Phase I Clinical Trials: Hypothesis Testing

Faculty Presenter
Keith Flaherty, MD,Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

Scholar Summary

Authored by Michelle Ting, MD, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA

Through his experience with BRAF inhibitors in the treatment of melanoma, Dr. Keith Flaherty walked us through the steps for developing a phase I clinical trial pipeline, which include finding a testable hypothesis, discovering how and why a drug may be clinically effective (or ineffective), and elucidating what factors account for variable effect and loss of effect of this agent. Using the original failed hypothesis that sorafenib should be effective in the treatment of BRAF-mutated melanoma, he impressed on us the importance of constantly evaluating and reevaluating (and sometimes discarding) multiple hypotheses and targets. This gives us the opportunity to better understand the genomics behind a disease and to optimize the use of drugs or drug combinations to circumvent drug resistance and ultimately advance disease management. This was an inspiring platform in which to illustrate the ideal translational research model of molecular target discovery: starting with a patient population to discover the gene of interest, characterizing the mutant gene, developing targeted inhibitors, performing preclinical studies, and finally bringing the drugs to patients through clinical trials.

Scholar Summary

Authored by Kartik Sehgal, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Phase I and II clinical trials are usually designed with the predominant objectives of evaluating safety and efficacy of drugs. Dr. Flaherty discussed a conceptual framework to consider while designing phase I/II trials. He used the example of discovery and therapeutic implication of BRAF inhibition in melanoma patients to explain these concepts.

  • The first and the most crucial step is to clearly identify and develop a ‘testable hypothesis’.
  • The next step is to ensure that the ‘drug being studied acts like a drug’. Dr. Flaherty described this concept to underline the importance of understanding the pharmacokinetics of the drug. Often this information becomes available through pre-clinical animal studies. This was a recurrent theme that was emphasized during the entire meeting.
  • The next step is to understand the ‘molecular job of the drug’. With this concept, he emphasized the importance of knowing the target of the drug and downstream effects from engagement of that target.
  • The next step is to have reliable data on the ‘clinical effect of the drug’. This is essential before advancing the drug to phase III trials, which are much larger and expensive studies. It is important to be very rigorous while analyzing data from phase I and II trials to avoid waste of valuable resources.
  • The next step is to understand the factors that account for ‘variable effect’. He emphasized the importance of finding a predictive biomarker, which can be developed as a companion diagnostic test with the drug. This is important to avoid ‘loss of effect’ while testing a drug in an unselected population. He explained this concept further with the example of EGFR inhibitors in unselected lung cancer patients. He also used this concept to underline the importance of academia in biomarker discovery and developing collaborations with the pharmaceutical industry to choose the right biomarker and drugs.

He used the example of development of BRAF inhibitors to explain these concepts. BRAF mutations occur in approximately 40-50% of melanoma patients. Karasarides et al had identified BRAF as a therapeutic target in 2004 by showing that silencing RNA against BRAF induced apoptosis. Dr. Flaherty described the way in which finding a selective BRAF inhibitor was important for taking this concept to the clinic. He showed the important pharmacokinetic data, which was obtained in the pre-clinical in vivo studies. He concluded the presentation by showing the remarkable response rates seen in the first clinical trial with PLX4032, which eventually led to FDA approval of this agent in BRAF-mutated melanoma patients.

Scholar Summary

Authored by Yazeed Sawalha, MD, Cleveland Clinic, Cleveland, Ohio, USA

In his presentation, Dr. Keith T. Flaherty discussed several key topics including academic career building with focus on clinical investigation, how to be effective in translating science into medicine, how to best serve both patients and the oncology field, and the importance of forming collaborations between academia and the private sector to advance drug development. Dr. Flaherty went over key steps to develop a pipeline of phase I/II trials. The first step is formulating a testable hypothesis. This is the starting point and the most important step. It can include pursuing hypotheses in more than one thematic area at the same time, but he advised against testing more than three hypotheses concurrently. Following steps include understanding drug pharmacokinetics, drug pharmacodynamics, and their functional/molecular characteristics; testing the drug clinical efficacy; and finding predictive biomarkers. Dr. Flaherty shared his personal experience and insights from his novel research on BRAF inhibitors in melanoma to guide the discussion.

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