Phase II

The primary aim of a Phase II trial is to define the spectrum of antitumor activity for the new drug using the optimal dose and schedule determined from Phase I trials. With cyto-toxic drugs, the traditional endpoint is response rate as measured by the percentage decrease in size of the tumor compared to the pretreatment size. However, objective response rate may not be an ideal endpoint for target-based agents because of their cytostatic properties. To overcome this difficulty, alternative endpoints have been used in Phase II clinical studies of targeted therapies. These include the following:

• Pharmacodynamic endpoints: for example, quantifying posttranslational changes in biological markers in either tumor or surrogate tissues

• Functional imaging studies to assess treatment response at the tumor site (FDG-PET or dynamic contrast-enhanced MRI)

• Assessment of time to disease progression and the proportion of patients with disease progression

• Quality of life (regarded as a secondary endpoint for cytotoxic agents)113

None of these endpoints has been well validated.116,117 An alternative approach to clinical trials investigating the activity of targeted therapies is the use of the randomized discontinuation design. All patients are enrolled to receive the drug for an initial 2- to 4-month period. Patients with progressive disease, toxicity, or noncompliance during this period are removed from the study. The remaining patients are then randomized to continue the drug or a placebo. The endpoint is the percentage of patients that remain with stable disease in the randomized period. The advantages of this method are that it can overcome the slow accrual of trials that offer treatment or placebo upfront, eligibility criteria can be relatively broad, and enrichment of the randomized group may increase the efficiency of the trial.118 Other Phase II trial designs include utilizing the patient as the internal control, whereby a single cohort of patients with progressive disease is treated with a cytostatic agent to determine whether the agent slows the rate of disease progression with reference to the pretreat-ment rate of progression. Similarly, neoadjuvant treatment can provide a valuable system with tumor sampling for molecular analysis that can be performed at progressive time points during treatment.

Phase III

The aim of Phase III trials is to determine efficacy or clinical benefit of a new regimen versus a standard therapy in a randomized study. Endpoints are usually progression-free survival or overall survival. With target-based agents, the traditional designs should remain relatively unchanged. It is important that the drug dose that optimally inhibits the target in question within patient tumor specimens be defined in advance of Phase III studies.

Patient Selection

The target should be critical to the biology of tumor [e.g., bcr-abl in chronic myeloid leukemia (CML)], and the targeted agent should be used in a biologically relevant population. Disease stage may also need to be considered in patient selection, as some agents may be less active in the advanced setting and more effective in patients with minimal disease. Many Phase III clinical trials conducted (with the exception of the trastuzumab and imatinib studies) have not selected patients based on target expression. It is noteworthy that had the Phase III study investigating the addition of trastuzumab to chemotherapy in patients with metastatic breast cancer not selected patients based on HER2 overexpression, the trial would have been negative.

At the same time, our understanding of the molecular profile in a tumor that may predict response to targeted therapies remains naive. Little is known about resistance to targeted therapies to guide appropriate strategies of combining different inhibitors together to inhibit redundant or parallel signaling pathways, thus maximizing clinical benefit. Future trials of targeted therapies must incorporate a prospective analysis of tumor tissue during treatment so that response can be correlated with the molecular phenotype (either through microarray or proteomic techniques), thus identifying predictive markers for future studies.

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