Phase III ASTRAL-2 and -3 trials of guadecitabine in patients with previously treated AML, MDS, or CMML fail to meet primary endpoints

On October 14, 2020, it was announced that the phase III trials ASTRAL-2 (NCT02920008) and ASTRAL-3 (NCT02907359) failed to meet their primary endpoints of a statistically significant improvement in overall survival between treatment with guadecitabine (SGI-110) and the control arm in patients with previously treated acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML).¹

Guadecitabine (SGI-110)

• Next-generation DNA hypomethylating agent
• Active metabolite: Decitabine
• Resistant to degradation by cytidine deaminase, therefore prolonging the bioavailability of decitabine in tumor cells
• Method of action: Inhibits DNA methyl transferases, therefore has the potential to reverse aberrant DNA methylation and restore the expression of silenced tumor suppressor genes
• Administration: Subcutaneously, low volume, stable formulation

ASTRAL-2 (NCT02920008)^1,2

• Randomized, open-label, multicenter trial, of guadecitabine compared with treatment of choice for patients with previously treated AML
• 302 patients randomized 1:1 to receive guadecitabine or treatment of choice
• Guadecitabine administered SC at 60mg/m² in 28-day cycles; 10 days in Cycle 1, followed by 10 or 5 days in Cycle 2, and 5 days in Cycle 3 onwards
• Treatment of choice included
  • high intensity: Intermediate- or high-dose cytarabine; mitoxantrone, etoposide, and cytarabine; or fludarabine, cytarabine, granulocyte colony stimulating factor, +/- idarubicin
  • low intensity: Low-dose cytarabine, decitabine, or azacitidine.
  • best supportive care
• Primary endpoint: OS
• Secondary endpoints: Event-free survival, long-term survival, number of days alive and out of the hospital, disease response, transfusion independence rate, complete response rate, composite complete response, hematopoietic cell transplant rate, duration of complete response, quality of life, incidence and severity of adverse events, and 30-day and 60-day mortality

ASTRAL-3 (NCT02907359)^1,3

• Randomized, open label, multicenter trial, of guadecitabine compared with treatment of choice for patients with MDS or CMML previously treated with HMAs
• 417 patients were randomized 2:1 to receive guadecitabine or treatment of choice
• Guadecitabine administered SC at 60 mg/m² on Days 1–5 of each 28-day cycle
• Treatment of choice included
  • low-dose cytarabine, 20 mg/m² SC or intravenously (IV), once daily on Days 1–14 of each 28-day cycle
  • standard intensive chemotherapy of a 7+3 regimen: Cytarabine 100–200 mg/m²/day continuous infusion for 7 days and daunorubicin 45–60 mg/m²/day, or idarubicin 9–12 mg/m²/day, or mitoxantrone 8–12 mg/m²/day, by IV infusion for 3 days
  • Best supportive care
• Primary endpoint: OS
• Secondary endpoints: Transfusion independence, marrow complete response rate, survival rate, leukemia-free survival, number of days alive and out of the hospital, disease response, duration of response, number of transfusions, health-related quality of life, incidence and severity of adverse events, and 30-day and 60-day mortality

The safety data of guadecitabine were consistent with previous studies. Although the trials did not meet their primary endpoint, guadecitabine was associated with improved outcomes in certain subgroups, which will be validated in further studies. The analysis of secondary endpoints is still ongoing and full data sets are due to be presented at a future scientific meeting.