Cancer clinical therapy development is moving beyond the classical clinical research trial paradigm used to develop new oncology treatments. This paradigm was based upon the sequential use of Phase I trials to define toxicity and tolerable doses and schedules. ?Phase II trials then search for signals of efficacy in particular disease types.? Phase III trials complete the paradigm and are designed to test new therapies against the current standards of care. Therapies successfully completing the Phase I, II, and III trials are presented to regulatory agencies for approval as widely available cancer treatments.
Although there will always be a role for some drugs to be developed using the classic Phase I-III mechanism for development, many newer cancer treatments will be targeted not against a cancer type but rather against specific molecular targets that may be identified in cancers arising in various different organs. Therefore it doesn?t make sense to do Phase I- III clinical trials in large number of patients with a histologically defined cancer (lung cancer, breast cancer, renal cancer, for example). Rather one needs to test the efficacy of a targeted therapy in tumors that carry the target of interest.
An example of this scenario is the HER2 target. HER2 was originally identified in breast cancer and a monoclonal antibody targeting HER2? (Herceptin) was developed and shown to be efficacious in HER2+ breast cancer. More recently HER2 was identified in about 20% of stomach cancers. Herceptin was shown to be active in HER2+ gastric cancer but not in the roughly 80% of tumors that were HER2-.
The gastric cancer HER2 story illustrates important points about targeted therapy development. First, clinical trials taking all comers with a histologically defined cancer like stomach cancer makes no sense. The patient population chosen must be from the 20% of patients whose stomach cancers express HER2. Also full toxicity evaluations and dose finding studies do not need to be done since we have much of these data from the experience with Herceptin in breast cancer.
The bottom line here is that as we get increasingly more sophisticated in defining molecular targets in cancer, we will be dealing with smaller clinical trials performed in carefully defined patient populations. The molecular biology of the cancer and the targeted therapy will be come increasingly more important in cancer therapy development.
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