Findings confirm advantages of fixed-ratio drug delivery and lay the groundwork for Phase 2 trials already underway in first-line and first-relapse Acute Myeloid Leukemia (AML) settings
PRINCETON, N.J., Dec. 9 /PRNewswire/ -- Celator Pharmaceuticals today announced that a Phase 1 dose escalating study of CPX-351 (cytarabine:daunorubicin) Liposome Injection established the recommended dose for Phase 2 studies and confirmed preliminary observations of safety, enhanced pharmacokinetics and promising anti-tumor activity in patients with advanced leukemia. A final analysis of the Phase 1 data (abstract #2984) and supportive findings from a pre-clinical pharmacodynamic model (abstract #942) were presented at the 50th American Society of Hematology (ASH) Annual Meeting in San Francisco.
“In the Phase 1 trial, CPX-351 had a tolerability profile that appears better than conventional cytarabine/daunorubicin treatment and produced impressive anti-leukemic responses, including complete remissions (CRs) at and below the maximum tolerated dose, in relapsed and refractory patients,” said Eric J. Feldman, MD, of the Weill Medical College of Cornell University and New York-Presbyterian Hospital, the principal investigator in the study. “These encouraging results suggest that CPX-351 may offer advantages to conventional administration of these commonly used drugs. We are excited to participate in the two Phase 2 studies.”
In the study, complete remissions were observed in 11 of 47 patients, including 10 patients (9 CRs and 1 CRp - complete remission without full platelet recovery) of 44 with AML and 1 patient of 3 with acute lymphocytic leukemia (ALL) following treatment with CPX-351. Of the 10 AML CRs, 7 occurred at the two highest dose levels, although complete remissions were achieved at dose levels as little as one third of the maximum tolerated dose (MTD). Of note, 7 CRs were achieved in 22 patients in the 1st salvage setting (patients in first relapse or with refractory disease) and 3 CRs were achieved in 22 patients in the 2nd or greater salvage settings. In addition, CRs were observed in patients older than 70 years, in those with complex cytogenetic abnormalities, and in patients with prior cytarabine/anthracycline treatment.
“The standard of care for AML hasn’t changed in 30 years and there is an urgent need to improve treatment for both newly diagnosed and relapsed patients,” said Arthur Louie, MD, chief medical officer at Celator Pharmaceuticals. “We began enrolling patients in a Phase 2 study in newly diagnosed, elderly patients with AML and we expect to start enrollment soon in a Phase 2 study in patients with AML in first relapse.”
CPX-351 represents a new approach to developing drug combinations in which drug molar ratios with synergistic anti-tumor activity are encapsulated in a drug delivery vehicle and the desired ratio is maintained following administration using Celator’s proprietary CombiPlex(R) technology platform. CPX-351 has been granted orphan drug status by the U.S. Food & Drug Administration for the treatment of AML.
“CPX-351 incorporates two of the most active agents against AML in a manner that, as we’ve shown in this study, maintains ratio-dependent synergy after administration,” said Scott Jackson, chief executive officer, Celator Pharmaceuticals. “We believe this unique capability has the potential to improve treatment outcomes for patients and we are looking to our randomized Phase 2 trials for proof of this principle.”
The safety profile of CPX-351 observed in the study was considered favorable. The most frequent and severe adverse events were those related to potential or documented infections including fever, febrile neutropenia, bacteremia, pneumonia and sepsis, common occurrences in the treatment of patients with AML. Although, mortality related to treatment is normally an issue when treating AML patients, there were no deaths within 7 days of treatment and 6 deaths (13%) within 30 days of receiving CPX-351. The induction mortality seen in the Phase 1 study was deemed encouraging by investigators. Major GI toxicity was uncommon with only 4 patients experiencing grade 3 or greater nausea and vomiting or mucositis.
Pharmacokinetic data collected during the study confirmed the bioavailability of cytarabine and daunorubicin, demonstrated a prolonged half-life for both drugs and their metabolites, and confirmed that the synergistic ratio was maintained for more than 24 hours after infusion.
The Phase 1 study enrolled 37 patients with advanced AML, secondary AML and ALL, during the dose-escalation phase. The maximum tolerated dose was established at 101 units/m2. An additional 10 patients were recruited and treated at this dose level to confirm tolerability and collect preliminary data on efficacy, bringing the total trial enrollment to 47. The recommended dose for Phase 2 study was determined to be 101 units/m2 given as a 90 minute infusion on treatment days 1, 3, and 5.
These findings were supported by a separate pre-clinical study that was also reported at the ASH meeting. Using a bone marrow engrafted human leukemia xenograft model, investigators compared CPX-351 with conventional cytarabine/daunorubicin treatment. The study confirmed that CPX-351, unlike the conventional combination, produced prolonged exposure of CPX-351 in the bone marrow and evidence of direct uptake of CPX-351 by leukemia cells with subsequent intracellular release of the drugs. Exposure of leukemic cells to synergistic drug ratios was confirmed.
In November, Celator announced enrollment of the first patient in a randomized Phase 2 study of CPX-351 versus conventional cytarabine and daunorubicin (“7 + 3") in patients with newly diagnosed AML, between 60 and 76 years of age. A second Phase 2 study of CPX-351 in patients 18-60 years old with AML in first relapse is also being initiated.
About Acute Myeloid Leukemia (AML)
The National Cancer Institute defines AML as a quickly progressing disease in which too many immature white blood cells (not lymphocytes) are found in the blood and bone marrow. In 2008, the American Cancer Society’s Cancer Facts and Figures estimates 13,290 new cases of AML and 8,820 deaths.
About Celator
Celator(R) Pharmaceuticals, Inc., with locations in Princeton, NJ, and Vancouver, BC, is a privately held pharmaceutical company developing new and more effective therapies to treat cancer. CombiPlex(R), the company’s drug ratio technology platform, represents a novel approach that identifies molar ratios of drugs that will deliver a synergistic benefit, locks the desired ratio in a drug delivery vehicle that maintains the ratio in patients with the goal of improving clinical outcomes. The company pipeline includes: CPX-1 (a liposomal formulation of irinotecan:floxuridine), currently in Phase 2 in patients with colorectal cancer; CPX-351 (a liposomal formulation of cytarabine:daunorubicin), currently in Phase 2 in patients with acute myeloid leukemia; CPX-571 (a liposomal formulation of irinotecan:cisplatin), a preclinical stage compound; and multiple research programs. Based on the applications of CombiPlex, Celator is positioned to advance a broad pipeline of combination therapies involving both previously approved and novel drug agents. For more information, please visit the company’s website at www.celatorpharma.com.
List of abstracts:
ASH Abstract # 942
Mayer L, Wahseng L, Dos Santos N, et al. Synergistic cytarabine:daunorubicin ratios delivered by CPX-351 to human leukemia xenografts is associated with liposome-mediated bone marrow drug accumulation, intracellular delivery of encapsulated agents to leukemia cells, and increase efficacy.
Poster presented Saturday, December 6, 2008.
ASH Abstract # 2984
Feldman EJ, Lancet J, Kolitz EJ, et al. Phase 1 study of a liposomal carrier (CPX-351) containing a synergistic, fixed molar ratio of cytarabine (Ara-C) and daunorubicin (DNR) in advanced leukemias.
Poster presented Monday, December 8, 2008.
CONTACT: Mike Beyer of Sam Brown, Inc.,+ 1-773-463-4211,
beyer@sambrown.com
Web site: http://www.celatorpharma.com//
