Year 1

Over the last several years, it has become increasingly clear that cancer is a diverse disease where the treatments must be individualized. In the last year alone, 8 new drugs have received FDA approvals to treat cancers ranging from those that originate in the bone marrow (lymphoma, or myeloma) to “solid” tumors (eg breast or lung cancer). Most new drug development focuses on identifying subgroups that are more likely to respond and therefore derive benefit from these new agents. Along these lines, the attraction of attacking the cancer stem cell has become a priority. The cancer stem cell model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments. This model even implies that tumors can achieve resistance by cell fate decisions in which some tumor cells are killed by therapeutics which makes the relevance of new drug development even more critical.
In our proposal, we are conducting a first in human Phase I clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). But, compared to chemotherapy, it appears to decrease more of the tumor initiating cell population in many cancer models. We have been able to identify those pre-clinical models that will predict which cancer are sensitive and which are resistant. The goal of our Phase I trial is to determine the maximum tolerated dose, the recommended Phase II dose, and any dose-limiting toxicities. We will further characterize safety, pharmacokinetic, and pharmacodynamic profiles along with any antitumor activity. In the last year, we have enrolled many patients and we are starting to develop a sense of how this drug works and in which cancers it may have the most potential relevance. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies and allow us the opportunity to facilitate a targeted clinical development plan.