In the January 2018 issue of Cancer, Gail J. Roboz (co-chair of the AML Global Portal (AGP) North American Steering Committee) from Weill Cornell Medicine, NY and Hagop M. Kantarjian from the MD Anderson Cancer Center, Houston, TX, and colleagues reported data from a cohort of Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) patients treated in the phase II portion of an open-label, multicenter phase I/II dose expansion study (NCT01261312) of guadecitabine (SG1-110), a next generation Hypomethylating Agent (HMA) , in patients with AML.1
Previous findings from a phase I study have established the Biologically Effective Dose (BED) of guadecitabine to be 60 mg/m2/d for 5 consecutive days in a 28-Day cycle.2 The main objective of this phase II dose expansion study was to investigate the dose-response relation beyond the BED for the 5-day regimen and evaluate the safety and efficacy of the BED with a 10-day regimen.1
Overall, 108 R/R AML patients were enrolled between 15 June 2012 and 19 August 2013. A total of 103 patients (median age = 60 years, range 22–82) were administered subcutaneous guadecitabine in a 28-day cycle. Fifty patients were randomly assigned to receive either 60 mg/m2 (n = 24) or 90 mg/m2 (n = 26) guadecitabine on Days 1–5 in a 5-day schedule. The remaining 53 patients were assigned to receive 60 mg/m2 guadecitabine on Days 1–5 and Days 8–12 in a 10-day schedule. The primary endpoint of the study was Composite Complete Response (CRc [CR, CR with incomplete platelet recovery, or CR with incomplete neutrophil recovery regardless of platelets]).1
There were similar response rates observed between the 60 mg/m2 and the 90 mg/m2 doses in the 5-day schedule. Thus, the cohorts were combined for comparison with the 10-day schedule.
- Clinical response
- CRc in patients in the 5-day and 10-day schedule: 16.0% (8/50) vs 30.2 (16/53), P = 0.1061
- CR in patients in the 5-day versus 10-day schedule: 8% (4/50) vs 18.9% (10/50), P = 0.15
- Median time to achieve CR in the 5-day and 10-day schedule: 236 days (range, 64–987 days) vs 77 days (range, 38–172 days), P < 0.04
- Median duration of response in the 5-day and 10-day schedule: 233 days (range, 42–898 days) vs 444.5 days (range, 15–880 days), P = n.s
- Twenty patients in the 5-day (n = 8) and 10-day (n = 12) schedule were bridged to Hematopoietic Cell Transplantation (HCT)
- Median Overall Survival (OS) in patients in the 5-day and 10-day schedule; 5.0 vs 7.1 months, P = 0.7783
- OS was significantly longer in patients who achieved a response compared to non-responders: not reached vs 5.6 months, P < 0.0001
- Median OS in patients who underwent HCT after guadecitabine treatment was significantly longer than patients who were not transplanted: not reached vs 5.6 months, P < 0.0001
- An increased incidence of grade ≥ 3 adverse events of myelosuppression and infection was observed in the 10-day regimen compared to the 5-day regimen
- 30-Day mortality rate in the 5-day and 10-day schedule were 3.8% and 1.9% respectively
Using the Long Interspersed Nuclear Element 1 (LINE-1 [ a surrogate for global DNA methylation]) assay, the authors found that compared to the 5-day schedule, there was a deeper and more prolonged LINE-1 demethylations observed in the 10-day schedule. Moreover, responders had significantly more potent demethylation than non-responders. The authors further noted that “treatment with HMAs can and should be continued until overt progression or unacceptable toxicity because responses occur late and disease relapse can be rapid upon discontinuation”.
In summary, guadecitabine demonstrated an encouraging clinical activity and tolerable safety profile in patients with R/R AML. As a result of the findings of this phase I/II study, a phase III ASTRAL-2 randomized study (NCT02920008) is currently underway. The phase III study is assessing the efficacy and safety of guadecitabine in adults with previously treated AML. Patients would be randomized to receive guadecitabine in a 10-day cycle for up to two cycles followed by ongoing 5-day cycle or physician’s choice of intensive salvage chemotherapy or best supportive care.
In an accompanying editorial in this same January 2018 issue of Cancer, Charles A. Schiffer, from Wayne State University School of Medicine, Detroit, commented on the findings of Roboz & Kantarjian et al.3 Charles Schiffer noted that while the findings of the phase II study were of interest, he thought they were “not decidedly better than what might have been achieved with other chemotherapy approaches”. He further highlighted that HMA-based epigenetic treatment has some limitations, including the fact that its mechanism remains an “empiric untargeted approach”, and thus suggested that different approaches would be required to increase cure rates of HMAs in the R/R AML population with “immunologic manipulation being the most intriguing new candidate”.
Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients.
In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10-day regimen).
Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m2/d [10-day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation.
Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population.