X

"Toxicity observed.

'Includes vascular (aorta, arteries) and soft tissue mineralization (e.g., stomach, heart, kidneys).

"Toxicity observed.

'Includes vascular (aorta, arteries) and soft tissue mineralization (e.g., stomach, heart, kidneys).

tinal tract (primarily ulcers/erosions in the mucosa) were observed across species and may have resulted from inhibition of MEK-related signal transduction pathways in these tissues (Brown et al., 2006). Gastrointestinal tract toxicity is dose-l imiting in dogs and monkeys and was anticipated to be the dose-l imiting toxicity of PD0325901 in the clinic. Therefore, gastrointestinal tract toxicity may preclude the development of other potential adverse events in humans, including potential dysregulation in serum phosphorus or calcium. It is not known whether systemic mineralization is relevant to humans. However, if PD0325901 does induce a dysregulation in serum calcium-phosphorus metabolism in humans, monitoring serum levels would provide an early indication of effects and guide modifications to dosing regimens.

To ensure patient safety in the phase I clinical trial with PD0325901, procedures were incorporated into the trial design to monitor for potential dys-regulation in serum calcium-phosphorus homeostasis. Measurements of serum calcium, phosphorus, creatinine, albumin, and blood urea nitrogen were performed frequently during the initial treatment cycle (21 days of dosing in a 28-day cycle), with periodic measurement in subsequent cycles, and the serum Ca x P product was calculated. The serum Ca x P product has been determined to be a clinically useful value as a means for evaluating risk for tissue and/or vascular mineralization with the recommendation that the value not exceed 70 based on clinical use of vitamin D analogs such as Rocaltrol and Hectorol (Roche Laboratories, 1998; Bone Care International, Inc., 1999; Block, 2000). Serum calcium and phosphorus are readily measured in a clinical setting with well-established reference ranges available. The trial included a protocol-specific dose -limiting toxicity for a Ca x P product > 70, which required a confirmatory measurement and dose interruption for that patient. In addition, serum vitamin D, PTH, alkaline phosphatase (total and bone), osteocalcin, and urinary C- and N-terminal peptide of collagen 1 (markers of bone resorption) were included for periodic measurement. Criteria considered for exclusion of candidate patients from the clinical trial included a history of malignancy-associated hypercalcemia, extensive bone metastasis, parathyroid disorder, hyperphosphatemia and renal insufficiency, serum calcium or phosphorus levels >1x the upper limit of normal, and/or concomitant use of calcium supplements and vitamin D in amounts exceeding normal daily allowances.

Project Management Made Easy

Project Management Made Easy

What you need to know about… Project Management Made Easy! Project management consists of more than just a large building project and can encompass small projects as well. No matter what the size of your project, you need to have some sort of project management. How you manage your project has everything to do with its outcome.

Get My Free Ebook


Post a comment