Publication on Pixantrone Preclinical Studies Demonstrates Reduced Cardiotoxicity Compared to Equiactive Doses of Doxorubicin and MitoxantroneInterim results in a randomized phase II/III clinical trial anticipated later this year
SEATTLE, June 26, 2007 /PRNewswire-FirstCall/ -- Cell Therapeutics, Inc. (CTI) announced the publication of preclinical studies, which demonstrate that treatment with pixantrone (BBR 2778) resulted in minimal or no significant cardiotoxicity, while doxorubicin and mitoxantrone induced significant cardiac damage. The studies compared the cardiac side effects of equiactive doses of pixantrone to doxorubicin and mitoxantrone in mice pre-treated with a cardiotoxic dose of doxorubicin as well as in mice without prior treatment. The article was published in the June 2007 journal Investigational New Drugs.
"In preclinical hematological tumor models pixantrone showed higher effectiveness and minimal or lack of cardiotoxicity as compared to mitoxantrone or doxorubicin. The findings reported in this article strongly support the clinical potential of pixantrone as a replacement for currently marketed anthracyclines. We hope our randomized phase II/III RAPID (PIX203) study in first-line aggressive NHL will confirm these preclinical results in patients and possibly diminish the most serious side effect associated with current standard treatments -- irreversible heart damage," said Gabriella Pezzoni, Ph.D., Scientific Director at Cell Therapeutics Europe S.r.l. (Milan).
In spite of their dose-dependent cardiotoxic effects, anthracyclines are still considered the standard of care because of their efficacy in several tumor types, including breast cancer, leukemia, and non-Hodgkin's lymphoma (NHL). Because of the irreversible nature of the cardiac damage that accompanies the use of currently marketed anthracyclines, patients who are treated with these agents are subject to a maximum cumulative life-time dose, which may result in premature discontinuation of therapy and limit the physician's ability to use this active class of anti-cancer drugs following disease relapse. Pixantrone, a novel anthracenedione analog, was developed to reduce treatment-related cardiotoxicity while retaining efficacy.
These findings suggest that pixantrone may have potential use in patients heavily pre-treated with anthracyclines, in patients with cardiac disorders, and in patients who might benefit from longer-term anthracycline therapy than can be administered with currently approved agents.
Details of the Preclinical Studies
The studies were designed to evaluate the potential cardiotoxicity of pixantrone in mice pre-treated with doxorubicin and to evaluate the potential cardiotoxicity of pixantrone as a single agent compared to doxorubicin and mitoxantrone. Mice pre-treated with a cardiotoxic dose of doxorubicin were then administered a saline placebo control, doxorubicin, pixantrone, or mitoxantrone. Mice that received a second cycle of doxorubicin or mitoxantrone developed marked or severe cardiotoxicity. Mice that received the placebo or pixantrone as the second cycle had slightly increased mean total cardiotoxicity score, indicating that earlier exposure to doxorubicin may continue to damage the heart. While cardiotoxicity observed in the mice treated with pixantrone was not statistically different compared to mice treated with placebo, it was statistically different from that observed in the groups treated with doxorubicin or mitoxantrone. In the mice pre-treated with doxorubicin, a second cycle of mitoxantrone or pixantrone resulted in mortality of 33 percent and 27 percent, respectively.
Mice that received two consecutive cycles of pixantrone as a single agent showed no significant cardiotoxicity and had a mean total toxicity score that was statistically similar to the placebo. The severity and extent of observed damage to heart tissue was minimal and considered reversible. However, mice receiving two cycles of doxorubicin or mitoxantrone experienced marked cardiac damage that was statistically worse than that observed in the pixantrone-treated mice. In addition, mortality ranged from 40 to 68 percent in mice receiving two cycles of doxorubicin to 68 percent in mice receiving two cycles of mitoxantrone. In mice receiving two cycles of pixantrone, the mortality rate was 0 percent.
Pixantrone in Clinical Studies
There are currently two clinical studies of pixantrone in aggressive NHL patients, including a phase III single agent trial, known as EXTEND and a phase II/III combination study, known as RAPID. The EXTEND trial explores the role of single agent treatment as a salvage regimen in patients with relapsed aggressive NHL who have failed at least two prior treatment regimens. Patients are randomized to receive either pixantrone or another single-agent drug of physician's choice currently used for the treatment of this patient population. An interim look is planned for the summer of 2007.
The RAPID trial is a first-line randomized phase II/III study of the CHOP-R versus CPOP-R in previously untreated aggressive NHL patients. The study is evaluating replacing doxorubicin in the standard CHOP-R combination regimen (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) with pixantrone as part of the CPOP-R regimen (cyclophosphamide, pixantrone, vincristine, prednisone, and rituximab). The objective of the study is to demonstrate similar objective response rates as the standard doxorubicin-based therapy with significantly less severe cardiac toxicities and other doxorubicin-related toxicities on the CPOP-R arm of the study. A total of 280 patients are expected to be enrolled.
The Company is awaiting feedback from the FDA on the design of a phase III trial of pixantrone for patients with indolent NHL. The trial, PIX303, will examine the complete remission rates and time to disease progression for the combination regimen of fludarabine, pixantrone and rituximab (FP-R) compared to the combination of fludarabine and rituximab (F-R) in the treatment of patients who have received at least one prior treatment for NHL. The trial is expected to enroll 300 patients.
Pixantrone is an investigational agent under development for the potential treatment of various hematological malignancies, solid tumors and immunological disorders. It was developed to improve the activity and safety of the anthracycline family of anti-cancer agents. Anthracyclines have been shown to be very active clinically in a number of tumor types. However, they are usually associated with cumulative heart damage that prevents them from being used in a large proportion of patients. Pixantrone has been designed to reduce the potential for these severe cardiotoxicities, as well as to potentially increase activity and simplify administration compared to the currently marketed anthracyclines.
About Cell Therapeutics, Inc.
Headquartered in Seattle, CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable. For additional information, please visit http://www.cticseattle.com.
This press release includes forward-looking statements that involve a number of risks and uncertainties, the outcome of which could materially and/or adversely affect actual future results. Specifically, the risks and uncertainties that could affect the development of pixantrone include risks associated with preclinical and clinical developments in the biopharmaceutical industry in general and with pixantrone in particular including, without limitation, the potential failure of pixantrone to have the same cardiotoxicity profile in humans as demonstrated in preclinical studies or to prove safe and effective for treatment of non-Hodgkin's lymphoma or other cancer, determinations by regulatory, patent and administrative governmental authorities, competitive factors, technological developments, costs of developing, producing and selling pixantrone, and the risk factors listed or described from time to time in the Company's filings with the Securities and Exchange Commission including, without limitation, the Company's most recent filings on Forms 10-K, 8-K, and 10-Q. Except as may be required by Italian law, CTI is under no obligation to (and expressly disclaims any such obligation to) update or alter its forward-looking statements whether as a result of new information, future events, or otherwise.
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CONTACT: Media, Dan Eramian, +1-206-272-4343, cell, +1-206-854-1200, forCell Therapeutics, Inc.; or Susan Callahan, +1-206-272-4472,, or Investors, Leah Grant, +1-206-282-7100,, both of Cell Therapeutics, Inc., fax,+1-206-272-4434; or Medical Information, 1-800-715-0944, firstname.lastname@example.org email@example.com firstname.lastname@example.org
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Posted: June 2007