The Lost Art of Phase I Oncology Clinical Trials

Medelis, Inc.

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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.
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.
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.
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.
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.
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.
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.”
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
www.medelis.com.

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