Astex and Otsuka Announce Phase 3 ASTRAL-2 and ASTRAL-3 Studies Fail to Meet Endpoints in Patients with Previously Treated AML and MDS

Oct 16, 2020 | Challenging Results, Hematology, News, Oncology

Astex and Otsuka Announce Phase 3 ASTRAL-2 and ASTRAL-3 Studies Fail to Meet Endpoints in Patients with Previously Treated AML and MDS

Astex Pharmaceuticals and Otsuka Pharmaceuticals announced top-line results of the ASTRAL-2 and ASTRAL-3 clinical studies that evaluated the efficacy and safety of guadecitabine (SGI-110) in adults with previously treated AML (ASTRAL-2), and with previously treated MDS/CMML (ASTRAL-3), respectively.  Neither study met the primary endpoint of statistically significant improvement in overall survival (OS) compared with the control arm of physicians’ choice of alternative therapy.  Evaluation of the studies’ prospective subgroups and secondary endpoints is ongoing.  Safety data were consistent with the expected safety profile of guadecitabine from prior studies. The full data will be presented at upcoming scientific meetings.

The ASTRAL-2 study evaluated the efficacy and safety of guadecitabine in adults with AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and who were refractory to initial induction (primary refractory) or in relapse after such initial induction with or without prior hematopoietic cell transplantation. The study randomized 302 patients from 98 investigator sites in 15 countries worldwide.  The study randomized patients 1:1 to receive in 28-day cycles either guadecitabine, delivered subcutaneously for 10 days in Cycle 1 followed by 10 or 5 days in Cycle 2, and 5 days in Cycle 3 onwards, or physicians’ choice of (i) a high intensity regimen comprising intermediate or high dose cytarabine; mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida); (ii) a low intensity regimen comprising low dose cytarabine or azacitidine or decitabine; and (iii) Best Supportive Care only.

The ASTRAL-3 study evaluated the efficacy and safety of guadecitabine in adults with MDS or CMML previously treated with a hypomethylating agent. The study randomized 417 patients from 91 investigator sites in 14 countries worldwide.  The study randomized patients 2:1 to receive in 28-day cycles either guadecitabine delivered subcutaneously for 5 days, or physicians’ choice of (i) low dose cytarabine; (ii) a standard intensive chemotherapy (IC) 7+3 regimen of cytarabine and an anthracycline, or mitoxantrone; and (iii) Best Supportive Care only.

Astex and Otsuka announced in July 2018 that the global phase 3 ASTRAL-1 randomized study of guadecitabine in adults with previously untreated AML who were not eligible for intensive induction chemotherapy failed to meet its co-primary endpoints.

About Guadecitabine

Guadecitabine is a next-generation DNA hypomethylating agent. Guadecitabine was rationally designed to be resistant to degradation by cytidine deaminase, prolonging the exposure of tumor cells to the active metabolite, decitabine, thus ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells. Guadecitabine, through the action of decitabine, inhibits DNA methyl transferase (DNMT), with the potential to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells, and may restore the expression of silenced tumor suppressor genes and tumor-associated antigens. Through this re-expression of silenced genes, guadecitabine may have the potential to sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as re-sensitizing cancer cells previously resistant to chemotherapeutics.

About Acute Myeloid Leukemia

AML is the most common form of acute leukemia in adults. An estimated 19,940 new cases of AML are projected in the U.S. in 2020 and an estimate of 11,180 patients are projected to die from AML in the U.S. in 2020. Although 60 to 80 percent of AML patients less than 60 years of age may achieve a complete response with standard intensive induction chemotherapy, the outlook for previously treated patients, and for patients 60 years of age or more, particularly those with comorbidities, is significantly worse, and these patients are in need of effective, less toxic therapies.

About Myelodysplastic Syndromes 

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. U.S. incidence of MDS is estimated to be 10,000 cases per year. The prevalence has been estimated to be from 60,000 to 170,000 in the U.S. MDS may evolve into acute myeloid leukemia in one-third of patients. The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML.

Source: Astex

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