Substitution of Pixantrone for Doxorubicin in CHOP Chemotherapy Regimen Produces High Rates of Complete Remissions and Long-Term Disease Free Survival in Patients with Relapsed/Refractory Aggressive NHL Who Previously Failed Frontline CHOP Therapy
SEATTLE, April 4, 2011 /PRNewswire/ — Cell Therapeutics, Inc. (“CTI”) (NASDAQ and MTA: CTIC) announced today that the April 2011 edition of the peer reviewed journal, Leukemia & Lymphoma (April 2011; 52(4): 620-628) published results of a phase I/II clinical trial evaluating the effect of cyclophosphamide, pixantrone, vincristine, and prednisone (“CPOP”) in treating patients with aggressive non-Hodgkin’s lymphoma (“NHL”) who relapsed following initial therapy with cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (“CHOP”). In the CPOP regimen, pixantrone substitutes for doxorubicin (H) in the CHOP regimen. Peter Borchmann, M.D., of the University Hospital of Cologne, led the study. CPOP produced high rates of complete remissions (“CR”) and overall response rate (“ORR”). In some patients, these remissions were highly durable despite patients having relapsed after receiving CHOP and other multi-agent therapies.
The study enrolled 35 patients in the phase I portion of the trial and 30 patients in the phase II portion of the trial. A major tumor response was reported for 80% and 73% of patients in phase I and II respectively, with 57% and 47% of the patients achieving a complete or unconfirmed CR. Median overall survival in the phase II portion of the trial was 17.9 months with four patients achieving notable long-term disease-free survival ranging from 55 to 77 months, despite in some cases having failed multiple prior regimens including stem cell transplantation. High response rates were also observed in the 43% of patients who had received prior rituximab as part of their front-line regimen (CHOP-R), with an ORR rate of 77% and CR rate of 54%. Myelosuppression was the most common toxicity. Side effects (grade 3/4) in phase I of the trial included febrile neutropenia (11%), grade 3/4 infections (3%), and cardiac failure (6%). In phase II of the trial, side effects (grade 3/4) included febrile neutropenia (20%), and cardiac failure (3%).
“Although there are a number of treatment regimens that have been studied as salvage therapies in patients with relapsed aggressive NHL, few have demonstrated a high proportion of complete responses and many of the remissions achieved are of relatively short duration,” said Jack W. Singer, M.D. Chief Medical Officer at CTI. “Patients who have completed a course of CHOP therapy are unable to be retreated with the same regimen due to the potential for severe heart toxicity when the lifetime limit of doxorubicin is exceeded. Pixantrone has substantially less cardiotoxicity than doxorubicin in animal models and was found to be adequately tolerated in patients treated with prior doxorubicin in phase I trials. The present study suggests that use of pixantrone with CPOP not only offers a high response rate, but in some patients these responses had impressive durability. Four patients in the study had unmaintained remissions of between 4+ and 6+ years duration following CPOP, which is highly unusual in the setting of treating relapsed disease. The opportunity to re-challenge patients with a CHOP-like regimen, using pixantrone instead of doxorubicin after relapse from initial therapy with CHOP indicates that pixantrone-based regimens may represent a new approach to managing relapsed aggressive NHL. A Phase III clinical trial with pixantrone in this setting has recently been initiated, the PIX-R TRIAL(TM).”
About Pixantrone and the CPOP Regimen
This trial examines the safety and potential efficacy of pixantrone (CPOP) when it is used in place of doxorubicin in the CHOP regimen for patients with relapsed aggressive NHL who had failed at least one prior treatment.
Patients received up to six cycles of CPOP therapy. Cycles were every 21 days. The phase I dose level was 80-180 mg/m for phase I, and the phase II recommended dose was 150 mg/m2. For both phases, dosing of the other agents in the CHOP regimen was standard; cyclophosphamide at 750 mg/m2 IV, vincristine at 1.4 mg/m2 IV on day one, and prednisone or prednisolone 100 mg orally on days one through five.
PIX-R TRIAL(TM) Design
The PIX-R trial is designed to be a randomized, multicenter study comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (“DLBCL”) or DLBCL transformed from follicular lymphoma who have received one to three prior lines of therapy, including CHOP-R or an equivalent regimen. The patients to be enrolled in the PIX-R trial cannot be eligible for high-dose (myeloablative) chemotherapy and stem cell transplant, but patients who relapse after such a procedure are eligible. The co-primary endpoints for the PIX-R trial are progression free survival and OS with secondary endpoints including ORR (ORR equals complete responses plus partial responses), complete response rate and safety. CTI is targeting to enroll 350 patients over 18 months in the PIX-R trial.
The PIX-R trial may serve as either a post-marketing commitment trial or as a follow-on pivotal trial depending on the outcome of a formal appeal that CTI submitted to the U.S. Food & Drug Administration’s (the “FDA”) Office of New Drugs in the FDA’s Center for Drug Evaluation and Research in December 2010 regarding its 2010 decision about CTI’s new drug application (the “NDA”) for pixantrone. The NDA for pixantrone was based on the results of the PIX 301 trial, a randomized trial comparing pixantrone as monotherapy to a choice of standard single-agent chemotherapy in relapsed/refractory aggressive NHLpatients. CTI expects a decision regarding its appeal in the second quarter of 2011.
In Europe, the Marketing Authorization Application (the “MAA”) for pixantrone as monotherapy for patients with relapsed or refractory aggressive NHL is currently under review by the European Medicines Agency (the “EMA”) based on the pixantrone (PIX 301) phase III study results.
Pixantrone is a novel aza-anthracenedione that has distinct structural and physio-chemical properties that make its anti-tumor activity unique in this class of agents. Similar to anthracyclines, pixantrone inhibits Topo-isomerase II but unlike anthracyclines–rather than intercalation with DNA–pixantrone alkylates DNA–forming stable DNA adducts, with particular specificity for CpG rich, hyper-methylated sites. These structural differences resulted in significantly enhanced anti-lymphoma activity compared to doxorubicin in preclinical models. In addition, the structural motifs on anthracycline-like agents that are responsible for the generation of oxygen free radicals and the formation of toxic drug-metal complexes have also been modified in pixantrone to prevent the binding of iron and perpetuation of superoxide production–both of which are the putative mechanism for anthracycline induced acute cardiotoxicity. These novel pharmacologic differences may allow re-introduction of anthracycline like potency in the treatment of relapsed/refractory aggressive lymphoma without unacceptable rates of cardiotoxicity.
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 www.CellTherapeutics.com.
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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 and the trading price of CTI’s securities. 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 prove safe and effective for the treatment of relapsed or refractory, aggressive NHL, that the substitution of pixantrone for doxorubicin in the CHOP regimen may not produces complete remissions and long-term disease free survival in patients with relapsed or refractory, aggressive NHL who previously failed frontline CHOP therapy, that there may not be a correlation between CR/CRu’s and progression free survival, that pixantrone may not show an overall improvement rate in survival for patients independent of factors known to influence survival, that CTI cannot predict or guarantee the pace or geography of enrollment of its clinical trials or the total number of patients enrolled, that CTI cannot predict whether PIX-R will serve as either a post-marketing commitment trial or as a pivotal trial, that CTI cannot predict the outcome of the formal dispute resolution process with the FDA, that the FDA may not make its decision on the appeal in the second quarter of 2011, that the FDA may request additional clinical trials, CTI’s ability to continue to raise capital as needed to fund its operations, competitive factors, technological developments, costs of developing, producing and selling pixantrone, and the risk factors listed or described from time to time in CTI’s filings with the Securities and Exchange Commission including, without limitation, CTI’s most recent filings on Forms 10-K, 10-Q and 8-K. Except as may be required by law, CTI does not intend to update or alter its forward-looking statements whether as a result of new information, future events, or otherwise.
SOURCE Cell Therapeutics, Inc.