CANCER AS A WORLDWIDE DISEASE

Oncology therapeutic research and development represents the greatest opportunity today for pharmaceutical companies to significantly affect morbidity and mortality in the developed world. More than 12 million new cancer cases emerged worldwide in 2007. In 2009, approximately 560,000 people were projected to die from malignancies in the United States. According to the World Cancer Center Report 2008, cancer is destined to become the leading cause of death on the planet by 2010. The number of new cancer cases per year is predicted to triple by the year 2030, which represents 20 million to 26 million new cases and 13 million to 17 million additional deaths annually. Of equal significance is the number of new drugs undergoing testing for treatment of various forms of cancer. As of April 2009, 831 drugs and vaccines were in clinical development, which is a 32 percent increase over the number of oncologic agents in development in April 2008.

This daunting unmet medical need, coupled with the rapid demise of the majority of cancer patients, requires that oncology drug development follow a much different paradigm than that used for the development of drugs for non-life-threatening diseases. The challenges of oncology drug development are underscored by the fact that phase 1 clinical trials commonly include patients with nonresponsive late-stage disease and a mean life expectancy of 3 to 5 months; patients treated with oncology drugs targeted against solid metastatic tumor disease (excluding a few cancers, such as hormone-dependent metastatic prostate cancer), typically have a mean life expectancy of only 1 to 2 years.

INTRODUCTION

For the development of cytotoxic anticancer pharmaceuticals, the initial phase 1 clinical trials in patients with advanced cancer disease usually include determining a maximum tolerated dose (MTD) and identifying dose-limiting toxicity (DLT). The MTD is usually defined as the dose tolerated by five out of six patients with acceptable levels of DLT and dose levels above which result in unacceptable DLT in two or more patients. The dose–response curve for many pharmaceuticals in this class is steep. Traditionally, the dose recommended for phase 2 trials of cytotoxic agents is based on the MTD determined in phase 1. The inherent assumption in establishing and using an MTD is that the therapeutic effect and the associated toxicities are correlated and that the mechanism of action of both the toxic and therapeutic effects is the same – higher doses result in greater efficacy. Therefore, it is not uncommon for the efficacious dose of anticancer pharmaceuticals to be at or near the MTD. Predicting the dose and exposure at which DLT will likely occur in humans provides value in designing and conducting the first clinical trial for a cytotoxic anticancer pharmaceutical.

Before testing in patients, the toxicities of these pharmaceutical candidates are studied in nonclinical species in toxicology studies to determine the DLT. Toxicokinetics (TK) represent the assessment of systemic exposure in toxicity studies, in which pharmacokinetic data are generated, either from the same animals used in the main toxicology study (usually for larger species such as dogs or monkeys) or from a satellite group (usually for smaller species such as rats or mice) at each dose level used in the main toxicology study.