EHA 2019 | Results from phase III ASTRAL-1 study of guadecitabine versus treatment of choice 

On Saturday 15 June 2019, during the 24^th meeting of the European Hematology Association (EHA) in Amsterdam, NL, the phase III results of the ASTRAL-1 study were presented by Professor Pierre Fenaux, Hôpital Saint Louis, Paris, FR.¹

The ASTRAL-1 study compared the use of guadecitabine (SGI-110) to treatment of choice (ToC) in patients with acute myeloid leukemia (AML) who had not received prior treatment and who were not eligible for intensive chemotherapy.

Background and phase II results

• Guadecitabine is a next generation hypomethylating agent 
  • Dinucleotide of decitabine results in slow deamination by cytidine deaminase, longer half-life and prolonged exposure to the active metabolite, decitabine

A previous phase II trial (NCT01261312) enrolled 103 patients; the total responses of these patients, by dose and length of administration are shown in Table 1.²

Table 1: Response rates to guadecitabine by dose and length of administration in phase II trial

Based on the results in Table 1, investigators decided to use a 60mg/m² dose of guadecitabine, administered over 5 days, for the phase III trial.

Phase III study design and patient characteristics

• Randomized 1:1 to either G or ToC
  • G: 60mg/m² subcutaneously for 5 days
  • ToC: decitabine (DEC), azacitidine (AZA), or low dose Ara-C (LDAC)
  • Table 2 shows treatments given pre- and post-randomization
• Primary endpoints: CR rate and overall survival (OS) rate
• The majority of patients were unfit and 75 years or older as shown in Table 3
• In total, 815 patients were randomized, with 793 treated (largest trial in treatment naïve patients with AML)

Table 2: Treatment given pre- and post-randomization

Table 3: Patient characteristics

Efficacy

Primary endpoint analysis in the intention-to-treat (ITT) population is shown in Table 4 (CR and OS for guadecitabine versus ToC).

Table 4: Primary endpoint analysis in ITT population

In the subgroup analysis, there were no differences between treatment arms based on age, sex, cytogenetic risk, ECOG score, or race. The exception was in patients with TP53 mutations who appeared to favor the control arm (ToC).

The survival analysis (Table 5) shows improved outcome for patients responding to ≥4 cycles or ≥6 cycles guadecitabine compared to ToC. This superior survival was more pronounced when patients received >6 cycles (P = 0.002) compared to >4 cycles (P = 0.02) of guadecitabine. These results indicate that prolonged exposure to guadecitabine is necessary to observe clinical benefit.

Table 5: Survival of patients with a response (CR, CRp, CRi or PR) who received ≥4 cycles and ≥6 cycles of guadecitabine

Adherence to treatment and safety

Treatment exposure is shown in Table 6, with reasons for discontinuation of treatment in patients receiving less than 4 cycles shown in Table 7 with the safety data on AEs and serious AEs (SAEs) shown in Table 8. As shown in Table 6, approximately 41% and 54% of patients did not receive 4, or 6 cycles, respectively.

Table 6: Treatment exposure

Table 7: Reasons for discontinuation of treatment (patients receiving <4 cycles)

Table 8: Safety data of AEs

The most common grade 3 and 4 AEs occurring in ≥20% of patients in either group were: febrile neutropenia, pneumonia, thrombocytopenia, neutropenia and anemia.

Conclusion

This study failed to meet the primary endpoint of a statistical difference in CR and OS between guadecitabine and ToC. However, a benefit was observed in patients who received >4 cycles, indicating that treatment duration is crucial to response. Around 40% of patient in both arms did not receive the minimum of 4 cycles to see the maximum of treatment benefit.

In relation to safety, both guadecitabine and all three ToC options were comparable, though higher rates of febrile neutropenia and pneumonia were noted in the guadecitabine arm.