Dr. Sam Lubner MD, FACP of University of Wisconsin Carbone Cancer Center presented to the Research Academy RATS a presentation on Clinical Trials

1. Clinical Trials and Cooperative
Group Studies
Sam J. Lubner MD, FACP
University of Wisconsin Carbone Cancer Center

2. Objectives
• Understand the concept of clinical trials and
the differences across the phases
• Understand why cooperative groups are
necessary for many/any disease type
• Bemoan why it takes so much time and
money to answer a relatively simple question

3. Why it matters
• It currently costs around $1.2B to successfully
bring a compound through trials to market.
• Most drugs fail.
– Enormous cost/risk for failure
• It takes about 8 years to go from phase 1
testing to approval (with some exceptions).

4. How do we decide what works?
• Pre-clinical data gives us a hint.
• In vitro as a start
• High-throughput screening
– Expose a ton of compounds to a series of cancers
all at once
• Animal models better
– Gives a sense of tolerability
• Tons of improvements in this area right now
• Tons more to do…

5. A story…

6. Ripped from the headlines
• Epidermal growth factor receptor (EGFR) was
found to be important in tumor growth in
cancer cells grown in culture
• Inhibition of EGFR was found to be possible in
1988.
• IMC-225 was created in the late 1990’s out of
a lab in Israel, and a company called ImClone
was started

7. Phase 1 clinical trials
• Dose-finding and toxicity finding, ‘first in
human’ studies
• Take a drug that has been through in vitro and
animal testing
• Start at the LD10 (the dose at which 10% of
animals died)

8. Traditional phase 1 studies
• Patients with refractory malignancies
• Already treated with ‘everything’
• Still feeling ok
• Truly altruistic
• High risk/high reward (for patients)
• Endpoints: toxicity, “Maximum Tolerated
Dose” (MTD)
• All open label, no randomization or placebo

9. How do they work?
• Classical 3+3 design
– Challenges
• Underdosing first few
cohorts
• Overdosing second-to-last
cohort
• Modified designs
– Targeting a “biologically
effective dose”

10. What does success look like?
• Dose found that is both biologically plausible
and tolerable to patients
• Responses achieved in a subset of patients
– Why did they respond?
– Were there similarities between the responders?
– Historical response rates: 5%
• Dose expansion cohorts in some subsets of
patients

11. Next chapter
• In a phase 1 study, IMC-225 showed 2 partial
responses out of 13 treated patients.
• Data published in 2000 in the Journal of
Clinical Oncology. (our big journal)
• Based on those responses, phase II studies
were proposed in colorectal and head and
neck cancers that overexpressed EGFR.

12. Phase II studies
• After the dose and schedule are worked out,
how do we determine success?
• Patients for whom there is biological
plausibility of effectiveness, or demonstrable
effectiveness in phase 1 studies
• More patients, looking for a signal of
effectiveness that can be more broadly
applied

13. Phase II
• Typically still pretty small
– 40-100 patients
• Open-label
• Occasionally randomized
– Can test two drugs at once, or one drug against what is
already out there
• Typically still late-line, heavily pretreated
• Endpoints would be some endpoint to serve as a
surrogate for helping people live longer
– Response rate
– Progression-free survival
– Disease control rate

14. Home run
• In a heavily pretreated population, a response
rate or stable disease rate of anything more
than a few percent is an important finding
• Start thinking about further clinical trials and
ways to adopt this into practice
• Sometimes, FDA approval happens after a
great phase II study.

15. Back to the story
• IMC-225, now called ‘cetuximab’, produced
response rate of 9% (5/57 patients) with
EGFR-overexpressing colon cancer
• Tons of excitement
• 60 Minutes did a piece on it, advocated for
expanded access through “compassionate
use”
• Heralded as a breakthrough, thought to get
FDA approval on a fast-track basis

16. A good thing…
• Expected FDA approval was held up because
an initial study in colorectal cancer failed to
show a survival benefit.
– This drug is why Martha Stewart went to jail…
• However, in a subset of patients, it generated
remarkable responses…

17. What happens now?
• In those 5 patients, what was unique?
• Is there a reason the others did not respond?
• Better understanding of disease biology led to
improved targeting.
• Data reanalysis suggested that the drug could
be saved…

18. Tempered enthusiasm
• With more study into
the pathway, we
learned more about
how the drugs work and
how cancer might have
primary
resistance/develop
secondary resistance to
the drugs

19. Back to the drawing board
• Further studies showed its effectiveness in the
treatment of colon cancer, both as a single
agent and combined with other
chemotherapies.
• FDA approval came based on a phase III study
showing a survival benefit in heavily
pretreated patients in February of 2004.

20. Next phase, USE IT FOR
EVERYTHING!!!
• Trials using cetuximab in every line, every
combination, and every setting were
undertaken

21. Phase III studies
• After showing safety (phase I) and a hint of
efficacy (phase II), a comparison against
existing treatments is necessary
• Much more costly
• Much more time-consuming
• Requires blinding, randomization to avoid bias

22. Phase III studies
• High-risk/High-reward (for companies)
• Requires a ton of regulatory oversight
– IRB
– Data safety monitoring
– Entirely protocol driven
• Typically sponsored by companies, best run by
governments/neutral parties

23. Design options
• How do we randomize?
• What is the effect size
we are looking for?
• Is randomization
ethical?
• Do we offer crossover?
• Unblinding at study
conclusion?

24. Phase III studies
• Really brass-tacks as far as endpoints
– Do patients live longer as a result of drug x when
compared to the standard
• Safety reporting
– Talk to your doctor about…
• “Registration trial”

25. Phase III trial
• In each clinical scenario, a phase III trial needs to be conducted to
show efficacy compared to what is already out there.
• CRYSTAL study (First line): response rates 59.3%, overall survival
improved in in KRAS WT patients compared to FOLFIRI alone
– 1198 patients
• COIN (First line): Response rates improved, OS not changed when
added to FOLFOX
– 1630 patients
• BOND-2 Outcomes worse with avastin and cetuximab combined
– More adverse events, worse PFS results
– 755 patients
• PETACC-8 (adjuvant): The addition of cetuximab did NOT improve
DFS compared with FOLFOX alone in resected stage III colon cancer
• 2559 patients, 340 sites.

26. Phase III trials
• Generally, cost per patient on a clinical trial is
between $25-40K.
• 6142 patients just on those four studies.
– $153,550,000-$245,680,000
• There were many more studies looking at the
same thing.

27. Competition in the marketplace
• Similar compound developed and tested by
Amgen
• Similarly confusing results were seen.
– Why did it work really well in some patients, and
so poorly in others?
– Why didn’t it work as adjuvant therapy?

28. After all that…
• Thousands of patients
• Billions of dollars
– 2008, ImClone (sole product was cetuximab) was
sold to Eli Lilly for $6.5 B…
• Hypotheses proven
– Targeting EGFR is possible, safe, and improves
overall survival for patients with metastatic colon
cancer
• Surprising findings

29. What else have we learned?
• Response rates are better with cetuximab in the first
line setting
• Overall survival not really changed when you start with
cetuximab or avastin in WT patients
• There are other mutations besides KRAS that mean
that the drug won’t work
– HRAS, NRAS, BRAF
• Responses are great but don’t last forever.
• Cetuximab and panitumumab work about the same
– Fewer infusion reactions with pan, less rash overall with
cet

30. Why does any of that matter to
you guys?
• As a group interested in maximizing efforts to
improve clinical trials for patients with colorectal
cancer, it is important to be mindful of the
process.
• When reviewing the study ask yourself:
– Is the question valid?
– Will the study answer the question?
– Is the study worth the risk?
• To the patient
• To society
• These questions are critically important

31. How can we do this?
• It takes hundreds/thousands of patients to
sort these questions out.
• Cooperative group studies critical to drug
development.

32. What are cooperative groups?
• Groups of doctors willing to work together to
answer important questions.
• Examples
– Eastern Cooperative Oncology Group/ACRIN
– Southwestern Oncology Group
– Big Ten Cancer Research Consortium
– National Cancer Clinical Trials Group
– Gynecologic Oncology Group

33. Cooperative groups
• Advantages
– Can get tons of patients
– Can be quick to accrue
once all sites are open
– Well-respected studies
– Leverage strengths of
different institutions
– Can ensure protocol
adherence
• Disadvantages
– Slow
• To design
• To open
– Practice sometimes not
uniform
– Different techniques at
different places
– Takes a ton of staffing to
get it right

34. How do they work?
• Ideas from investigators in the group go to the
steering committee.
– Usually esteemed investigators/thought leaders
• The steering committee decides yay/nay
• Idea needs a sponsor
– Industry?
• Who provides drug?
– Private donations?
• Who pays for science?
– Government (gold standard)

35. Once the go-ahead is achieved
• Members of the cooperative group decide
whether or not to open at their sites
– Seems like a no-brainer
– But…
• Accrual is complete
• Findings are presented/published
• Sam/Dusty/Nataliya get promoted.

36. What about this moonshot thing?
• Goal is to make discoveries faster, at lower
cost
• Is it the science that is so hard, or the
infrastructure?

37. I mean, how hard can it be?