Bristol-Myers Squibb (BMS) recently announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for CC-486 (oral azacitidine), an oral hypomethylating agent, for maintenance treatment in adult patients with acute myeloid leukemia (AML) who are in remission following intensive induction chemotherapy. Specifically, it is indicated for maintenance therapy in adult AML patients who have achieved their first complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after intensive induction chemotherapy (with or without consolidation chemotherapy) and who are not eligible for or have chosen not to undergo hematopoietic stem cell transplantation (HSCT). The FDA has granted priority review to this NDA and has set a Prescription Drug User Fee Act (PDUFA) target action date of September 3, 2020.
This New Drug Application (NDA) is based on the efficacy and safety results from the pivotal Phase III QUAZAR AML-001 study. The study evaluated the efficacy and safety of CC-486 (oral azacitidine) as first-line maintenance therapy in patients with newly diagnosed acute myeloid leukemia (AML) who achieved remission after intensive induction chemotherapy. The results demonstrated that, in the setting of first-line maintenance therapy, CC-486 treatment led to statistically significant and clinically meaningful improvements in overall survival (median OS: 24.7 months vs. 14.8 months; p=0.0009) and relapse-free survival (median RFS: 10.2 months vs. 4.8 months; p=0.0001) compared with the placebo group.
Acute Myeloid Leukemia (AML) is the most common type of acute leukemia. AML originates in the bone marrow but rapidly enters the bloodstream. Unlike normal blood cell development, in AML, the rapid accumulation of abnormal white blood cells in the bone marrow can interfere with the production of normal blood cells, leading to a reduction in healthy white blood cells, red blood cells, and platelets. AML is a complex and heterogeneous disease associated with various genetic mutations, and if left untreated, the condition typically deteriorates rapidly.
CC-486 (oral azacitidine) is an oral hypomethylating agent that incorporates into DNA and RNA, enabling sustained epigenetic modulation due to prolonged exposure. Currently, CC-486 is being developed as an epigenetic modifier for the treatment of various hematologic malignancies. The primary mechanisms of action are considered to be DNA hypomethylation and direct cytotoxicity against abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore the normal function of genes critical for differentiation and proliferation.
Noah Berkowitz, M.D., Senior Vice President of Global Clinical Development in Hematology at Bristol-Myers Squibb, stated: “Typically, adult patients with newly diagnosed acute myeloid leukemia (AML) achieve complete remission through induction therapy, but many experience relapse and poor outcomes. Patients in remission are seeking treatment options that reduce the likelihood of relapse and extend overall survival. The FDA’s acceptance today of our New Drug Application (NDA) for CC-486 represents an important step toward addressing the urgent unmet medical need for potential new maintenance therapies in AML. We look forward to working closely with the FDA during the review of CC-486.”
QUAZAR AML-001 was an international, randomized, double-blind, placebo-controlled Phase III study enrolling patients aged ≥55 years with de novo or secondary acute myeloid leukemia (AML) with intermediate- or high-risk cytogenetics who achieved first complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after intensive induction chemotherapy. Patients received intensive induction chemotherapy with or without consolidation chemotherapy, as selected by the investigator, and were deemed not to be candidates for hematopoietic stem cell transplantation (HSCT) prior to study entry.
Following intensive induction chemotherapy, 81% of patients achieved complete remission (CR), and 19% achieved complete remission with incomplete hematologic recovery (CRi). Eighty percent of patients had received at least one cycle of consolidation therapy prior to study enrollment. A total of 472 patients were subsequently randomized in a 1:1 ratio to receive either CC-486 300 mg (n=238) or placebo (n=234), administered once daily for 14 days per 28-day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred.
With a median follow-up of 41.2 months, the CC-486 treatment group demonstrated significant improvement in the primary endpoint of overall survival (OS) compared with the placebo group. The median OS from randomization was 24.7 months in the CC-486 group versus 14.8 months in the placebo group (p=0.0009; HR=0.69 [95% CI: 0.55, 0.86]). For the key secondary endpoint of relapse-free survival (RFS), the median RFS was 10.2 months in the CC-486 group compared with 4.8 months in the placebo group (p=0.0001; HR=0.65 [95% CI: 0.52, 0.81]). Improvements in both OS and RFS were observed with CC-486 versus placebo regardless of cytogenetic risk category, prior consolidation status, or complete remission/complete remission with incomplete hematologic recovery (CR/CRi) status at enrollment. Health-related quality of life (HRQoL) remained stable from baseline in the CC-486 group compared with the placebo group.
The median treatment duration was 12 cycles (range, 1–80) for CC-486 and 6 cycles (range, 1–73) for placebo. The most common adverse events (AEs) of any grade with CC-486 versus placebo were nausea (65% vs. 24%), vomiting (60% vs. 10%), and diarrhea (50% vs. 22%). The most common grade 3–4 AEs with CC-486 versus placebo were neutropenia (41% vs. 24%), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%). Serious adverse events occurred in 34% of patients in the CC-486 group and 25% of those in the placebo group, primarily infections, which were reported in 17% and 8% of patients in the respective groups. Treatment discontinuation due to AEs occurred in 13% of patients in the CC-486 group and 4% in the placebo group.
Original source: U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol Myers Squibb’sapplication for CC-486 for Maintenance Treatment of Adult Patients in Remission with Acute Myeloid Leukemia
Original Title: New Drug for First-Line Maintenance Therapy in Remission of Acute Myeloid Leukemia (AML)! Bristol-Myers Squibb’s CC-486 (Oral Azacitidine) Receives Priority Review from the U.S. FDA!
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