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.
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 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.
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.
Medelis: How should a CMO incorporate this data into the protocol?
Dr. Von Hoff: You establish it as an endpoint. So in addition to all the other endpoints that measure anti-tumor activity in a classic phase I trial, you add a line that specifies that one of the secondary endpoints is the time patients are on treatment with a new agent versus the time they were on their “just-prior drug.”
Medelis: You refer to measuring “time on therapy” as opposed to “time to progression?” What’s the distinction?
Dr. Von Hoff: With “time to progression” you need to be taking regular measurements such as scans. In comparison, “time on therapy” takes other things into consideration.
Medelis: That turns it into a more subjective, general indicator. Is that good?
Dr. Von Hoff: It helps because it takes into consideration clinical judgment, or people’s observational powers, which can be beneficial in addition to scans.
Medelis: And therein lies the art of the matter: the power of observation.
Dr. Von Hoff: What makes a clinical investigator great at his or her trade is the ability to observe keenly. Careful observation is critical at every stage.
Medelis: Are CMOs starting to do this as a matter of course — using time on drug to demonstrate improvement, then using that data to make a case to potential sponsors?
Dr. Von Hoff: I have written about this but have never seen a CMO plot time on a new drug versus the time on a just-prior therapy. This idea of using the patient as their own control is a lost concept in drug development. Dr. Bob Temple at the FDA, an icon in clinical trial design, calls it a lost art. He’s referring to the ability to document changes in the natural history of a patient’s tumor, and how this information can give you a sense of whether the drug will work.
Medelis: Does the approach of using a patient as their own control still work in the case of cyostatic drugs, which affect cells without decreasing tumor size?
Dr. Von Hoff: Even if an agent isn’t shrinking the tumor, it may be keeping it stable for long periods. If you plot the time a patient is on a new drug versus the time they were on the therapy they just progressed on, you can gauge whether an agent changed the natural history of the patient’s tumor. And, if at the higher doses, you have more people with longer time to progression as compared to lower doses, then you have a trend that your drug is actually doing something. If the patient had been on the next drug for only one month, then you know it didn’t do anything for them. But if you can beat what the patient just had, you really have a good prognostic sign.
CMOs and others just aren’t giving this information enough value.
Medelis: At what point would you feel validated to invest more deeply in a particular therapy based on information deduced from using the patient as their own control?
Dr. Von Hoff: If you treat 30 patients and 30% stay on a new therapy for a longer time than the just-prior drug they had progressed on, then that would justify a deeper investment. Patients’ tumors grow at an inexorable rate. If you find an agent that can taper that growth, then it is probably doing something and should be pursued.
Medelis: So the phase I shouldn’t just focus on maximum tolerable dose?
Dr. Von Hoff: Exactly. It’s an opportunity to look for therapeutic effect as well. If it’s there, patients benefit and you have a great start.
Medelis: So the payoff for CMOs changing how they see the phase I could be substantial.
Dr. Von Hoff: There’s no question in my mind. If a CMO started comparing time on new drug versus time on just-prior therapy, they would have a better idea as to whether the new agent had promise. All it takes is a more proactive approach to the phase I.
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