Til NASDAQ OMX Copenhagen A/S
Meddelelse nr. 08-12 / København, 17. maj 2012


København, Danmark – 17. maj 2012 – Topotarget A/S (NASDAQ OMX: TOPO) meddelte
i dag, at kliniske data (videnskabelige resuméer) for belinostat blev
offentliggjort for ASCO 2012 den 16. maj 2012.


Nedenfor ses de videnskabelige kliniske resuméer, der nu er tilgængelige på
ASCO’s hjemmeside (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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Baggrundsoplysninger


Om Topotarget

Topotarget (NASDAQ-OMX: TOPO) er et internationalt biofarmaceutisk selskab med
hovedsæde i København. Selskabet beskæftiger sig med klinisk udvikling og
registrering af onkologiprodukter. Topotarget fokuserer i samarbejde med
Spectrum Pharmaceuticals, Inc., på udviklingen i de pivotale studier af dets
førende lægemiddelkandidat, belinostat, som har vist positive resultater som
enkeltstofbehandling af blodkræftsygdomme samt positive resultater i solide
kræftsvulster. Belinostat kan anvendes i kombination med fulde doser kemoterapi
og er i registreringsfase inden for PTCL (perifert T-celle lymfekræft). For
yderligere oplysninger henvises til www.topotarget.com.


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Meddelelse nr. 08-12 Kliniske data for belinostat til ASCO 2012.pdf