FDA Grants Priority Review to Oral Hypomethylating Agent for Frontline Maintenance in AML


"The acceptance of our submission for CC-486 represents an important step towards a potential new maintenance treatment to address an urgent medical need for patients with AML and we look forward to working with the FDA during its review of CC-486."

The FDA has granted a priority review to an investigational oral hypomethylating agent, CC-486, as a maintenance treatment for adult patients with acute myeloid leukemia (AML) who achieved a complete remission (CR) or CR with incomplete blood count recovery (CRi) after receiving induction therapy with or without consolidation therapy.1 Eligible patients for potential treatment with CC-486 are those who are not eligible for hematopoietic stem cell transplantation (HSCT) or those who chose not to undergo HSCT.

When accepting the new drug application (NDA) for review, the FDA set a Prescription Drug User Fee Act target date of September 3, 2020, for a decision on the application.

The NDA was based on findings from the pivotal phase III QUAZAR AML-001 trial, in which treatment with CC-486 led to an overall survival (OS) of 24.7 months compared with 14.8 months with placebo (HR, 0.69; 95% CI, 0.55-0.86; P = .0009).1,2

“Often, newly diagnosed adult patients with AML achieve a complete response with induction therapy, however many patients will relapse and experience a poor outcome. Patients in remission are seeking treatment options that decrease the likelihood of relapse and extend overall survival,” said Noah Berkowitz, MD, PhD, senior vice president, Global Clinical Development, Hematology, Bristol Myers Squibb, in a statement. “Today’s acceptance of our submission for CC-486 represents an important step towards a potential new maintenance treatment to address an urgent medical need for [patients with] AML and we look forward to working with the FDA during its review of CC-486.”

QUAZAR AML-001 is a randomized, double-blind, placebo-controlled trial that explored the efficacy and safety of CC-486 (oral azacitidine) plus best supportive care versus best supportive care alone as maintenance therapy in patients with de novo or secondary AML who are in first remission following intensive induction therapy with or without consolidation chemotherapy (NCT01757535).

Patients in the trial were between the age 55 and 86 years old (median 68 years), had newly diagnosed and histologically confirmed disease, de novo or secondary AML—secondary to prior myelodysplastic syndrome or chronic myelomonocytic leukemia, an ECOG performance status ≤3, and had achieved CR/CRi within 4 months.

Those with AML and translocations or molecular evidence of translocations, CR/CRi from treatment with a hypomethylating agent, prior bone marrow or stem cell transplantation, a recent diagnosis of malignant disease, or proven central nervous system disease were excluded from the study.

The trial included a screening, treatment, and follow-up phase. An extension phase was also included for patients who were in the CC-486 arm and demonstrated a clinical benefit, allowing them to continue to receive treatment until the drug becomes commercially available or the patient meets the criteria for discontinuation.

A total of 472 patients were randomized to receive either 300 mg of CC-486 (n = 238) or placebo (n = 234) administered on days 1 through 14 of a 28-day cycle. Treatment continued until >15% blasts was observed, unacceptable toxicity, or HSCT.

OS was the primary end point, and secondary end points included relapse-free survival (RFS), health-related quality of life (HRQoL), and safety.

Findings were presented at the 2019 American Society of Hematology Annual Meeting after a median of 41.2 months of follow-up.2

Eighty-one percent of the patients were in CR at baseline and 19% in CRi; 80% had also received at least 1 cycle of consolidation therapy prior to starting in the trial.

The median RFS was 10.2 months with CC-486 compared with 4.8 months with placebo (HR, 0.65; 95% CI, 0.52-0.81; P = .0001).

Improvements were seen in both OS and RFS across patient subgroups by cytogenetic risk category.

HRQoL was also preserved from baseline in patients receiving CC-486 over those receiving placebo.

The most common adverse events (AEs) reported with CC-486 versus placebo, respectively, were nausea (65% vs 24%), vomiting (60% vs 10%), and diarrhea (50% vs 22%). The most common grade 3/4 AEs for CC-486 and placebo, respectively, were neutropenia (41% vs 24%), thrombocytopenia (23% vs 22%), and anemia (14% vs 13%).

Serious AEs were reported in 34% of patients in the CC-486 arm and in 25% in the placebo arm. Infections, the most common serious AEs, were observed in 17% and 8% of patients in the CC-486 and placebo arms, respectively. Thirteen percent of patients in the CC-486 arm and 4% in the placebo arm discontinued treatment due to AEs, most often due to gastrointestinal events.


1. U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol Myers Squibb’s Application for CC-486 for Maintenance Treatment of Adult Patients in Remission with Acute Myeloid Leukemia [press release]. Princeton, NJ: Bristol Myers Squibb; May 1, 2020. https://bit.ly/2VQKAlM. Accessed May 1, 2020.

2. Wei A, Dohner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission. Blood. 2019;134(suppl 2; LBA 3). doi: 10.1182/blood-2019-132405.

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