Traditionally, oncology drug developers have regarded the phase I clinical 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 biotech 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.

1. 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.

2. 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.

3. 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.

4. 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. (recently acquired by Genzyme). He is founder and
Editor Emeritus of Investigational New Drugs ­ The Journal of New Anticancer Agents as well as the
Editor­in­Chief 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.

5. 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 ACR, 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 that 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.

6. 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. The longer she is on a therapy,
the more the drug is doing something —
otherwise, you wouldn’t keep the patient on
the 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.

7. 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, and the patient’s immune system. We may
not know all those 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.

8. 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 data bank.
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.

9. How should a CMO incorporate this data into
the protocol?
You establish it as an endpoint and it is very
convincing. So in addition to all the other
endpoints that measure anti­tumor 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.

10. 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
everything 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.

11. That turns it into a more subjective, general
indicator. Is that good?
Yes, because it takes into consideration clinical
judgment, or people’s observational powers, which as
it turns out in medicine, can be more effective than
scans. Sometimes we look at a patient and think,
“Boy, he doesn’t look too good.” He says he’s fine,
but maybe he’s lost a few pounds. He doesn’t have
that twinkle in his eye, or he seems to be giving up.
What those signs mean to me is the tumor is
generating cytokines.
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.

12. 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.
In addition to the usual scans, it takes clinical
judgment into consideration, and that should
never be underestimated. Heck, Grandma
knew when you didn’t look good. She
watched you grow up. 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.

13. 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 to build a story for raising money. 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.

14. Does the approach of using a patient as their own control
still work in the case of cyotoxic drugs, which kill 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 triumph.
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.

15. 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, ever­
quickening 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.

16. 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.

17. 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 can hit it out
of the park.
I presented at the recent AACR meeting showing a
response in 89% of patients with basal cell carcinoma to
an oral Hedgehog inhibitor from Genentech. This was a
standard phase I, single agent, so it was pretty
remarkable. The second presentation I made was in
pancreatic cancer and it involved a 70% response rate.
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.

18. 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, the rewards are
there for the patients and for the progression
of the drug. 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.

19. 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.

20. 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.