the lost art of phase i oncology clinical trials

8/14/2019 The Lost Art of Phase I Oncology Clinical Trials

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Medelis, Inc.4105 N 20th St Ste 215Phoenix, Arizona 85016Phone: 602.840.1101www.medelis.com

The Lost Opportunity inPhase 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.


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Medelis provides a full range of oncology contract research & drug development

services from preclinical through NDA. Download our abstracts or read our blog atwww.medelis.com.

Welcome

This presentation is based on our December 2008issue ofPeer Perspectives in Oncology, a free Q&Aseries focused on issues that face Chief Medical

Officers today: rising costs, optimum patient accrual,targeted therapeutics, patient safety, FDAregulations, efficacy, budgets, and timelines.

You can sign up to receive an email notice for future

issues at www.medelis.com/oncology_abstracts.html.
http://www.medelis.com/oncology_abstracts.html.http://www.medelis.com/oncology_abstracts.htmlhttp://www.medelis.com/oncology_abstracts.html


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The Lost Opportunity in Phase I Oncology Trials

Traditionally, drug developers have regarded the phase I trial ashaving a utility limited to the assessment of safety, tolerability,and pharmacokinetics and pharmacodynamics of a drug.

In this issue ofPeer Perspectives in Oncology, renownedoncology investigator Dr. Daniel Von Hoff describes how ChiefMedical Officers can design better oncology phase I trials toglean meaningful efficacy data by using the patient as his or herown control. He further explains how a CMO can gatherevidence showing a drug changes the natural history of apatients disease, demonstrating improved care and a strongercase for moving a drug into phase II.
http://www.medelis.com/oncology_abstracts.html


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About Dr. Daniel Von Hoff

Daniel D. Von Hoff, M.D. is Senior Investigator and Head of Translational Research at the TranslationalGenomics Research Institute's (TGen) Translational Drug Development Division and Head, PancreaticCancer Research Program in Phoenix, Arizona. He also serves as Chief Scientific Officer for U.S. Oncologyand 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 thelaboratory. 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 ofmolecularly targeted therapies.

Dr. Von Hoff's laboratory interests and contributions have been in the area of in vitro drug sensitivitytesting to individualize treatment for the patient. He and his laboratory are now concentrating ondiscovery of new targets in pancreatic cancer. Dr. Von Hoff has published more than 529 papers, 129book 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 AmericanCollege of Physicians, and a member and past board member of the American Society of ClinicalOncology. He is a founder of ILEX Oncology, Inc. (acquired by Genzyme). He is founder and EditorEmeritus 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.


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Dan, you believe that many CMOs today are missing a valuable opportunity to gainmore meaningful data from phase I oncology trials. That seeing each patient as hisor her own control may hold a key to later success and create a more compellingstory for management & investors. Can you describe in detail what you mean?

Yes, and its very simple. Typically, a CMO sees phase I as atoxicity trial, not a therapeutic trial, because of course it isntrandomized. But the doctors at the bedside and the patientsthemselves dont see it as purely a toxicity trial. Were looking for

improvement and survival. And even during phase I, we can gleanimportant efficacy clues by using the patient as his or her owncontrol.

Recently, at AACR, I reported on findings involving nine patients ina phase I trial showing dramatic tumor shrinkage with no side

effects with an oral agent. Clearly the drug did something. Itslowed down the disease and the patients benefited. In fact, thedrug changed the natural history of each patient.


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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 patients disease.


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In the context of a trial, it seems counter-intuitive to look at the individual patient.

The reason its so important to look at each individual

patient is because each patients tumor has a

different natural history. Everyones 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 doingsomething right.


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Do you systematically track this informationfor each patient?

Yes. In fact, I now recommend including this

kind of information time to progression on

each drug in the protocol so it becomespart of each patients database.


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How should a CMO incorporate this data intothe 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, youadd a line that specifies that one of the

secondary endpoints is the time patients are

on treatment with a new agent versus thetime they were on their just-prior drug.


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You refer to measuring time on therapy as opposedto time to progression? Whats the distinction?

With time to progression you need to be

taking regular measurements such as scans.

In comparison, time on therapy takes otherthings into consideration.


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That turns it into a more subjective, generalindicator. Is that good?

It helps because it takes into consideration

clinical judgment, or peoples observational

powers, which can be beneficial in addition toscans.


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And therein lies the art of the matter: thepower 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.


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Are CMOs starting to do this as a matter of course using timeon drug to demonstrate improvement, then using that data tomake 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 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. Hes referring to the ability to document

changes in the natural history of a patients tumor, and

how this information can give you a sense of whether

the drug will work.


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Does the approach of using a patient as their own controlstill work in the case of cyostatic drugs, which affect cellswithout decreasing tumor size?

Even if an agent isnt 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

patients tumor. And, if at the higher doses, you have more peoplewith 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 didnt 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 arent giving this information enough value.


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At what point would you feel validated to invest moredeeply in a particular therapy based on informationdeduced 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 thatwould justify a deeper investment. Patients

tumors grow at an inexorable rate. If you find

an agent that can taper that growth, then it isprobably doing something and should be

pursued.


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Why isnt this a more common practice?

Its not how people report. Instead of time ona therapy, they report stable disease overtime. Unless they know how fast the tumor

was growing in the first place, there is noreference point. If a patient has a short timeto progression when you put them on study,they have a fast-growing tumor. If you slowits growth, you can tell right away bycomparing time to progression.


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So the phase I shouldnt just focus onmaximum tolerable dose?

Exactly. Its an opportunity to look for

therapeutic effect as well. If its there,

patients benefit and you have a great start.


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So the payoff for CMOs changing how theysee the phase I could be substantial.

Theres no question in my mind. If a CMO

started comparing time on new drug versus

time on just-prior therapy, they would have abetter 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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About Peer Perspectives in Oncology

In Peer Perspectives in Oncology, Medelis brings together some of the

industrys most respected researchers to talk about the issues facing

Chief Medical Officers today. Theyre 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, well 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.
http://www.medelis.com/oncology_abstracts.html


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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 forEuropean & Asian sponsors and is headquartered in Port Vendres, France.
http://www.medelis.com/

the lost art of phase i oncology clinical trials

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