Phase 3 Studies of Guadecitabine in AML, MDS/CMML Fail to Meet Primary End Point

Results from the phase 3 ASTRAL-2 and ASTRAL-3 clinical studies that evaluated the efficacy and safety of guadecitabine (SGI-110) in adults with previously treated acute myeloid leukemia (AML), and with previously treated myelodysplastic syndromes or chronic myelomonocytic leukemia (MDS/CMML), respectively, found that neither study met its primary end point, according to Astex Pharmaceuticals and Otsuka Pharmaceutical Company, the co-developers of the agent.

More specifically, neither study met the primary end point of a statistically significant (P < .05) improvement in overall survival (OS) compared with the control arm of physicians’ choice of alternative therapy. However, evaluation of the studies’ prospective subgroups and secondary endpoints remains ongoing.

Importantly, the safety data observed in the 2 trials were consistent with the expected safety profile of guadecitabine from prior studies. Astex indicated that the full data from each study will be presented at upcoming scientific meetings.

“We are disappointed in the outcome of the ASTRAL-2 and ASTRAL-3 studies,” Mohammad Azab, Astex’s president and chief medical officer, said in a press release. “The ASTRAL series of studies were designed to deliver a new therapeutic option to patients with AML or MDS/CMML, and although guadecitabine is an active drug, the studies failed to demonstrate a statistically superior survival outcome compared to current therapeutic alternatives.”

“The ASTRAL studies generated for the medical community one of the largest bodies of clinical and genetic data from prospective randomized studies using hypomethylating agent (HMA) treatment,” Azab continued. “Guadecitabine was associated with improved outcomes in certain subgroups, but that needs to be validated by additional studies. We are extremely grateful to all the patients, physicians and other healthcare professionals, and collaborating research and manufacturing organizations who contributed to this global effort.”

The ASTRAL-2 study (NCT02920008) evaluated the efficacy and safety of guadecitabine in adults with AML who had been previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and who were refractory to initial induction or in relapse after such initial induction with or without prior hematopoietic cell transplantation. In total, 302 patients from 98 investigator sites in 15 countries worldwide were enrolled in the study.

Participants were randomized 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 (Etopophos), and cytarabine (MEC); or fludarabine (Fludara), cytarabine, G-CSF, +/- idarubicin (Idamycin) (FLAG/FLAG-Ida); (ii) a low intensity regimen comprising low dose cytarabine or azacitidine (Onureg) or decitabine (Dacogen); or (iii) best supportive care only.

Key secondary end points for the trial include 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 all-cause mortality.

The ASTRAL-3 study (NCT02907359) evaluated the efficacy and safety of guadecitabine in adults with MDS or CMML previously treated with a hypomethylating agent. Overall, 417 patients from 91 investigator sites in 14 countries worldwide were included in the study.

Patients were randomized 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; or (iii) best supportive care only.

Key secondary end points for the study include 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 all-cause mortality.

Of note, guadecitabine is an investigational compound and is not currently approved in any country.

Reference:

Astex and Otsuka announce results of phase 3 ASTRAL-2 and ASTRAL-3 studies of guadecitabine (SGI-110) in patients with previously treated acute myeloid leukemia (AML) and myelodysplastic syndromes or chronic myelomonocytic leukemia (MDS/CMML) [news release]. Pleasanton, CA and Tokyo, Japan. Published October 14, 2020. Accessed October 15, 2020. https://astx.com/astex-and-otsuka-announce-results-of-phase-3-astral-2-and-astral-3-studies-of-guadecitabine-sgi-110-in-patients-with-previously-treated-acute-myeloid-leukemia-aml-and-myelodysplastic-syndromes-or/