Maintenance therapy with CC-486 (oral azacitidine) led to a highly statistically significant and clinically meaningful improvement in overall survival compared with placebo in patients with newly diagnosed acute myeloid leukemia who achieved first complete response or CR with incomplete blood count recovery with induction therapy.
Jay Backstrom, MD, MPH
Maintenance therapy with CC-486 (oral azacitidine) led to a highly statistically significant and clinically meaningful improvement in overall survival (OS) compared with placebo in patients with newly diagnosed acute myeloid leukemia (AML) who achieved first complete response (CR) or CR with incomplete blood count recovery (CRi) with induction therapy, according to topline findings from the phase III QUAZAR AML-001 trial (NCT01757535).1
Additionally, relapse-free survival (RFS), a secondary endpoint, also had a statistically significant improvement with CC-486 versus placebo, announced Celgene, the developer of the agent, in a press release. Regarding safety, CC-486 was also found to be well tolerated and no unexpected safety signals were reported.
"AML remains a deadly blood cancer where most patients are not curable and less than 30% of patients survive five years," Jay Backstrom, MD, MPH, chief medical officer for Celgene, stated in a press release. "The CC-486 QUAZAR AML-001 study is the first phase III trial to demonstrate that the addition of maintenance therapy has the potential to extend overall survival in a broad population of patients with newly diagnosed AML who have achieved remission with induction chemotherapy."
Full data from the study will be presented at an upcoming medical meeting. Celgene stated that it is also planning regulatory submission of the investigational compound for the first half of 2020.
CC-486 is a cytidine nucleoside analogue and incorporates into DNA and RNA; its mechanism of action is believed to cause DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Furthermore, the antineoplastic effect of the agent is hypothesized to cause death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanism.
In the international, double-blind, placebo-controlled, phase III QUAZAR AML-001 trial, investigators randomized 472 patients 1:1 to receive either CC-486 at 300 mg or placebo once daily for 14 days of a 28-day cycle plus best supportive care until disease relapse. Patients must have achieved first CR or CRi with induction chemotherapy, with or without consolidation therapy.
Patients were aged ≥55 years, had an ECOG performance status of 0, 1, 2, or 3, and had a diagnosis of de novo AML or AML secondary to prior myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). Those with inv(16), t(16;16), t(15;17), or t(9;22) abnormalities were excluded from enrollment, as well as those with prior bone marrow or stem cell transplantation, achieved CR/CRi following therapy with hypomethylating agents, diagnosis of malignance disease within the previous 12 months, and central nervous system leukemia.
The primary endpoint of the study was OS, and key secondary endpoints included RFS, safety and tolerability, healthcare resource utilization, and patient-reported outcomes per the FACIT-Fatigue Scale and EQ-5D questionnaire.
The study was amended to include an extension phase, which allowed patients who were currently receiving CC-486 and demonstrated investigator-assessed clinical benefit to continue receive it after unblinding until the patient(s) met the criteria for study discontinuation, or until CC-486 becomes commercially available and reimbursed.
All patients who were on the placebo arm and those who had been discontinued from the treatment phase, regardless of randomization arm, and continued in the follow-up phase of the trial will be followed for survival in the extension phase.
Prior data of extended dosing with CC-486 in patients with MDS, CMML, and AML showed that the safety profile of the oral agent was comparable with injectable azacitidine. The extended cycles, which comprised 21 days each, led to induced responses and the majority of adverse events were hematological and gastrointestinal.2