Early phase clinical trials

In addition, we need to have reasonable confidence that a particular selected route of adminis- 

Discussions in this chapter emphasize statistical considerations in early phase clinical trials. These include study designs employed, the types of data collected, and the usefulness and limitations of these data. 

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The central role that the PI3K/AKT pathway plays in cancer continues to fuel excitement in this arena as a potential target for cancer therapy. Progress with small molecule AKT inhibitors continues to be made, as judged by the compounds described in this review. However, the full scope of the clinical effectiveness of targeting this pathway has yet to be proven, as most of the reported small molecule AKT inhibitors are still in pre-clinical development, with only a few examples in early phase clinical trials. 

The NIH and the pharmaceutical industry have formed a new partnership to overcome barriers to early-phase clinical trials. The Secretary of Health and Human Services, Tommy Thompson, announced on July 9, 2003 grant awards for six cancer centers involved in a unique public-private partnership. Five pharmaceutical companies together with NCI put forth a total of 5.7 million for this partnership. Institutions receiving the funding include Massachusetts General Hospital University of Colorado Health Sciences Center Washington University, St. Louis University of Pittsburgh Cancer Institute University of California, Davis Cancer Center and Ohio State University Comprehensive Cancer Center (http //WWW. bms.com/news/other/data/pf other.news.385 5. html). 

Coin E, Digesu GA, Olivieri L. Overactive bladder treatments in early phase clinical trials. Expert Opin Inves-tig Drugs 2007 16 999-1007. 

The preclinical stage of drug development focuses on activities necessary for filing an IND/CTA. The completed IND/CTA contains information that details the drug s composition and the synthetic processes used for its production. The IND/CTA also contains animal toxicity data, protocols for early phase clinical trials, and an outline of specific details and plans for evaluation. Process research, formulation, metabolism, and toxicity are the major areas of responsibility in this development stage. Analysis activities that feature LC/MS primarily focus on the identification of impurities, de-gradants, and metabolites. 

In this chapter we have discussed the importance, and the strengths, of early phase clinical trials. Before moving on to later phase clinical trials, it is also appropriate to consider their limitations. The word "limitations" should not be seen as a negative assessment in this context. As we will discuss in Chapter 12, later-phase preapproval clinical trials also have their limitations. Acknowledgment of the strength and the limitations of any method of inquiry is legitimate and helpful As Katz (2001, p xi) noted, "to work skillfully with evidence is to acknowledge its limits."... 

P. F. Thall, E. H. Estey, and H. G. Sung, A new statistical method for dose-finding based on efficacy and toxicity in early phase clinical trials. Invest New Drugs 17 155-167... 

Although recombinant proteins are more difficult to generate at a clinical grade, there are some promising early phase clinical trials. One example is vaccinating with recombinant NY-ESO-1, a cancer-testis antigen, of patients with cancers known to express NY-ESO-1. Recombinant NY-ESO-1 antigen... 

TroVax is Oxford BioMedica s therapeutic cancer vaccine, consisting of the 5T4 antigen [104] encoded by a modified vaccinia Ankara (MVA) virus. Early phase clinical trials reported potent CD4 + T cell and antibody responses in colorectal and prostate cancer patients [105, 106]. Time to progression was significantly longer in patients who developed 5T4-specific cellular responses compared with those who did not (5.6 vs. 2.3 months, respectively). However, there were no objective clinical responses. 

Unlike with kidney injury biomarkers, where between 2008 and 2010 the FDA, the EMA and the PMDA qualified the use of seven urinary biomarkers for GLP rat studies to support the safe conduct of early phase clinical trials, GI injury is stiU in its infancy with regard to discovery, development, and implementation of biomarkers. The challenges of developing biomarkers are even greater when the complexity of GI injuries is looked upon more carefully. These injuries include, but are not limited to, nausea, vomiting, ulceration, inflammation of the intestine, mucositis, altered fecal output, abdominal pain/discomfort, GI bleeding, and/or perforation which can be inflicted by various dmg classes, chemical classes, or therapeutic areas. 

Between 2008 and 2010, the FDA (2008), the EMA (2008), and the PMDA (2010) qualified the use of seven urinary biomarkers for GLP rat studies to support the safe conduct of early-phase clinical trials KlM-1, CLU, TFF-3, p2-microglobulin, CysC, albumin, and total protein. These are detailed below. 

Drugs that are FDA approved (classical nitrates, nitrites, molsidomine) or have completed early phase clinical trials in other indications (NO-NSAIDS) have, at present, the best prospects for clinical use. The in vitro genotoxicity of several examples of most classes of NORMs is a dampener to use in cancer chemoprevention, even in the absence of any evidence of carcinogenicity. 

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