Cell Therapeutics, Inc. (CTI), a biopharmaceutical company, has announced results from sub-set analyses of data from the phase III EXTEND, or PIX301, clinical trial of PIXUVRI (pixantrone). The analyses evaluated the efficacy of PIXUVRI in the subset of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL), as confirmed by central independent pathological review, who had failed 2 or 3 prior treatment regimens (third and fourth line in the licensed patient population).
Compared to physicians' choice of other agents given as monotherapy, single agent PIXUVRI resulted in 30 per cent of patients who had previously received rituximab achieving a complete or unconfirmed durable complete response lasting on average 9.5 months with 67 per cent of patients surviving at two years. In contrast, only 5.6 per cent of patients in the comparator arm achieved an unconfirmed complete response. The benefit of PIXUVRI has not be established in patients when used as 5th-line or greater chemotherapy.
These analyses were presented by Professor Ruth Pettengell, MD, St. George's Hospital, at the 18th Congress of the European Hematology Association (EHA) in Sweden.
Ruth Pettengell, M.D., of St. George's Hospital, University of London, the lead investigator for the EXTEND trial, said, "PIXUVRI is the first medicinal product approved in the EU for treatment of patients with aggressive B-cell NHL." Pettengell further added, "These subset analyses support PIXUVRI's use and benefit as a third and fourth line treatment, whether or not the patient was previously exposed to rituximab. Prior to PIXUVRI, treatment options were limited to palliative therapy or clinical trials. PIXUVRI may provide the ability to re-introduce effective salvage therapy even after patients fail standard aggressive second line treatment."
Additional highlights from these post-hoc analyses include: PIXUVRI demonstrated superior complete response rates and progression-free survival (PFS) in all the subgroups analysed:
In patients who had aggressive B-cell histology as determined by site pathologists only, who had failed two or three prior lines of therapy, PIXUVRI was more efficacious than physicians' choice of monotherapy, both in patients who had received prior rituximab and those who did not. Among the patients whose histology was confirmed by the panel and who had received rituximab prior to randomization, response rates and PFS were as follows for PIXUVRI compared to physicians' choice of therapy, respectively: CR/CRu=30.0 percent vs. 5.6 percent; ORR=45.0 percent vs. 11.1 percent; PFS=5.4 vs. 2.8 months.
In patients with aggressive B-cell NHL, there was a 48 percent improvement in PFS that were confirmed by central review compared to 15 percent improvement in PFS based on site determination. This suggests that the superior efficacy of PIXUVRI in the patients who had previously received rituximab was not due to inclusion of a disproportionate share of patients who could not be confirmed as having aggressive B-cell NHL on central pathological review.
In May 2012, the European Commission granted conditional marketing authorization for PIXUVRI as a monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive NHL based on the results of the EXTEND, or PIX301, pivotal randomized Phase 3 clinical trial. The benefit of PIXUVRI treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. The Summary of Product Characteristics (SmPC) has the full prescribing information, including the safety and efficacy profile of PIXUVRI in the approved indication. The SmPC is available at www.pixuvri.eu. CTI is currently accruing patients into a Phase 3 trial comparing PIXUVRI and rituximab with gemcitabine and rituximab in the setting of aggressive B-cell NHL. PIXUVRI does not have marketing approval in the United States.
PIXUVRI is a novel aza-anthracenedione with unique structural and physiochemical properties. Unlike related compounds, PIXUVRI forms stable DNA adducts and in preclinical models has superior anti-lymphoma activity compared to related compounds. PIXUVRI was structurally designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite -- both of which are the putative mechanisms for anthracycline induced acute and chronic cardiotoxicity. These novel pharmacologic properties allow PIXUVRI to be administered to patients with near maximal lifetime exposure to anthracyclines without unacceptable rates of cardiotoxicity.
Similar to accelerated approval regulations in the United States, conditional marketing authorizations are granted in the EU to medicinal products with a positive benefit/risk assessment that address unmet medical needs and whose availability would result in a significant public health benefit. A conditional marketing authorization is renewable annually. Under the provisions of the conditional marketing authorization for PIXUVRI, CTI will be required to complete a post-marketing study aimed at confirming the clinical benefit previously observed.
The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use has accepted PIX306, CTI's ongoing randomized controlled phase III clinical trial, which compares PIXUVRI-rituximab to gemcitabine-rituximab in patients who have relapsed after one to three prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant. As a condition of approval, CTI has agreed to have available the PIX306 clinical trial results by June 2015.
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