Potent Hypomethylating Agent Is Tested in 2 Hematologic Malignancy Trials

Two randomized phase III clinical trials, ASTRAL-2 (NCT02920008) and ASTRAL-3 (NCT02907359), are designed to determine whether guadecitabine (SGI-110), a potent second-generation hypomethylating agent, could answer unmet medical needs for patients with certain types of blood cancer.¹

RATIONALE

Patients with relapsed/refractory acute myeloid leukemia (AML) have limited options for treatment, especially if they are not candidates for hematopoietic cell transplant or do not have targetable genetic mutations. Individuals with a myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) face a similar challenge, and most do not respond to high-dose chemotherapy, which is the first line of therapy, said investigator Guillermo Garcia-Manero, MD, deputy chair, translational research, Department of Leukemia, The University of Texas MD Anderson Cancer Center.²

Data suggest second-generation hypomethylating agents such as guadecitabine may in part overcome resistance to hypomethylating drugs such as azacitidine or decitabine, he added. Guadecitabine inhibits DNA methyltransferase, a family of enzymes that catalyze DNA methylation and regulate many normal cellular processes. Aberrant DNA methylation is one of the mechanisms that result in inactivation of tumor suppressor genes, leading to genomic instability, increased cellular proliferation, decreased apoptosis, and increased metastasis. One effect of guadecitabine’s reversing the aberrant hypomethylation is the upregulation of tumor-associated antigens. It can also sensitize tumor cells to other anticancer agents or resensitize resistant cancer cells to chemotherapeutics.

TRIAL DESIGN

In ASTRAL-2, outcomes with guadecitabine are being compared with physician’s choice of therapy: cytarabine in various doses and combinations, low-dose cytarabine or a hypomethylating agent different from guadecitabine, or best supportive care.

In ASTRAL-3, guadecitabine is also being compared with physician’s choice of therapy but is using different regimens from those of ASTRAL-2, including a chemotherapy option and no hypomethylating agents other than the study drug. The therapies are more appropriate for patients with MDS and CMML: low-dose cytarabine, standard intensive chemotherapy of a 7 + 3 regimen, or best supportive care. The primary endpoint for both trials is overall survival.

WHO IS ELIGIBLE?

ASTRAL-2 is accepting patients who have AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and must be refractory to initial induction (primary refractory) or in relapse after initial induction. ASTRAL-3 is enrolling patients with MDS or CMML who were previously treated with at least 1 hypomethylating agent.

REFERENCES

• Clinical pipeline. Astex Pharmaceuticals website. astx.com/research-development/clinical-pipeline/guadecitabine-sgi-110-dnmt-inhibitor-treatment-naive-aml/. Accessed May 1, 2018.
• Savona M, Garcia-Manera G, Roboz GJ, et al. Randomized phase 2 study of guadecitabine in patients with MHA-naïve risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). Poster presented at: 14th International Symposium on Myelodysplastic Syndromes; May 3-6, 2017; Valencia, Spain. Abstract 013. astx.com/wp-content/uploads/2017/05/2017_SGI-110_Poster_MDS_abst_MDS17-013_Savona_final.pdf. Accessed May 1, 2018.