FDA Grants CPX-351 Breakthrough Designation for AML

Jeffrey E. Lancet, MD

The FDA has granted a breakthrough therapy designation to CPX-351 (Vyxeos) as a treatment for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC), according to a statement from the drug’s developer, Celator Pharmaceuticals.

The designation was primarily based on a phase III trial in which CPX-351 significantly reduced the risk of death by 31% compared with cytarabine and daunorubicin (7+3) for older patients with high-risk, secondary AML. 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).

“We are very happy the FDA granted breakthrough therapy designation for Vyxeos,” Scott Jackson, CEO of Celator Pharmaceuticals, said in a statement. “The breadth of the designation, which includes all adults with t-AML and AML-MRC, is encouraging as AML patients are in need of advancements in treatment.”

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.

“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 when the survival data were released in March 2015. “This represents a major step forward for a very difficult-to-treat patient population.”

An earlier assessment of the study had shown promising signs of efficacy, suggesting that overall survival 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 CR 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 2 arms. The most common grade 3/4 hematologic AEs were infections, febrile neutropenia, and bleeding events. The most common nonhematologic grade 3/4 AEs were organ systems related, including cardiac, gastrointestinal, general systems, metabolic disorders, musculoskeletal, nervous system, respiratory, skin, and renal.

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.

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 2 phase II studies. In these studies, CPX-351 showed promising results for patients with newly diagnosed and relapsed AML.

The breakthrough designation is meant to expedite the development of therapies that offer substantial benefits over existing option. Celator reported in its release that it intends to submit a new drug application to the FDA for CPX-351 by the end of the third quarter of 2016.

“We look forward to working with the FDA to bring Vyxeos to patients as quickly as possible,” said Jackson.