Liposome Injection Receives Fast Track Designation for AML

Jorge Cortes, MD, ASCO president

Jorge Cortes, MD

The FDA has granted a Fast Track Designation to CPX-351, a liposomal formulation of cytarabine and daunorubicin, for the treatment of elderly patients with relapsed acute myeloid leukemia (AML).

The designation is meant to expedite the development and review of CPX-351, which encapsulates cytarabine and daunorubicin at a 5:1 molar ratio. Celator will now have open communication with the FDA throughout the development process, and can file sections of a New Drug Application on a rolling basis.

“We are pleased that the FDA has granted Fast Track status for CPX-351 for the treatment of elderly patients with secondary AML,” said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals, in a statement.

The designation is 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.¹

Patients in the control arm received 100 mg/m²of IV cytarabine daily by continuous infusion for 7 days and 60 mg/m²of daunorubicin on days 1, 2, and 3. Those randomized to the investigational arm were administered CPX-351 at 100 u/m²IV on days 1, 3, and 5. The infusion time was approximately 90 minutes.

The primary endpoint for the study was complete response (complete remission [CR] + CR with incomplete blood count recovery [CRi]). The secondary endpoints were CR+CRi duration, overall survival (OS), and event-free survival (EFS).

The complete response rate with CPX-351 was 66.7% versus 51.2% with standard chemotherapy (P= .07). Median 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.

Ten patients in the control arm who had persistent AML following treatment crossed over to the experimental arm and were administered CPX-351 as salvage therapy. Four of these patients had responses (3 CR, 1 CRi) and the OS data for the study was potentially confounded, as all four patients were alive for >1 year.

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).

“AML patients treated with CPX-351 had a higher likelihood of remission, without evidence of increased early mortality, than patients treated with standard chemotherapy. In addition, CPX-351 led to longer survival in the large subset of patients whose AML arose out of a previously diagnosed hematologic disorder or a history of prior cytotoxic treatment, commonly referred to as secondary AML,” said lead author Jeffrey Lancet, MD, section chief of Leukemia at the H. Lee Moffitt Cancer Center and Research Institute, in a statement released when the results were published.

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.²Patients 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.

“Patients with first relapse AML have generally a poor prognosis, with a limited likelihood of response following salvage treatment. This is particularly true for patients classified by the EPI as poor-risk upon entering the trial,” said lead investigator Jorge Cortes, MD, deputy chair of the Department of Leukemia at The MD Anderson Cancer Center. “We were very pleased to see promising response rates in this difficult-to-treat population.”

Cortes et al considered the toxicities associated with CPX-351 to be manageable.

Patients receiving CPX-351 had slower neutrophil and platelet recovery. The most common nonhematologic grade 3/4 adverse events in the CPX-351 arm included febrile neutropenia, bacteremia, pneumonia, fatigue, hypokalemia, and pyrexia.

“The insights from this phase II study were very relevant as we designed our phase III pivotal study in older patients with secondary AML, commented Arthur C. Louie, MD, chief medical officer of Celator.

The ongoing randomized phase III study (301; NCT01696084) is comparing frontline CPX-351 with standard 7+3 chemotherapy (cytarabine and daunorubicin) in patients aged 60 to 75 years with relapsed AML. Patients are receiving the same dosages at the same schedules as in Lancet et al’s phase II study with matching treatment arms.

The study has completed enrollment and, according to Jackson, response data should be available in the second quarter of this year. Data for the primary endpoint, overall survival, should be available in the first quarter of next year.

“If our phase III study, comparing CPX-351 to the current standard of care, is successful, the Fast Track Designation may provide an added benefit of facilitating the NDA review process,” said Jackson.

References

Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML [published online March 31, 2014].Blood. 2014;123(21):3239-3246.

2. Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML.Cancer. 2015;121(2):234-242.