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The Lost Opportunity in Phase I Oncology Trials
A Q&A with Daniel Von Hoff, M.D.
Introduction
Traditionally, drug developers have regarded the phase I trial as having a utility limited to the assessment of safety, tolerability, and pharmacokinetics and pharmacodynamics of a drug.
In this issue of Peer Perspectives in Oncology, renowned oncology investigator Dr. Daniel Von Hoff describes how Chief Medical Officers can design better oncology phase I trials to glean meaningful efficacy data by using the patient as his or her own control. He further explains how a CMO can gather evidence showing a drug changes the natural history of a patient’s disease, demonstrating improved care and a stronger case for moving a drug into phase II.
About Dr. Daniel Von Hoff
Daniel D. Von Hoff, M.D. is Senior Investigator and Head of Translational Research at the Translational Genomics Research Institute's (TGen) Translational Drug Development Division and Head, Pancreatic Cancer Research Program in Phoenix, Arizona. He also serves as Chief Scientific Officer for U.S. Oncology and the Scottsdale Clinical Research Institute, and is a founding shareholder and advisory board member of Medelis.
Dr. Von Hoff's major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents we now use routinely, including mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, CPT-11, gefitinib and others. At present, he and his colleagues are concentrating on the development of molecularly targeted therapies.
Dr. Von Hoff's laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient. He and his laboratory are now concentrating on discovery of new targets in pancreatic cancer. Dr. Von Hoff has published more than 529 papers, 129 book chapters, and more than 891 abstracts.
Dr. Von Hoff was appointed to President Bush's National Cancer Advisory Board from June 2004 - March 2010. He is the past President of the American Association for Cancer Research, a Fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology. He is a founder of ILEX Oncology, Inc. (acquired by Genzyme). He is founder and Editor Emeritus of Investigational New Drugs - The Journal of New Anticancer Agents as well as the Editor-in-Chief of Molecular Cancer Therapeutics. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows.
The Lost Opportunity in Phase I Oncology Trials
Medelis: Dan, you believe that many CMOs today are missing a valuable opportunity to gain more meaningful data from phase I oncology trials. That seeing each patient as his or her own control may hold a key to later success and create a more compelling story for management & investors. Can you describe in detail what you mean?
Dr. Von Hoff: Yes, and it’s very simple. Typically, a CMO sees phase I as a toxicity trial, not a therapeutic trial, because of course it isn’t randomized. But the doctors at the bedside and the patients themselves don’t see it as purely a toxicity trial. We’re looking for improvement and survival. And even during phase I, we can glean important efficacy clues by using the patient as his or her own control.
Recently, at AACR, I reported on findings involving nine patients in a phase I trial showing dramatic tumor shrinkage with no side effects with an oral agent. Clearly the drug did something. It slowed down the disease and the patients benefited. In fact, the drug changed the natural history of each patient.
Medelis: How should this information be used?
Dr. Von Hoff: It can be a key part of the story you tell to sponsors and investors when raising money. You show how long the patient was on a prior therapy and now how long she is on your new therapy. If the patient is on the new therapy longer than she was on the prior therapy, the new drug is doing something – it is changing the natural history of that patient’s disease.
Medelis: In the context of a trial, it seems counter-intuitive to look at the individual patient.
Dr. Von Hoff: The reason it’s so important to look at each individual patient is because each patient’s tumor has a different natural history. Everyone’s cancer is different in heterogeneity and tempo, or natural history. We may not know all the variables, but we do know that if the cancer changes, as measured by increased time on therapy, we must be doing something right.
Medelis: What is the dosing strategy in the complete phase Ib?
Dr. Von Hoff: Essentially you're escalating the dose of your monoclonal antibody or whatever the other new agent may be. For example, I recommend using the full dose of the standard drug as specified on the package insert. Then, on top of the standard doses, we would then use one-third the single-agent dose of the monoclonal antibody in three patients, two-thirds in three patients, and a full dose in three patients.
Medelis: Do you systematically track this information for each patient?
Dr. Von Hoff:
Yes. In fact, I now recommend including this kind of information — time to progression on each drug — in the protocol so it becomes part of each patient’s database.
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