Nonetheless, despite the fact that the therapeutic window of valproic acid is very wide, there is a clear dose effect relationship with depressed level of consciousness therefore we felt important to investigate if doses selleck Palbociclib below 60 mg Kg which produce grade III toxicity lead to histone hyperacetylation in tumors. These facts led to us to perform this phase I study to find the adequate biological dose of magnesium valproate. The advent of the so called targeted therapies has led to reconsider the appropriateness of the traditional or classi cal designs for phase I trials which takes into account tox icity as the most important parameter for dose escalation. Instead some authors have proposed that the endpoint in phase I studies of targeted therapies should be a change in the level or activity of the target or enzyme or other surro gate marker.
Because it is clear that the antiprolifera tive, differentiating and or pro apoptotic effects of HDAC inhibitors result from the histone hyperacetylation it seems logical to evaluate the acetylation status of H3 and H4 histones as the endpoint of the trial. On the other hand, not necessarily, the highest hyperacetylation should occur at the higher dose of the tested agent, being possible that a plateau in the effect can be seen in a range of doses that do not produce limiting toxicity. In this sense, the concept of adequate instead of the optimal biological dose emerges because, by one hand, the number of patients required for finding the optimal dose may be to high for an agent that by itself is expected to produce a negligible clinical response rate or tumor shrinkage which equate to expose a larger number of patients to a potentially ineffective agent by its own.
Another issue for selecting adequate instead of optimal dose design is the fact that it allows investigators to quickly proceed to phase II trials. Perhaps the only situation where an optimal dose design is preferred accounts when the study drug is planned to proceed to larger phase III tri als. On this basis, we opted to perform an adequate dose phase I. To our surprise, using doses as low as 20 40 mg kg, the biological effect was observed, being remarkable that no patient presented any grade 3 event. In nine patients, depressed level of consciousness was grade 2. Molecular efficacy in terms of H3 and H4 hyperacetyla tion in tumors was observed in most patients. in fact if we take into Carfilzomib account the effects on H3, at 20 mg Kg 2 out of 2 evaluated had hyperacetylation, 3 out of 4 at 30 mg Kg, and 4 out of 4 patients at 40 mg Kg. For H4 a very similar pattern emerged 2 2, 3 4 and 2 4 had hyperacetylation at 20 mg, 30 mg and 40 mg Kg. When evaluating for both H3 and H4 acetylation the numbers are 2 2, 2 4, and 2 4.