To NASDAQ OMX Copenhagen A/S
Announcement No. 08-12 / Copenhagen, May 17, 2012
Copenhagen, Denmark – May 17, 2012 – Today Topotarget A/S (NASDAQ OMX: TOPO) announced that abstracts on belinostat clinical data were released for ASCO 2012 on May 16, 2012.
Below are the abstracts that are now available on ASCO’s website (www.asco.org).
A phase (Ph) 1/2 study of belinostat (Bel) in combination with cisplatin, doxorubicin and cyclophosphamide (PAC) in the first line treatment of advanced or recurrent thymic malignancies.
Authors: Anish Thomas, Arun Rajan, Sean Khozin, Eva Szabo, Corey Carter, Udayan Guha, Michell Manu, Arlene Berman, Tricia Kunst, Richard Piekarz, David S. Schrump, Giuseppe Giaccone.
Affiliations: Medical Oncology Branch, Surgery Branch and CTEP, National Cancer Institute, NIH, Bethesda MD, USA.
Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models.
Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS<2, measurable disease, and adequate renal, hepatic, and hematopoietic functions were eligible. Ph1 evaluated safety and tolerability of the combination using increasing dose levels (DL) of Bel (1000-2000 mg/m² over 48 h CIVI) and PAC (50/50/500 mg/m² IV/cycle) (3+3 dose escalation schema), administered every 21 days for no more than 6 cycles followed by optional maintenance Bel every 4 weeks. Primary endpoint of Ph2 is overall response rate (ORR).
Results: From March 2010 to January 2012, 13 patients were enrolled [7 thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 mg/m2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase 2 dose (RP2D) was set at DL1. Most common Grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection.
Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.
Topotarget A/S comments: This is a phase I/II trial where belinostat is given as a continuous i.v. infusion over 48 hours in combination with standard chemotherapy given to patients with advanced or recurrent thymic malignancies. The recommended dose of belinostat for the phase II part of the protocol was determined to be 500 mg/m2 per day for two days. Despite this being an early stage of the protocol, several responses have been seen. Out of the 13 enrolled patients, 1 had CR, 6 had PR, and 6 SD. Furthermore, four patients previously deemed unresectable underwent surgical resection. These early clinical results indicate significant antitumor activity that may warrant the initiation of additional studies. The results also supports the evaluation of alternative administration methods for belinostat, and we are looking forward to obtaining additional data as the phase II part of the trial is still enrolling patients.
A Phase II Study of PXD101 (belinostat) in Relapsed and Refractory Aggressive B-Cell Lymphomas (rel/ref ABCL): SWOG S0520.
Authors: Daniel O. Persky, Steven H. Bernstein, Bryan Goldman, Lisa M. Rimsza, Richard I. Fisher, Thomas P. Miller
Affiliations: 1University of Arizona Cancer Center, Tucson, AZ, USA
Background: The mechanism of action of histone deacetylase inhibitors (HDACI) in lymphomas is unknown. Loss of major histocompatibility Class II antigens (MHC II) in diffuse large B-cell lymphomas (DLBCL) is associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHC II is controlled by CIITA, which is itself regulated by histone acetylation. We hypothesized that PXD101 (belinostat), an HDACI, would increase MHC II expression in tumor cells, enhance immunosurveillance, and improve outcome.
Methods: The primary objective was to evaluate response rate and toxicity of PXD101 in patients (pts) with rel/ref ABCL with up to 5 prior chemotherapy regimens. Secondary objectives were to estimate the 6-month progression-free survival (PFS) and to assess MHC II and TIL. In a two-stage design, if at least 1 response was observed in the first 20 pts, another 20 pts would be accrued. PXD101 was administered at 1000 mg/m2 IV days 1-5 of 21-day cycle for up to 2 years.
Results: The study was closed due to lack of response in the first stage. Of 22 pts enrolled, 19 were evaluable. Median age was 69, and median number of prior treatments was 3 (range 1-4). 18 pts had DLBCL and 1 had B-cell lymphoma, unclassifiable. Grade 4 toxicities were fatigue and muscle weakness (1) and lymphopenia (1). Despite initially finding no responses, 2 partial responses (PR) were observed at 5 and 13 months after registration, for an overall response rate (95% CI) of 10.5% (1.3-33.1%); 3 pts had stable disease (SD), lasting 4.7, 30.4+, and 40.7+ months. With a minimum follow-up of 2.0 yrs, median and 6-month PFS are 2.1 months (1.3-3.8) and 21.1% (6.6-41.0%); median and 6-month overall survival are 13.4 months (95% CI not yet estimable) and 57.9% (33.2-76.3%), respectively.
Conclusions: Despite early closure, delayed PR was seen in 2 of 19 pts, and 2 pts had SD lasting 30.4+ and 40.7+ months. Therefore 4 pts (21%) who did not achieve complete response, very unusually, have not progressed for ≥2.0 yrs. Standard chemotherapy response assessment may not be appropriate for HDACI, which may require development of new biomarkers of response. Further work focuses on combining HDACI with standard chemotherapy.
Topotarget A/S comments: In this study, patients with relapsed/refractory aggressive B-cell lymphoma were treated with belinostat given as monotherapy. The study was closed after 22 patients had enrolled as no responses were seen. However, in the follow-up period, 2 patients had partial remission and 3 patients had stable disease for a prolonged period of time. In all, 4 patients (21%) had no progression for >2 years. The authors conclude that additional work is needed where belinostat is given in combination with standard chemotherapy. It is important to note that patients enrolled into this trial had B-cell lymphoma which is a completely different disease compared to PTCL which is a T-cell lymphoma. The lack of initial responses amongst patients with B-cell lymphoma does not have an impact on the outcome of the treatment of patients with PTCL in the ongoing pivotal PTCL trial.
Topotarget A/S
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Background information
About Topotarget
Topotarget (NASDAQ-OMX: TOPO) is an international biopharmaceutical company headquartered in Copenhagen, Denmark, dedicated to clinical development and registration of oncology products. Topotarget focuses, in collaboration with Spectrum Pharmaceuticals, Inc., on the development in pivotal studies of its lead drug candidate, belinostat, which has shown positive results as a monotherapy treating hematological malignancies and positive results in solid tumors. Belinostat may be used in combination with full doses of chemotherapy, and is in a pivotal trial within PTCL (peripheral T-cell lymphoma). For more information, please refer to www.topotarget.com.
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This announcement may contain forward-looking statements, including statements about our expectations of the progression of our preclinical and clinical pipeline including the timing for commencement and completion of clinical trials and with respect to cash burn guidance. Such statements are based on management's current expectations and are subject to a number of risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Topotarget A/S cautions investors that there can be no assurance that actual results or business conditions will not differ materially from those projected or suggested in such forward-looking statements as a result of various factors, including, but not limited to, the following: The risk that any one or more of the drug development programs of Topotarget A/S will not proceed as planned for technical, scientific or commercial reasons or due to patient enrolment issues or based on new information from non-clinical or clinical studies or from other sources; the success of competing products and technologies; technological uncertainty and product development risks; uncertainty of additional funding; Topotarget A/S' history of incurring losses and the uncertainty of achieving profitability; Topotarget A/S' stage of development as a biopharmaceutical company; government regulation; patent infringement claims against Topotarget A/S' products, processes and technologies; the ability to protect Topotarget A/S' patents and proprietary rights; uncertainties relating to commercialization rights; and product liability exposure. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise, unless required by law.
