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In JCO, Danusertib results of a Phase 1 trial. Phase 2 in patients with lung cancer and other solid tumors ongoing.

Nerviano Italy, 8 October 2009 - Nerviano Medical Sciences today announced a publication in the peer-reviewed scientific journal, Journal of Clinical Oncology (*), of the first clinical trial performed in man in patients with advanced solid tumors with Danusertib (PHA-739358). "Danusertib, developed by Nerviano Medical Sciences, inhibits all Aurora kinases which are essential in cell cycle progression and mitosis, and are over expressed in many malignancies" states Francesco Colotta NMS R&D Director.

This Phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of Danusertib administered intravenously on days 1, 8, and 15 every 4 weeks in 6-hour and 3-hour infusion schedules at doses which were progressively increased. Fifty patients with advanced cancers refractory to standard therapies were treated.

The recommended dose for phase II was defined as 330 mg/m2 for the 6-hour IV infusion schedule. It would have been lower with the 3-hour schedule, and therefore a recommended dose was not defined with it.
In terms of pharmacokinetics, the systemic exposure increased linearly with the dose and was not influenced by the infusion duration. Inhibition of histone H3 phosphorylation, witnessing the inhibition of Aurora kinase B, was observed in skin biopsies starting from the dose of 190 mg/m2.
This study demonstrated that treatment with PHA-739358 was well tolerated. In addition, disease stabilization was reported in 24% of all evaluable patients and lasted 6 months or more for 5 patients. One of them, included because of a progressive non-small cell lung cancer, went off study while still stable after more than 2 years of treatment.
Dr Bernard Laffranchi, head of Clinical Research, said: "These indications of antitumor activity, also present in the second phase I study performed in solid tumors in the USA and which will be published soon, warranted confirmation in subsequent studies".
This trial was conducted in collaboration with Dr Hans Gelderblom of theUniversity Medical Center in Leiden, Dr Maja De Jonge and Prof. Jaap Verweij of the Erasmus Medical Center in Rotterdam.
"Danusertib is a highly innovative drug: it was in fact the first Aurora kinase inhibitor to be tested in man and it remains the most advanced in clinical development with several Phase 2 trials ongoing. The results obtained so far in more than 500 patients indicate that Danusertib has optimal pharmacokinetic profile, good tolerability and induce disease stabilization even long lasting in severely advanced cancer patients. We are highly encouraged by these results to continue with conviction and faith our ongoing Phase 2 trials in multiple types of cancers" Colotta says.

(*) Journal of Clinical Oncology http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.21.6655

 
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