Tissue mineralization produced in rats administered the MEK inhibitor PD0325901 provides a case study of how a unique and serious toxicity observed in preclinical safety testing was effectively managed to allow progression of an experimental drug into human clinical trials. A number of key factors were critical for allowing continued development of this compound to occur, rather than early termination. PD0325901 represented a novel and targeted therapeutic agent for the treatment of various solid tumors, thereby allowing a high risk-benefit ratio to exist due to the significant unmet medical need posed by cancer. Phase I oncology trials typically occur in cancer patients with limited treatment options. Therefore, the barriers to entry for novel anticancer agents in the clinic are generally lower than for phase I trials involving healthy volunteers and therapies for non - life - threatening indications.

Early in the toxicology program with PD0325901, lesions observed in rats were similar to those seen with vitamin D toxicity, and serum chemistry data indicated changes in phosphorus and calcium. This information provided the basis for the hypotheses to be proposed regarding the mechanism for vascular and soft tissue mineralization. Because mineralization occurred in rats administered PD0325901 rather than only in dogs or monkeys, an animal model suitable for multiple investigative studies was readily available. Despite the apparent species specificity for this toxicity, it was not appropriate to discount the risks toward humans because of a "rat-specific" finding. Rather, it was important to generate experimental data that characterized the toxicity and provided a plausible mechanism as a basis for risk management. Studies conducted with PD0325901 examined the dose-response and exposure-response relationships for toxicity and pharmacologic inhibition of MEK, the time course for lesion development, whether the changes observed were reversible or not, and whether associations could be made between clinical laboratory changes and anatomic lesions. We were able to identify biomarkers for tissue mineralization that were specifically related to the mechanism, were readily available in the clinical setting, noninvasive, and had acceptable assay variability. It is important that biomarkers proposed for monitoring for drug toxicity be scientifically robust and obtainable, and meet expectations of regulatory agencies. Finally, the data generated during the preclinical safety evaluation of PD0325901 were used to design the phase I-II clinical trial to ensure patient safety. This included selection of a safe starting dose for phase I, criteria for excluding patients from the trial, and clinical laboratory tests to be included as biomarkers for calcium-phosphorus dysregulation and tissue mineralization. In conclusion, robust data analyses, scientific hypothesis testing, and the ability to conduct investigative work were key factors in developing a biomarker for a serious preclinical toxicity, thereby allowing clinical investigation of a novel drug to occur.

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