Phase I Clinical Trials: Protocal Development
Keith Flaherty, MD,Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
Authored by Jonathan Chou, MD, University of California, San Francisco, San Francisco, California, USA
Dr. Flaherty discussed his experience as an early investigator developing therapeutics for the BRAF oncogene and the multiple lessons he learned along the journey. He disclosed that one of the key observations came out of a UK Cancer Genome Study in which mutations in BRAF were identified in 66% of melanomas. What was intriguing was that all of the mutations were within the kinase domain, with a single point mutation accounting for 80% of those mutations (Davies et al, Nature 2002). Dr. Flaherty discussed that this key discovery was timely and that it was important to pay attention to other fields of discovery, and to not drop a good idea when it falls to you. He began doing preclinical work in the lab, and his group found that BRAF was necessary for melanoma cell growth. Knockdown of BRAF in melanomas led to apoptosis, and the in vivo studies showed that tumor growth could be delayed. He discussed that although he had been working on angiogenesis in kidney cancer, this was also a great opportunity to test whether a drug that was being developed to target VEGF (sorafenib) could also be used to target BRAF. Dr. Flaherty related that despite the early enthusiasm for this approach, the critical phase 3 clinical trial showed that adding sorafenib to chemotherapy did not improve overall survival, with the hazard ratio of 1. Despite this, he showed that using sorafenib did inhibit angiogenesis but did not reduce tumor growth or progression, refuting the hypothesis that inhibiting angiogenesis was sufficient as a therapeutic. This led to the hypothesis that despite using sorafenib, a drug that could target multiple kinases, including VEGF and presumably BRAF, that the true target and oncogenic driver, BRAF, may not be sufficiently inhibited. Given this, a pharmaceutical company, Plexxikon, developed a compound specific for the BRAF V600 mutation. Here the trials showed dramatic responses, which has launched multiple careers and areas of inquiry to understand resistance mechanisms. Dr. Flaherty emphasized the importance of developing a pipeline of early phase therapeutics and the need for finding predictive biomarkers at the beginning with the development of the drug. One example he gave was that by focusing only on the BRAF V600E mutation, they had initially missed another important cohort of patients, who harbored a different point mutation, the V600K mutation. Overall, Dr. Flaherty’s story of how he was able to take an observation from tumor sequencing, show the importance of the mutation in disease progression, and then develop a therapeutic to target this mutation and its resistance/bypass mechanisms is truly inspiring for me as young physician-scientist.
Authored by by Namrata S. Chandhok, MD, Yale University School of Medicine, New Haven, Connecticut, USA
Dr. Flaherty’s talk was a discussion focused on academic career building for early career physicians with a focus on clinical investigation. Using personal anecdotes in drug development in melanoma, he was able to highlight the primary objectives of his talk, namely how to translate science to medicine, best serve our patients, and serve the field in our respective areas of interest over the course of our careers.
The discussion started with Dr. Flaherty’s personal disclosures, which he used to demonstrate the interdependent relationship between academia and industry. He explained that both sectors have their own strengths and weaknesses, and because of this they remain inherently interdependent. While the pharmaceutical industry is critical to drug development, their primary accountability is to their shareholders; as academic physicians, our loyalty lies with our patients. While loyalties between the two sectors differ, pharma and academia share a common interest: bringing new drugs to patients. The goal of a clinical investigator is to align with industry to bring promising agents with strong scientific rationale to patients, but also to “keep our compass on the patient” and to separate from industry partners as soon as our interests as clinicians start to diverge from those of the private sector. He noted that academia bears the responsibility to address important scientific questions that are outside the realm of the private sector. As academicians, it remains our responsibility to pursue necessary, but perhaps less lucrative, discoveries to best serve our patients.
With regard to early phase trials, Dr. Flaherty noted that current phase 1 trials have exceeded their original goals of safety and pharmacology testing. Current early phase trials should be developed as “pre-pivotal” trial investigation, i.e. have all the necessary components to lead directly into a phase III trial. This means that there should be a clear investigational plan from the outset that may be improved upon via amendments as necessary. Because of this change in structure, successful clinical translational investigators need to become involved in drug development as early as possible, write the most clinically sound phase 1 studies, and follow through all the way through until approval.
The reality of drug development is that many drugs will fail; to maximize our chance of academic success, clinical investigators should think about two or three “shots on goal” i.e. develop expertise in two or three thematic areas expertise on which to focus for clinical investigation. Career building should be scientific, not simply combining two drugs together and exploring efficacy.
The next key component of early phase trials discussed was pharmacokinetics. Dr. Flaherty recommended developing a basic understanding of pharmacokinetics in order to have educated conversations with people in the field. He also recommended developing a deep understanding of the important questions that must be answered in drug development (ex: does the drug act like a drug, does it engage the correct target, does it have the expected downstream consequence, does it have the intended clinical benefit, etc.). Again, while it is in our interest to be able to answer all of these questions, these queries may not be the priority for our pharmaceutical partners, and it is our responsibility to forge relationships that will help answer these key questions. For example, biomarker development frequently remains in the academic realm. It is beneficial to try and negotiate co-development of diagnostics with drug development whenever possible, as it is significantly easier to do prospectively (as opposed to retrospectively). We discussed the example of the cetuximab, and KRAS mutational status as a biomarker to differentiate responders from non-responders. The scientific rationale for this was very clear, but given that the biomarker was only considered after responses in patients, it took several years for implementation into clinical practice. Dr. Flaherty noted that it is not always this clear, but if we as junior investigators have a clear idea for a biomarker that is scientifically valid and may serve as a “black and white fingerprint” for responders versus non responders, we should aggressively pursue this with the necessary collaborators; these are the grants that are likely to be funded and the studies that will potentially have significant clinical impact.
Dr. Flaherty then emphasized that the focus of clinical investigation should be on the development of good ideas with the help of mentors and acquisition of the necessary drugs and infrastructure. As junior investigators, we don’t need to re-invent the wheel but to do things in a clear logical order and do them well. He also explained that for junior investigators it would be a mistake to walk away from seemingly obvious ideas based on the assumption that other people will continue to pursue them. With his own career path pursuing B-RAF mutations in melanoma, he demonstrated that persistence is key to academic success.
The lecture was clear, inspiring and peppered with useful tips for early career physicians in oncology.
Summary points for early career investigators pursuing careers in clinical investigation:
- Work with industry, but remember that patient care remains your primary goal.
- Develop expertise in two or three thematic areas and work with pharmaceutical companies on development, trial design, and execution as early in the process as possible.
- Broadly develop understanding in important subject areas such as pharmacokinetics.
- Find good mentorship, pharmaceutical partnership, and infrastructure to support your goals.
- Be patient, and don’t walk away from a good idea!