the treatment of solid tumors. These include studies investigating combination with carboplatin in the treatment of platinum-resistant ovarian cancer; in hepatocellular (liver) cancer following failure of Nexavar® (sorafenib), and in combination with irinotecan in the treatment of colorectal cancer.