Cell Therapeutics, Inc. (CTI) announced the final clinical trial design of a randomized pivotal trial of pixantrone for the treatment of Diffuse Large B-Cell Lymphoma (DLBCL) following discussions with the US Food and Drug Administration's (the FDA) Division of Haematologic Products (the DHP). The new clinical trial, referred to as the PIX-R or PIX 306 trial, will compare a combination of pixantrone plus rituximab to a combination of gemcitabine plus rituximab in patients with relapsed or refractory DLBCL who have received one to three prior lines of therapy, utilizing Progression Free Survival (PFS) and Overall Survival (OS)as co-primary endpoints of the study.

The PIX-R trial is targeting to enroll approximately 350 patients over 18 months and will include patients who have failed at least one line of previous therapy and patients who are not candidates for myelo-ablative chemotherapy and stem cell transplant. During its discussions with the DHP the Company was advised that only OS would be acceptable for a formal Special Protocol Assessment (SPA) agreement, however the DHP noted that the Company could conduct a study utilizing PFS along with OS as co-primary endpoints which would be an acceptable design outside of the formal SPA process. Regulatory acceptability will depend on the magnitude of the difference between the trial study arms as well as a risk and benefit analysis.

“CTI has worked with the DHP since August on an appropriate clinical trial design that may serve as either a post-marketing commitment trial or as a follow-on pivotal trial depending on the outcome of an appeal of CTI's new drug application for pixantrone based on the PIX 301 trial at the FDA's Office of New Drugs,” stated James A. Bianco, MD, CEO of Cell Therapeutics.

“We believe that pre-clinical data and results from a randomized clinical trial have already demonstrated synergy exists between pixantrone and rituximab when they are used in combination. We believe that pixantrone administered as a single agent had a significant effect on prolonging PFS with an accompanying trend in OS in the PIX 301 trial. Given these results and the similar patient population in the PIX-R trial, including the choice of comparator regimen, we believe this trial has the potential to establish the clinical benefit of pixantrone in this patient group to fulfill an important unmet medical need,” added Dr Bianco.

In December 2010, CTI submitted a formal appeal to the FDA's Office of New Drugs (OND) in the FDA's Centre for Drug Evaluation and Research 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 Non-Hodgkin's lymphoma (NHL) patients. CTI recently met with the OND to discuss the appeal. The OND requested, and CTI plans to supply the FDA with, additional analyses from the PIX 301 trial. CTI expects a decision regarding its appeal early 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.

The PIX-R trial is designed to be a randomized, multi-centre study comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients with relapsed or refractory 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 PFS and OS with secondary endpoints including overall response rate (ORR equals complete responses plus partial responses), complete response rate and safety. To date, over 100 large U.S.-integrated oncology sites have signed up to participate in the PIX-R trial and 40 of such sites are preparing to initiate enrollment when the trial begins, which may be as early as later this month. CTI is targeting to enroll 350 patients over 18 months in the PIX-R trial.

CTI plans to perform the primary analysis of PFS first, which, depending on the outcome of CTI's appeal with the OND, could serve as the basis for resubmission of the NDA for pixantrone under accelerated approval regulations. Co-primary endpoints allow the analysis and reporting of PFS without a statistical penalty while the trial data matures and before OS is analyzed. OS, as the co-primary endpoint, will be analyzed at the end of the trial.

Pixantrone is a novel aza-anthracenedione that has distinct structural and physio-chemical properties that make its anti-tumour 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 and forms 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 diffuse large lymphoma without unacceptable rates of cardiotoxicity.

CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable.