The Lost Art Of Phase I Oncology Clinical Trials
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Medelis, Inc. 4105 N 20th St Ste 215 Phoenix, Arizona 85016 Phone: 602.840.1101 www.medelis.com
The Lost Opportunity in Phase I Oncology Trials A Q&A with renowned oncology investigator Daniel D. Von Hoff, M.D., who advocates for a phase I approach that looks beyond toxicity and gleans meaningful efficacy data, creating a more compelling rationale for further investment and improved patient care.
Welcome
This presentation is based on our December 2008 issue of Peer Perspectives in Oncology, a free Q&A series focused on issues that face Chief Medical Officers today: rising costs, optimum patient accrual, targeted therapeutics, patient safety, FDA regulations, efficacy, budgets, and timelines. You can sign up to receive an email notice for future issues at www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
The Lost Opportunity in Phase I Oncology Trials
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. Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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, ludarabine, 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 Editorin 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 postdoctoral fellows.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
How should this information be used? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
In the context of a trial, it seems counter intuitive to look at the individual patient. 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
Do you systematically track this information for each patient? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
How should a CMO incorporate this data into the protocol? 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 “justprior drug.” Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
You refer to measuring “time on therapy” as opposed to “time to progression?” What’s the distinction?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
That turns it into a more subjective, general indicator. Is that good? It helps because it takes into consideration clinical judgment, or people’s observational powers, which can be beneficial in addition to scans.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
And therein lies the art of the matter: the power of observation. 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
I have written about this but have never seen a CMO plot time on a new drug versus the time on a justprior 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
Why isn’t this a more common practice?
It’s not how people report. Instead of time on a therapy, they report stable disease over time. Unless they know how fast the tumor was growing in the first place, there is no reference point. If a patient has a short time to progression when you put them on study, they have a fastgrowing tumor. If you slow its growth, you can tell right away by comparing time to progression. Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
So the phase I shouldn’t just focus on maximum tolerable dose? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
So the payoff for CMOs changing how they see the phase I could be substantial. There’s no question in my mind. If a CMO started comparing time on new drug versus time on justprior 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.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
About “Peer Perspectives in Oncology”
In Peer Perspectives in Oncology, Medelis brings together some of the industry’s most respected researchers to talk about the issues facing Chief Medical Officers today. They’re issues we all face on a daily basis: Rising costs. Optimum patient accrual. Targeted therapeutics. Patient safety. FDA regulations. Efficacy. Budgets. Timelines. In this Q&A series, we’ll discuss these challenges with leading experts who deliver practical, frontline insights gleaned from years of experience bringing new drugs to market. To download additional issues in the series, please visit www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
About Medelis
Medelis, Inc. is a singlesource provider for oncology CRO and drug development services, providing a total solution for biotechnology and pharmaceutical companies seeking rapid drug development and approval. Medelis' medical founders, team physicians and clinical trial management physicians are internationallyrecognized oncology thought and opinion leaders who understand the future of personalized medicine and threshold of credibility trials. Offerings include strategic plans for regulatory approval from phase I through NDA and complete clinical trial design, management and execution. Medelis is privatelyheld and located in Phoenix, Arizona with other U.S. locations in Nashville, Boston and Reno. Medelis Europe oversees projects for European & Asian sponsors and is headquartered in Port Vendres, France.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
The Lost Opportunity in Phase I Oncology Trials A Q&A with renowned oncology investigator Daniel D. Von Hoff, M.D., who advocates for a phase I approach that looks beyond toxicity and gleans meaningful efficacy data, creating a more compelling rationale for further investment and improved patient care.
Welcome
This presentation is based on our December 2008 issue of Peer Perspectives in Oncology, a free Q&A series focused on issues that face Chief Medical Officers today: rising costs, optimum patient accrual, targeted therapeutics, patient safety, FDA regulations, efficacy, budgets, and timelines. You can sign up to receive an email notice for future issues at www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
The Lost Opportunity in Phase I Oncology Trials
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. Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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, ludarabine, 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 Editorin 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 postdoctoral fellows.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
How should this information be used? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
In the context of a trial, it seems counter intuitive to look at the individual patient. 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
Do you systematically track this information for each patient? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
How should a CMO incorporate this data into the protocol? 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 “justprior drug.” Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
You refer to measuring “time on therapy” as opposed to “time to progression?” What’s the distinction?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
That turns it into a more subjective, general indicator. Is that good? It helps because it takes into consideration clinical judgment, or people’s observational powers, which can be beneficial in addition to scans.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
And therein lies the art of the matter: the power of observation. 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
I have written about this but have never seen a CMO plot time on a new drug versus the time on a justprior 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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?
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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
Why isn’t this a more common practice?
It’s not how people report. Instead of time on a therapy, they report stable disease over time. Unless they know how fast the tumor was growing in the first place, there is no reference point. If a patient has a short time to progression when you put them on study, they have a fastgrowing tumor. If you slow its growth, you can tell right away by comparing time to progression. Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
So the phase I shouldn’t just focus on maximum tolerable dose? 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 provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
So the payoff for CMOs changing how they see the phase I could be substantial. There’s no question in my mind. If a CMO started comparing time on new drug versus time on justprior 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.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
About “Peer Perspectives in Oncology”
In Peer Perspectives in Oncology, Medelis brings together some of the industry’s most respected researchers to talk about the issues facing Chief Medical Officers today. They’re issues we all face on a daily basis: Rising costs. Optimum patient accrual. Targeted therapeutics. Patient safety. FDA regulations. Efficacy. Budgets. Timelines. In this Q&A series, we’ll discuss these challenges with leading experts who deliver practical, frontline insights gleaned from years of experience bringing new drugs to market. To download additional issues in the series, please visit www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
About Medelis
Medelis, Inc. is a singlesource provider for oncology CRO and drug development services, providing a total solution for biotechnology and pharmaceutical companies seeking rapid drug development and approval. Medelis' medical founders, team physicians and clinical trial management physicians are internationallyrecognized oncology thought and opinion leaders who understand the future of personalized medicine and threshold of credibility trials. Offerings include strategic plans for regulatory approval from phase I through NDA and complete clinical trial design, management and execution. Medelis is privatelyheld and located in Phoenix, Arizona with other U.S. locations in Nashville, Boston and Reno. Medelis Europe oversees projects for European & Asian sponsors and is headquartered in Port Vendres, France.
Medelis provides a full range of oncology contract research & drug development services from preclinical through NDA. Download our abstracts or read our blog at www.medelis.com.
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