Phase II Results Demonstrate Long Lasting Tumour Responses for Pixantrone in Relapsed Aggressive NHL
Tuesday August 26, 2:08 am ET
BRESSO, Italy, Aug. 26 /PRNewswire-FirstCall/ -- Novuspharma SpA (Nuovo Mercato: NOV.MI), a biopharmaceutical company focused on developing novel treatments for cancer, today announces the publication of the results of a phase II study for Pixantrone (BBR 2778) in relapsed aggressive non-Hodgkin's lymphoma (NHL). These results demonstrated an overall response rate of 30%, with 17% of patients experiencing a complete disappearance of their tumour following Pixantrone therapy. Response to treatment was long lasting, averaging 11 months, with some patients still in remission 24 months following treatment. Grade 4 neutropenia was the most frequently reported side effect, observed in 13 patients and requiring dose reduction in only 5 patients. The results were published in the August issue of Haematologica, Journal of Haematology (Borchmann et al., Volume 88, No. 8), in a paper entitled: Phase-II study of the new aza-anthracenedione BBR 2778 in patients with relapsed aggressive non-Hodgkin's lymphomas.
"We are extremely encouraged by the high rate of durable tumour responses revealed by these results, especially when one considers that the majority of these patients were elderly, had chemotherapy-resistant disease and almost all had failed prior anthracycline-containing regimens," noted Silvano Spinelli, Chief Executive Officer of Novuspharma.
"This impressive efficacy, coupled with the low incidence of cardiac-related events despite re-exposure to therapeutic doses of Pixantrone, supports the preclinical profile which suggested that Pixantrone may be less cardiotoxic and more effective than existing anthracyclines and anthracenediones. Taken together with our phase I experience in a similar population of patients with aggressive NHL, this study increases our experience with single-agent Pixantrone to 42 patients where we have observed 7 complete remissions and 5 partial remissions. We believe this data will serve as the basis for planning a pivotal trial in the third line treatment setting for aggressive NHL, which we would aim to initiate early next year."
Trial design and patient characteristics
This study was an open-label, non-randomised, non-comparative, multicentre phase II trial, which enrolled patients with relapsed aggressive NHL, as defined by the REAL classification. Single agent Pixantrone was administered at 85 mg/m(2) on day 1, 8 and 15 of a 4-week cycle. Pixantrone belongs to the DNA intercalator family of chemotherapy agents, which include the widely used anthracyclines and anthracenediones. These agents are associated with a high rate of tumour responses in blood borne tumours such as lymphoma and are potentially curative in front-line therapy. However, the currently marketed agents from this class suffer from cumulative cardiotoxicity, which prevents them being used in those patients who relapse. Pixantrone was designed by scientists at Novuspharma by modifying the structure of the currently marketed DNA intercalators to remove those portions of the molecules responsible for cardiotoxicity, while retaining those responsible for anti-tumour activity.
Of the 33 patients enrolled in the trial, 78% had chemotherapy-resistant disease, having received 2 or more prior chemotherapy regimens, with their cancer progressing within 123 days following their last treatment on average. Patients had previously received 300mg/m2 of anthracycline on average (range 100-600mg/m2) which would typically make them ineligible for further treatment with currently marketed anthracycline agents. Pixantrone was considered as therapy for these relapsed patients due to the potentially superior cardiac safety profile it displayed in preclinical studies compared to doxorubicin and mitoxantrone. Of the 33 patients enrolled, 22 (67%) were over the age of 65, 25 had advanced stage disease (stage III or IV) and 15 had extra-nodal disease (i.e. their cancer had spread from the lymphatic system). Of the 33 patients enrolled, 7 had mantle cell lymphoma, which represents a particularly resistant and hard to treat form of lymphoma.
Efficacy and safety results
The primary objective of the trial was to evaluate the efficacy of Pixantrone in terms of the overall patient response rate (CR+PR) according to the WHO criteria. 30 patients were evaluable for a response, of which 5 achieved a complete response (CR) and 4 achieved a partial response (PR), representing an overall response rate of 30% (27% on an intent to treat basis). 5 additional patients achieved an unconfirmed partial response (PRu, i.e. a response determined by a single measurement but not confirmed 12 weeks later) and 3 patients achieved stable disease. Tumour responses were durable, lasting over 24 months (range 2.3 to 24+ months). Notably, of the 7 patients with mantle cell lymphoma, 6 experienced a response, with 1 patient achieving a CR and 5 patients having a PRu.
Additional objectives of the trial included an assessment of progression-free survival, overall survival and safety. Among the patients who responded to therapy, the average time to tumor progression was 11 months from the time of first response (2.3 to 24+ months). Follow-up is still ongoing. 19 patients had died of disease progression 12 months after study termination. The most frequently reported toxicity associated with Pixantrone treatment was neutropenia (depressed levels of white blood cells), with grade 4 neutropenia being seen in 13 of 33 patients (39%). Generally this was short lived, lasting a median of 7.5 days and could be easily controlled using immune cell growth factors. Five patients required dose reduction for neutropenia. One patient experienced grade 4 anemia, with no patients experiencing grade 4 thrombocytopenia (reduction in clot forming platelets).
Pixantrone's cardiac safety was assessed by using a MUGA-scan to monitor the left ventricular ejection fraction (LVEF) of the heart. An absolute decrease in LVEF greater than 10% and possibly treatment related was seen in 3 patients and this was accompanied by cardiac symptoms in 2 patients. All 3 of these patients had previously received the currently marketed DNA intercalators and 1 had a pre-existing cardiac condition. Such a low level of cardiac events is encouraging considering that the majority of patients had previously received their lifetime maximum permitted dose of DNA intercalators/anthracyclines and normally would have been precluded from receiving further treatment with these agents.
Novuspharma SpA and its merger agreement with Cell Therapeutics (CTI) Novuspharma, based in Bresso, Milan, is an emerging biopharmaceutical company leveraging its expertise in the field of oncology to discover and develop innovative new treatments for cancer. It has three products in clinical development and a dynamic research programme. Novuspharma was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, to exploit the R&D team's proven track record in product development. On June 17, 2003, Novuspharma announced it had signed a merger agreement with Cell Therapeutics (CTI) of Seattle. CTI is a public biopharmaceutical company, which markets TRISENOX® in the US and Europe and is developing XYOTAX(TM) (CT-2103), which is in pivotal phase III trials for non-small cell lung cancer.
Pixantrone (BBR 2778) and non-Hodgkin's lymphoma
Pixantrone is a DNA intercalator with improved efficacy and safety, which Novuspharma is developing for non-Hodgkin's lymphoma (NHL). NHL is caused by the abnormal proliferation of lymphocytes (immune system cells) and is estimated to affect more than 276,000 patients in the U.S. NHL can be broadly divided into two forms, indolent NHL (a slow growing, chronic disease) and aggressive NHL (an acute form). Novuspharma has proposed a pivotal development programme for Pixantrone in third-line aggressive NHL and is conducting a number of additional combination trials in both aggressive and indolent forms of the disease. |
