CPX-351 Improves OS in Phase III AML Study

Jeffrey E. Lancet, MD

Frontline treatment with CPX-351 (Vyxeos) significantly reduced the risk of death by 31% compared with cytarabine and daunorubicin (7+3) for older patients with high-risk, secondary acute myeloid leukemia (AML), according to data from a phase III trial released by the drug's developer, Celator Pharmaceuticals, Inc.

The study showed a median OS of 9.56 months with CPX-351 versus 5.95 months with 7+3 (HR, 0.69; P = .005). Based on results from the phase III study, Celator announced plans to submit a new drug application to the FDA later in 2016. Additionally, a marketing authorization application with the European Medicines Agency is anticipated in early 2017. The company expects to present data from the study at the 2016 ASCO Annual Meeting.

“The overall survival advantage seen with CPX-351 compared to 7+3, along with a superior response rate and no increase in serious toxicity indicates that we'll likely have a new standard of care for treating older patients with secondary AML,” principal investigator for the study Jeffrey E. Lancet, MD, senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center, said a statement. “This represents a major step forward for a very difficult-to-treat patient population.”

The randomized, controlled phase III trial consisted of 309 patients across 39 sites throughout both the United States and Canada who were between the ages of 60 and 75. Patients enrolled in the study were split into either an age group consisting of patients between the ages of 60 to 69 or from 70 to 75. Those enrolled were further stratified based on AML type.

Patients were randomized in a 1:1 ratio to receive either CPX-351 or 7+3. Those receiving CPX-351 were given a first induction of 100u/m² on days 1, 3, and 5. Patients in the control arm received daily cytarabine 100 mg/m² for 7 days, followed by daunorubicin 60 mg/m² on days 1, 2, and 3. Second induction for patients enrolled in the CPX-351 arm was 100u/m² on days 1 and 3, while patients receiving conventional cytarabine and daunorubicin were given cytarabine 100mg/m² daily for 5 days with daunorubicin 60 mg/m² on days 1 and 2.

At 12 months, 41.5% of patients enrolled in the CPX-351 arm remained alive versus 27.6% in the 7+3 arm. At 24 months, 31.1% of patients enrolled in the CPX-351 arm of the study remained alive compared with 12.3% with 7+3. In the short term, 60-day all-cause mortality was 13.7% versus 21.2% in the CPX-351 and control arm, respectively.

An earlier assessment of the study had shown promising signs of efficacy, suggesting that OS would be significantly improved. This early analysis, which was conducted in June 2015, showed a relative improvement in induction response of over 40% with CPX-351 compared with conventional 7+3 cytarabine/daunorubicin in patients with secondary AML.

Induction response rates (complete remission [CR] plus complete remission with incomplete hematologic recovery [CRi]) were 47.7% for CPX-351 versus 33.3% for 7+3, yielding a relative benefit of 43.2% with the investigational treatment (P = .016). For CR alone, the rates were 37.3% and 25.6%, between CPX-351 and 7+3, respectively (P = .04).

Patients who achieved a CR or CRi were eligible to receive consolidation chemotherapy. In the investigation arm, consolidation CPX-351 was administered at 65 u/m² on days 1 and 3. In the control arm, consolidation therapy consisted of daily cytarabine at 100 mg/m² for 5 days and daunorubicin at 60mg/m² on days 1 and 2 (5+2).

A statistically significant difference was not observed for grade 3/4 adverse events (AEs) between the two arms. The most common grade 3/4 hematologic AEs were infections, febrile neutropenia, and bleeding events. The most common non-hematologic grade 3/4 AEs were organ systems related, including cardiac, gastrointestinal, general systems, metabolic disorders, musculoskeletal, nervous system, respiratory, skin, and renal.

“These findings confirm that Vyxeos provides the first opportunity we've had in decades to extend survival for patients with high-risk AML,” Gail Roboz, MD, Professor of Medicine and Director of the Leukemia Program at the Weill Medical College of Cornell University and the New York-Presbyterian Hospital in New York, said in a statement. “Also, more patients in remission means more who are eligible for potentially curative therapy.”

In January 2015 the FDA granted Fast Track status to CPX-351 for the treatment of elderly patients with secondary AML. The designation was based on the results of two phase II studies. In these studies, CPX-351 showed promising results for patients with newly diagnosed and relapsed AML.

CPX-351 is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio that was developed using a system known as "CombiPlex," which was developed by Celator. This platform is meant to improve upon existing therapies through in vitro studies that illuminate an optimal molar ratio for combinations.

“The successful outcome of this phase III trial represents an important advance for AML patients, their families and clinicians,” Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals, said in a statement. “It also marks a major milestone for Celator, for Vyxeos, and for our CombiPlex platform.”