Summary
Escalating dosing with the experimental oral hypomethylating agent CC-486 appears to be safe and well-tolerated for patients experiencing first acute myeloid leukemia (AML) relapse, according to analysis of data from the QUAZAR AML-001 phase III clinical trial. (Abstract 7513).
The findings were presented at the 2020 ASCO Annual Meeting by Hartmut Döhner, MD, a clinical professor and researcher at the University of Ulm, in Germany. An escalated 21-day dosing schedule was well-tolerated, prolonged survival, and restored remission in about 1 in 4 patients.
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Original Article
QUAZAR Trial: Escalated CC-486 Dosing Safe After First AML Relapse
Oncology Times
By Kurt Samson
Escalating dosing with the experimental oral hypomethylating agent CC-486 appears to be safe and well-tolerated for patients experiencing first acute myeloid leukemia (AML) relapse, according to analysis of data from the QUAZAR AML-001 phase III clinical trial. (Abstract 7513).
The findings were presented at the 2020 ASCO Annual Meeting by Hartmut Döhner, MD, a clinical professor and researcher at the University of Ulm, in Germany. An escalated 21-day dosing schedule was well-tolerated, prolonged survival, and restored remission in about 1 in 4 patients.
On May 1, the FDA granted priority review for CC-486 as a maintenance treatment for adult AML patients in complete remission (CR) but incomplete blood count recovery (CRi), following induction therapy, with or without consolidation treatment. The agent is for patients who are not candidates for, or who choose not to proceed to, hematopoietic stem cell transplantation. The agency has set a goal date of September to complete its review.
Escalated 21-day dosing with CC-486 resulted in prolonged overall survival and restoration of remission in approximately one-fourth of trial subjects. Although hematologic adverse events first reported during escalated dosing in both arms may be due, in part, to disease relapse, Döhner explained.
A 21-day dosing schedule should be considered for patients receiving CC-486 who experience relapse with 5–15 percent blasts, he said.
The goal of AML maintenance therapy is to decrease the risk of relapse by suppressing growth of residual leukemic cells post-induction. CC-486 allows for extended dosing schedules—greater than 7 days in a 28-day treatment cycle—to sustain therapeutic activity.
In the QUAZAR AML-001 trial, CC-486 maintenance treatment significantly prolonged overall and relapse-free survival over placebo in AML patients with their first remission following induction chemotherapy. The subjects initially received CC-486 or placebo for 14 days per cycle, but patient who relapsed with 5–15 percent blasts could receive escalated 21-day cycle dosing.
Patients were 55 years of age or older, with intermediate- or poor-risk cytogenetics, and had achieved their first CR/CRi. Within 4 months, the subjects were randomized to receive CC-486 300 mg or placebo on day 1-14 of a 28-day treatment cycle, and their CR/CRi status was assessed every 3 cycles.
Patients relapsing with 5–15 percent blasts in blood or bone marrow could receive the drug for 21 days at the investigator’s discretion, and treatment could continue until greater than 15 percent blasts, unacceptable toxicity, or stem cell transplantation.
A total of 91 patients were assigned to one or more treatments over a 21-day dosing schedule. Median time to dose escalation was 9.2 months for CC-486 subjects and 6.0 months for patients given placebo. The median number of 21-day dosing cycles was 2.0 in both arms, with 43 percent and 18 percent of patients, respectively, receiving more than 3 cycles.
Among 78 evaluable subjects, 23 percent of CC-486 patients and 11 percent in the placebo group regained CR/CRi, and median overall survival was 22.8 months for CC-486 patients versus 14.6 months with placebo, respectively, and 1-year survival rates were 80.4 percent in the treated subjects compared to 59.5 percent for placebo patients.
The most common side effects or adverse events, with first onset during a 21-day dosing schedule, were febrile neutropenia (CC-486 24% vs. 3% in placebo patients), thrombocytopenia (22%, 23%), anemia (22%, 20%), and neutropenia (20%, 10%), respectively.
Escalated 21-day dosing was well-tolerated and prolonged overall survival, and restoration of remission, in approximately one-fourth of patients.
Although hematologic AEs were first reported during escalated dosing in both arms, this may have been due, in part, to disease relapse, the researcher said. The results indicate that such a dosing schedule be considered for AML patients receiving CC-486 who experience relapse with 5–15 percent blasts.”
Kurt Samson is a contributing writer.