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The Complete Phase 1b:
An Approach for Getting to Phase II Faster
A Q&A with Daniel Von Hoff, M.D.
Introduction
In this issue of Peer Perspectives in Oncology, renowned oncology investigator Dr. Daniel Von Hoff describes a unique approach to the phase I trial that offers faster drug development. Known as “the complete phase Ib,” the design streamlines phase I by testing various drug combinations in one trial with multiple arms running in parallel. This structure creates rapid accrual rates, substantial economies of scale and significant time savings for sponsors versus the traditional sequential approach. It also garners enthusiasm from investigators and patients, who ultimately gain greater potential for improved therapeutic benefits and care.
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. (recently 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 Complete Phase 1b:
An Approach for Getting to Phase II Faster
Medelis: Dan, you have evolved an approach to the phase Ib that has repeatedly shown to generate more useful information in less time, getting you to the phase II more quickly. How does it differ from the traditional phase I?
Dr. Von Hoff: The typical phase I approach is essentially serial drug development, which involves running multiple separate trials. Each site at each trial adds a layer of time, cost, and management oversight. What I call “the complete phase Ib” is a simple solution that essentially tests the various drug combinations in one phase Ib with multiple arms run in parallel.
For example, assume you have good preclinical data on a single agent that may be more effective in combination with another agent—for example, a monoclonal antibody plus gemcitabine (GEMZAR®). Most Chief Medical Officers anticipate that the pivotal clinical trials will be standard therapy with or without the new drug, and they prepare for that eventuality by conducting a phase I trial of the combination. Typically, this involves launching five, six, or sometimes more combination phase I trials. Each trial has to be negotiated and managed separately, and each must have its own protocol, adding layer upon layer of cost and effort.
The strategy I'm suggesting eliminates all these separate serial trials because it puts the combinations into one phase Ib trial.
Medelis: One study with multiple arms sounds deceptively simple. Would you provide an example of how this might work?
Dr. Von Hoff: Take the example of a monoclonal antibody. The preclinical information shows great efficacy, and it looks good in separate combinations – with AVASTIN®‚ gemcitabine, DOXIL®, and SUTENT®. Now you’re looking at doing four separate phase I trials to test each combination, with each trial probably costing approximately between five hundred and eight hundred thousand dollars when all is said and done. What we propose with the complete phase Ib involves just one protocol with patients being streamed into different arms depending on what is most appropriate for the individual patient.
Conceptually, here’s how it would work. Mrs. Jones has newly diagnosed advanced disease where the standard treatment is gemcitabine. You’re going to give her gemcitabine anyway, so she gets gemcitabine plus the monoclonal antibody.
Mr. Smith comes in with advanced kidney cancer. He is going to get Sutent anyway, so he’s put on Sutent plus the monoclonal antibody.
Medelis: So at minimum, in the complete phase Ib, every patient is on the standard therapy?
Dr. Von Hoff: Yes, and that alone is especially motivating to patients, since they’re getting the approved drug plus an additional agent that could potentially optimize therapy. Also, most patients who walk into an oncology practice are eligible.
The other advantage is that patients who are early on in their disease immediately enter a phase I trial receiving the best possible treatment. This speeds things up considerably, and it also means the patient population is relatively healthier, having received less previous treatment. This greatly increases the chances of seeing a response in the phase I trial. Investigators, patients, physicians and the sponsor stay more motivated as a result. Of course, there is a chance that you might see more side effects, but we haven't found that to be the case.
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 always have three patients at each dose level?
Dr. Von Hoff: Treating three patients per level gives confidence in safety at each level. It only takes three levels at the most because you already know the dose of your investigational agent, and we have the dose for the standard agent.
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