The Complete Phase Ib: An Approach For Getting To Phase II Faster

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The Complete Phase

Ib: An Approach for
Getting to Phase II
Faster
A Q&A with renowned oncology investigator Dr.
Daniel D. Von Hoff, M.D., who describes a clinical trial
design that streamlines phase I by testing various
drug combinations in one trial with multiple arms
running in parallel.
Welcome
This presentation is based on our July 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 Complete Phase Ib: An Approach for
Getting to Phase II Faster
In this conversation, 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
Medelis care.
provides a full range of oncology contract research & drug
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
Medelisprovidesfora multiple
full range of oncology
medical contract
students, medical research
oncology fellows, & drug students, and post-doctoral fellows.
graduate
Dan, you’ve 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?
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.
One study with multiple arms sounds deceptively
simple. Would you provide an example of how this
might work?
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.
So at minimum, in the complete phase Ib,
every patient is on the standard therapy?
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’s a chance that you might see more side
effects, but we have not found that to be the case.
What is the dosing strategy in the complete
phase IB?
Essentially you are 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.

Do you always have three patients at each
dose level?
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.

Is it necessary to have animal data on each
arm?
I like to have some animal model data that establishes

the combination effects, ensuring excessive weight loss
and other effects do not occur, for instance. If the
animals haven’t lost weight, then I’m usually not
worried about the combination in patients. As an extra
safety measure, we also do abbreviated kinetic
sampling.

How important is entry criteria in the context
of the complete phase Ib?
Entry criteria are important and can change the value of

an agent under study. If, for example, a monoclonal
antibody appears to sensitize to a drug such as Doxil,
you might establish an entry criterion specifying the
patient can have prior exposure to Doxil. Adding the
monoclonal antibody in this context puts enormous
value on it, in a sense rescuing the patients.

What you mean by “rescuing patients?”
A good example involves one of the best trials ever done. It was by
Merck AG for the approval of ERBITUX® (Cetuximab). The entry
criterion was patients with colon cancer progressing on CPT-11
(irinotecan). Patients were either given Erbitux plus CPT-11, or Erbitux
alone.
What was so clever about the trial was that the investigators exploited
preclinical evidence that the Erbitux/CPT-11 combination would be
rescuing some of these patients, and they established Erbitux as the
control.
The trial was highly positive. It showed clinically what the preclinical
findings demonstrated — that adding Erbitrux to the CPT-11 dose at
which patients’ disease was progressing reverses resistance. There
was the additional advantage of greater patient support for this type
of phase I since they were getting standard therapy, something an
Institutional Review Board is very positive about.
How are accrual rates affected with your
approach?
Compared to the typical phase I approach, the complete

phase Ib can produce rapid accrual rates because of
patient acceptance. You’re adding an agent to standard
therapy and not complicating patients’ involvement by
doing things sequentially.

Can you discuss the logistical aspects for the complete
phase Ib — total number of sites and patients, for
instance?
With our group, U.S. Oncology, we would run a complete

phase Ib in up to five sites, depending on the number of arms.
Keep
in mind, this is not a randomization and each arm could be,
say, the
monoclonal antibody in combination with any appropriate
standard
agent. Each arm includes about 9 to 12 patients. If you really
know
your investigational agent well, you can cut the investigational
agent
down to half the dose and then the full dose, so it is either one
or
two escalations. That would mean three patients per level so it
While the complete phase Ib looks to be more costly
than a single phase I trial, are there cost savings
compared to conducting sequential phase I trials?
The real savings is time. You don’t have to deal with separate
amendments. There is only one protocol, creating an
operational economy of scale in a sense. In weekly calls,
everybody is on the same page. If one arm has a problem —
for instance, two out of three people have dose-limiting
toxicity — then you substitute in your next arm with an
amendment. Previously, if this happened, you would have to
shut down that one trial, losing all your start-up costs. It’s a
“plug-and-play” modular approach.
The other advantage is that sponsors are happy because the

trial gets up and running quickly. The one problem we may
have is there are more patients than slots to be filled.
In other words, you might be over-accrued?
Yes, and it can be a problem because it yields a lot of data, and the CMO
has to tease apart the best potential directions to pursue. In this context, a
randomized phase II becomes the obvious next step.
Here is a classic example. We have many patients with colon cancer who
are on Avastin, an inhibitor of VEGF. Stopping Avastin is problematic
because it leaves the VEGF unopposed, potentially leading to a cancer
flare. In a case such as this one, clinicians are much more comfortable with
a complete phase Ib that has an Avastin arm — if they see activity with the
monoclonal antibody plus Avastin, it is extremely important. If the patient
was on an Avastin-containing combination for five months before the
cancer progressed, and then s/he goes on the monoclonal antibody plus
Avastin for up to nine months, what you are in fact doing is changing the
natural history of the patient’s tumor. You can see how there is a lot of
information to be mined from this approach, giving the CMO many options
Medelis provides
for phasea full
II. range of oncology contract research & drug
What effect does the complete phase Ib have
on the randomized phase II?
The complete phase Ib gets you ready for your

randomized phase II faster by cutting down time for the
whole development program. Instead of a sponsor
funding, negotiating, and managing, say, five trial sites,
five budgets, five contracts, five protocols, with the
complete phase Ib, you test all the possible
combinations suggested by the animal systems or
cultures in one trial. The first scenario could take a few
years; the latter, probably about six months … and that
includes doing the trial.

Has the complete phase Ib caught on? Is big
pharma adopting this approach?
In 2007, at ASCO, when we presented the complete

phase Ib approach as a way to get to the randomized
phase II more quickly, there were only about 25 people
talking about it. Now I get a call once a week and we
have six trials running. It makes sense for big pharma
because it generates the chunk of information you need
at one time, rather than serially, for better decision-
making.

What happens when the complete phase Ib approach
pushes for drug combinations that aren’t approved?
Who pays for the drug?
If you have good evidence for using an agent in an arm

but it isn’t indicated yet, then the sponsor would help
pay for that drug for that patient. Or, there may be
literature indicating that an agent works but the
company hasn’t filed an NDA for an extension. In these
cases, you at least have a fighting chance with the
insurance company. And even if insurance doesn’t pay,
the sponsor has a rationale and incentive for covering
the cost of the agent.

What’s the FDA’s position on this approach? Have they
implemented any new regulations to facilitate it?
Each trial is filed with an IND and performed with the

utmost safety. In reality, it’s not fundamentally any
different than doing six trials in serial fashion.

Keeping investigators engaged and interested is critical
for any trial. How have investigators responded to the
complete phase Ib?
Investigators are enthusiastic about this approach. One

reason is that patient enrollment is extremely fast; now
you have the opportunity to treat almost every patient
who walks into the clinic. The patient population is
relatively healthier because they’ve received less
treatment, which increases the chances of seeing a
response in the phase Ib trial. Patients, their families
and doctors like it because the patient has the greatest
chance of getting a positive effect because, in most
cases, the drugs are already approved for their type of
cancer. And they’re getting an extra kicker — another
agent that might help them even more.
Looking ahead a few years, what do you see? Will the
complete phase Ib become the “typical” approach?
I would say that it’s just another drug development

methodology. It doesn’t have to become the standard to
have utility. I’m hoping there will be even better ideas
down the road. Right now, we know it saves time and
effort. You see responses. And I think there’s a lot in it
for patients, which is one reason it’s catching on so fast.

The focus on combinations seems to be a major shift. It
wasn’t so long ago that sponsors were pursuing
approval for single agents only.
Cytostatic agents are okay by themselves but many

types are better in combination. Many of the recent
approvals are for combinations, potentially increasing
the relevance and need for the complete phase Ib. In
the old days, you usually got approval as a single agent
and then you would start the combination work.

How is the focus on combination therapy changing
business alliances among companies that are inherently
competitive?
There are some pioneering companies who are now

establishing overarching agreements to facilitate
combining their drugs, including investigational drugs
not yet approved. It is a powerful edge for two
pharmaceutical companies to work together in this
manner. It also gives smaller biotechs opportunities to
bridge to big pharma.

In your experience, how open have companies
been to these possibilities?
We do not have any trouble with established agents.

Most of the time, the sponsor of the standard agent will
supply the drug for a study because it could potentially
expand the agent’s utility, and they’re getting the rest
of the study free. If a biotech company can get the big
guys to supply the agent, then that really cuts down on
the cost. Everybody benefits.

What would happen if you had two
investigational agents in an arm?
That would take a lot more negotiation. But let’s face it,
if two investigational agents look more promising in
combination than either agent alone, why would you not
want to collaborate? I think those who do not will be left
in a cloud of dust.

At what stage in the drug development cycle should a
CMO of a small to medium-sized biotech start planning
for these potential alliances?
Right away, and definitely at the preclinical stage. A CMO

should be thinking, what is standard therapy now? What kind
of preclinical information will be required to structure one
study with multiple arms?
This kind of forward thinking can help enormously with funding

since you are talking about saving time and money — you are
funding just one study — and you don’t have to find the
needle in the haystack to get patients on these studies. It
generates interest in the molecule because you have
responses in various combinations. Once you see a response,
you have your evidence for moving forward. It sets you right
up for the
Medelis provides a full randomized
range of oncologyphase
contractII.
research & drug
So the complete phase Ib sounds like a win-win-win
since there is benefit to patients, investigators, and
sponsors?
Approaching the phase Ib as not just a toxicity trial but also a

therapeutic opportunity is actually a quadruple win. CMOs
benefit on the business side; they get better data faster,
helping to drive fundraising and corporate development.
Investigators have an opportunity to make an impact,
delivering better care and the chance for a better outcome.
And sponsors get answers faster and with less bureaucratic
hassle since trial management is streamlined.
Last but not least, the complete phase Ib is an important

opportunity to truly help patients. And in the end, that’s the
most valuable win of all.
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.
About Medelis
Medelis, Inc. is a single-source 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 internationally-recognized 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 privately-held 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.

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Medelis, Inc.

4105 N 20th St Ste 215

The Complete Phase

This presentation is based on our July 2008

You can sign up to receive an email notice for

In this conversation, renowned oncology investigator Dr.

This structure creates rapid accrual rates, substantial

The typical phase I approach is essentially serial drug development, which

Take the example of a monoclonal antibody. The preclinical information shows

Yes, and that alone is especially motivating to patients, since

The other advantage is that patients who are early on in their

Essentially you are escalating the dose of your

For example, I recommend using the full dose of the

Medelis provides a full range of oncology contract research & drug

Treating three patients per level gives confidence in

Medelis provides a full range of oncology contract research & drug

I like to have some animal model data that establishes

Medelis provides a full range of oncology contract research & drug

Entry criteria are important and can change the value of

Medelis provides a full range of oncology contract research & drug

Compared to the typical phase I approach, the complete

Medelis provides a full range of oncology contract research & drug

With our group, U.S. Oncology, we would run a complete

The other advantage is that sponsors are happy because the

The complete phase Ib gets you ready for your

Medelis provides a full range of oncology contract research & drug

In 2007, at ASCO, when we presented the complete

Medelis provides a full range of oncology contract research & drug

If you have good evidence for using an agent in an arm

Medelis provides a full range of oncology contract research & drug

Each trial is filed with an IND and performed with the

Medelis provides a full range of oncology contract research & drug

Investigators are enthusiastic about this approach. One

I would say that it’s just another drug development

Medelis provides a full range of oncology contract research & drug

Cytostatic agents are okay by themselves but many

Medelis provides a full range of oncology contract research & drug

There are some pioneering companies who are now

Medelis provides a full range of oncology contract research & drug

We do not have any trouble with established agents.

Medelis provides a full range of oncology contract research & drug

Medelis provides a full range of oncology contract research & drug

Right away, and definitely at the preclinical stage. A CMO

This kind of forward thinking can help enormously with funding

Approaching the phase Ib as not just a toxicity trial but also a

Last but not least, the complete phase Ib is an important

In Peer Perspectives in Oncology, Medelis brings together

To download additional issues in the series, please visit

Medelis, Inc. is a single-source provider for oncology CRO and drug

Medelis is privately-held and located in Phoenix, Arizona with other

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