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Pivotal Trial of Vosaroxin / Cytarabine Combo Fails to Meet Primary Endpoint in AML Patients
Mixed results have been reported from a pivotal phase III, randomized, double-blind, placebo-controlled study of vosaroxin (Qinprezo, Sunesis Pharmaceuticals) and cytarabine (Cytosar-U, Upjohn Company) in patients with first-relapsed or refractory acute myeloid leukemia (AML).
The trial enrolled 711 patients, who were stratified for age, geography, and disease status. The study did not meet its primary endpoint of demonstrating a statistically significant improvement in overall survival (OS), with a median OS of 7.5 months for vosaroxin and cytarabine compared with 6.1 months for placebo and cytarabine (hazard ratio, 0.865; P = 0.06).
Because stem-cell transplant (SCT) may confound the primary analysis, a predefined analysis of OS censoring for transplantation was planned. In this analysis, patients receiving the vosaroxin combination had a median OS of 6.7 months compared with 5.3 months for placebo and cytarabine (HR, 0.809; P = 0.02). The trial also demonstrated a clinically significant benefit in the complete remission (CR) rate (30.1% vs. 16.3%, P = 0.0000148), the secondary endpoint.
The trial stratified patient populations into two groups by age at enrollment: those younger than 60 years of age, and those 60 years of age and older. In a predefined analysis of patients younger than 60 years of age (n = 260), where the rate of SCT was 45.8%, the vosaroxin combination demonstrated a median OS of 9.1 months compared with 7.9 months for placebo and cytarabine (HR, 1.079; P not significant), and a CR rate of 26.9% compared with 20.8% (P = 0.24).
In the analysis of patients 60 years of age and older (n = 451), where the rate of SCT was 20.2%, the vosaroxin combination demonstrated a median OS of 7.1 months compared with 5.0 months for placebo and cytarabine (HR, 0.755; P = 0.006), and a CR rate of 31.9% versus 13.8%, respectively (P = 0.0000048).
In the intent-to-treat population, grade-3 or higher nonhematologic adverse events (AEs) that were more common in the vosaroxin combination arm included gastrointestinal and infection-related toxicities. The rate of serious AEs was 55.5% in the vosaroxin combination arm compared with 35.7% in the placebo and cytarabine arm. Thirty-day and 60-day all-cause mortality were comparable between the two groups (7.9% versus 6.6%, and 19.7% versus 19.4%, respectively).
Vosaroxin is an anticancer quinolone derivative — a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrated that vosaroxin intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest, and apoptosis.
The FDA has granted an “orphan drug” designation to vosaroxin for the treatment of AML. Vosaroxin has also been granted a “fast track” designation for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.
Source: Sunesis Pharmaceuticals; October 6, 2014.