CC-486 as Maintenance Therapy Extends Survival in AML Patients, Phase 3 Trial Shows

CC-486 as Maintenance Therapy Extends Survival in AML Patients, Phase 3 Trial Shows

People with acute myeloid leukemia (AML) who are in complete remission after their first-line chemotherapy and not suitable for a stem cell transplant have significantly better survival outcomes if offered maintenance therapy with CC-486, Bristol-Myers Squibb‘s oral formulation of azacitidine, data from a Phase 3 trial show.

Patients treated with this experimental medication in the pivotal QUAZAR AML-001 trial lived about 10 more months than those on a placebo, and a median of 10.2 months without disease relapse — compared to 4.8 months for those on placebo.

CC-486 was also better at preserving patients’ health-related quality of life. Bristol-Myers is planning to request regulatory approval of CC-486 as a maintenance therapy in early 2020 based on these results.

These findings were presented in December at the American Society of Hematology (ASH) 2019 Annual Meeting in Orlando, in the late-breaker oral presentation “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.”

Azacitidine is a chemotherapy agent that works at the DNA level, switching ‘on’ genes that are often ‘turned off’ by cancer cells to allow their uncontrolled proliferation and survival. This works to lower the number of abnormal blood cells and helps to control cell growth.

The treatment is aimed at slowing disease progression with as few side effects as possible, maintaining quality of life. It is approved as an under-the-skin injection for many blood cancers under the brand name Vidaza (by Celgene; generics also available). Vidaza was approved to treat AML patients in the European Union in 2015, but AML is not among its approved indications in the U.S.

For optimal therapeutic effect, however, azacitidine injections must be given over several treatment cycles. This led Celgene, now part of Bristol-Myers, to develop an oral formulation that is more convenient to administer, possibly expanding the use of azacitidine as a maintenance therapy.

The QUAZAR AML-001 trial (NCT01757535) was designed to evaluate the safety and efficacy of Celgene’s oral formulation of azacitidine, CC-486, as a maintenance therapy for patients in complete remission after intensive first-line induction chemotherapy, with or without consolidation chemotherapy.

Those enrolled are age 55 or older, not candidates for a stem cell transplant, and have intermediate- to poor-risk cytogenetics (alterations in chromosomes). Within four months of attaining a complete remission, patients were randomly assigned to receive CC-486 or placebo, once daily, in a two-weeks-on, two-weeks-off schedule.

QUAZAR’s main goal is to determine if CC-486 extends patients’ lives compared to a placebo. Secondary measures include relapse-free survival (the time until disease relapse or death), health-related quality of life, and safety. Minimal residual disease status (the few cells that remain after treatment which could lead to relapse) is being examined as an exploratory measure.

At the time of the analysis, 472 patients were enrolled and treated. They were a median age of 68  and most (91%) had primary AML — as opposed to secondary AML (8%), which develops from other blood diseases.

After following patients for a median of 41.2 months (about 3.5 years), researchers found that CC-486 significantly extended overall survival to 24.7 months, compared to 14.8 months in those given placebo. This represented a 31% reduction in the risk of death, with the trial meeting its primary objective. (The trial, which runs through December 2021, finished its primary data collection in July 2019.)

The key secondary endpoint of relapse-free survival was also met, with CC-486 reducing the risk of relapse of death by 35%. It also preserved health-related quality of life compared to a placebo.

Interestingly, the survival benefits were seen regardless of patients’ cytogenetic risk, the full or incomplete recovery of blood stem cells after intensive chemotherapy, and the use of consolidation chemotherapy.

Patients assigned CC-486 remained on treatment for longer than those on placebo (12 cycles versus 6 cycles), supporting the treatment’s benefits and tolerability. Adverse events like nausea, vomiting, and diarrhea were seen more frequently with CC-486.

The most common severe (grade 3) or life-threatening (grade 4) adverse events were low neutrophil (a type of white blood cell) numbers, anemia, and low platelet counts. Serious adverse events were more common with CC-486 (34%) than placebo (25%), which were mainly infections. More patients on CC-486 stopped taking the treatment due to adverse events (13% vs. 4% for placebo).

“Despite a number of recent advances in the treatment of AML, the prognosis remains poor, as most patients will relapse and ultimately die of their disease,” Andrew Wei, MBBS, PhD, from Alfred Hospital and Monash University in Melbourne, Australia, said in a press release. “The role of maintenance therapy in AML has historically been a contentious issue.

“Based on the results of the QUAZAR study, we are excited about the clinical development of CC-486 and the potential to establish maintenance therapy as a new treatment paradigm for patients with AML in first remission,” Wei added.

“We are extremely encouraged by the results of the QUAZAR AML-001 study as a part of our continuing commitment to both epigenetic research and myeloid diseases,” said Samit Hirawat, MD, chief medical officer of Bristol-Myers Squibb. “We now look forward to taking the next steps to bring CC-486 to eligible AML patients in need.”