Initial Phase III Data Positive for CPX-351 in High-Risk AML

Jeffrey Lancet, MD

Treatment with CPX-351, a liposomal formulation of cytarabine and daunorubicin, led to a relative improvement in induction response of over 40% compared with conventional 7+3 cytarabine/daunorubicin in patients with secondary acute myeloid leukemia (AML), according to early results from a phase III study.

Celator Pharmaceuticals Inc, the company developing the novel agent, also reported that data on the study’s primary endpoint of overall survival (OS) are anticipated in the first quarter of 2016. Previously reported phase II data showed a survival benefit with CPX-351 versus standard chemotherapy in patients with secondary AML.

“The results are encouraging because this is the third randomized study in which CPX-351 outperformed the control arm of cytarabine plus an anthracycline in overall response rate,” lead author Jeffrey Lancet, MD, senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center, said in a press release. “With induction therapy for AML, response rate has historically served as a surrogate for overall survival, and these data suggest a clinically meaningful benefit for CPX-351 over standard chemotherapy.”

The open-label phase III study randomized 309 patients with secondary AML in a 1:1 ratio to CPX-351 or 7+3. Patients in the 7+3 arm received 100 mg/m² of daily cytarabine through continuous infusion for 7 days and 60 mg/m² of daunorubicin on days 1, 2, and 3. CPX-351 was administered at 100 u/m² IV on days 1, 3, and 5. The infusion time for the liposome injection was approximately 90 minutes.

The trial enrolled patients aged 60 to 75 years and was conducted at 39 locations in the United States and Canada.

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.

“The magnitude of the CR plus CRi rate increase is promising and we may be one step closer to having a superior treatment option for patients with this devastating disease. The improvement in response rate portends well for a clinically meaningful survival benefit,” Gail Roboz, MD, associate professor of Medicine and Director of the Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital, said in the press release.

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, the first of which examined the drug as a first-line treatment for 126 patients with newly diagnosed AML who were aged 60 to 75 years.

In this study, the complete response rate with CPX-351 was 66.7% versus 51.2% with 7+3 (P = .07). Median event-free survival (EFS) and OS were also higher in the CPX-351 arm at 6.5 versus 2.0 months and 14.7 versus 12.9 months, respectively.

Positive data were also observed in a planned subset analysis of patients with secondary AML. There was a 6.0-month, statistically significant OS benefit in this subgroup (12.1 vs 6.1 months; HR = 0.46; P = .01). EFS was 4.5 months with CPX-351 versus 1.3 months with standard chemotherapy (HR = 0.59; P = .08). Response rates were 57.6% versus 31.6%, respectively (P = .06).

The authors of the study concluded that CPX-351 had an acceptable safety profile. Cytopenia recovery was longer for patients receiving CPX-351, with a higher incidence of grade 3/4 infections; however, there was not an accompanying increase in infection-related mortality or 60-day mortality.

The other phase II study examining CPX-351 included 125 patients aged 18 to 65 years with relapsed AML following an initial complete remission of ≥1 month. Patients were randomized in a 2:1 ratio to receive CPX-351 (100 u/m²; days 1, 3, and 5 by 90-minute infusion; n = 81) or investigators’ choice of salvage chemotherapy (n = 44). The control-arm regimens typically included cytarabine and an anthracycline in combination with one or more additional drugs.

The study protocol stratified patients using the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on age, cytogenetics, duration of first CR, and transplant history.

The study did not meet its primary endpoint of a statistically significant OS improvement at 1-year posttreatment. However, there was a statistically significant OS benefit with CPX-351 among the protocol-defined EPI poor-risk subset (HR = 0.55; P = .02). A higher response rate (39.3% vs 27.6%), EFS improvement (HR = 0.63; P = .08), and lower 60-day mortality rate (16.1% vs 24.1%) were also observed with CPX-351 in this poor-risk subgroup.

Commenting on the initial phase III outcomes, Scott Jackson, CEO of Celator, said, “We look forward to the continued follow up of these patients. If approved, CPX-351 will be well positioned to become the standard of care for high-risk AML patients. Further, we believe that significant opportunities exist for the additional development of CPX-351 as the backbone of treatment for AML and other blood cancers.”