Transcript HCC Journal Club.sept2009.phaseI

HCC Journal Club
September 2009
Statistical Topic: Phase I studies
Selected article:
Fong, Boss, Yap, Tutt, Wu, et al.
Inhibition of Poly(ADP-Ribose) Polymerase in
Tumors from BRCA Mutation Carriers
The New England Journal of Medicine
July 9, 2009.
Vol. 361, No. 2, pp. 123-134
Phase I studies
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What are the goals?
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Dose-finding
Safety
PK and PD
How are they designed?
What is the rationale for doseselection?
Fong et al.
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Stated goals: Determine the following—
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Safety
adverse-event profile
dose-limiting toxicity
maximum tolerated dose (MTD)
Dose at which PARP is maximally inhibited
PK profile
PD profile
Study Design
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“modified accelerated titration”
Not at all!
TRUE Accelerated titration design:
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Treat 1 person per dose until either
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one DLT is observed
OR, two grade 2 toxicities
Then, treat 3 patients per dose level
Dose steps can be doubling or not.
Fong study:
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uses standard 3+3.
probably called modified AT because allows doubling of
dose in the absence of grade 2 or higher.
Is NOT accelerated titration in the spirit of the original
paper
Back to basics: Acceptable toxicity
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What is acceptable rate of toxicity?
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20%?
30%?
50%?
What is toxicity????
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Standard in cancer: Grade 4 hematologic or
grade 3/4 non-hematologic toxicity
Always?
Does it depend on reversibility of toxicity?
Does it depend on intensity of treatment?
 Tamoxifen?
 Chemotherapy?
‘3+3’ Design
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“Standard” Phase I trials (in oncology) use what is often
called the ‘3+3’ design (aka ‘modified Fibonacci’):
Treat 3 patients at dose K
1. If 0 patients experience dose-limiting toxicity (DLT), escalate to dose K+1
2. If 2 or more patients experience DLT, de-escalate to level K-1
3. If 1 patient experiences DLT, treat 3 more patients at dose level K
A. If 1 of 6 experiences DLT, escalate to dose level K+1
B. If 2 or more of 6 experiences DLT, de-escalate to level K-1
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Maximum tolerated dose (MTD) is considered highest
dose at which 1 or 0 out of six patients experiences DLT.
Doses need to be pre-specified
Confidence in MTD is usually poor.
0.0
0.2
0.4
0.6
0.8
Proportion of Patients with DLT
1.0
Observed Data in Fong Study
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2
3
Dose Level
4
5
0.8
0.6
0.4
0.2
0.0
Proportion of Patients with DLT
1.0
Observed Data: with 95% confidence intervals
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2
3
Dose Level
4
5
This is actually better than most
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Most studies treat only 3 or 6 at
each dose level
With 0 of 6 DLTs:
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Estimated DLT rate = 0%
95% CI for DLT rate = [0%, 45%]
With 1 of 6 DLTs:
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Estimated DLT rate = 17%
95% CI for DLT rate = [0%, 64%]
Why do we use it all the time?
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It is terribly imprecise and inaccurate in its estimate of
the MTD
Why?
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MTD is not based on all of the data
Algorithm-based method
Ignores rate of toxicity!!!
Likely outcomes:
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Choose a dose that is too high
 Find in phase II that agent is too toxic.
 Abandon further investigation or go back to phase I
Choose a dose that is too low
 Find in phase II that agent is ineffective
 Abandon agent
We could use smarter designs!
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Phase I is the most critical phase of drug
development!
What makes a good design? MTD situation:
 Accurate selection of MTD
 dose close to true MTD
 dose has DLT rate close to the one specified
 Relatively few patients in trial are exposed to toxic
doses
What makes a good design? Non-toxic agent
situation:
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Accurate selection of dose (range) which hits target
Relatively few patients are treated
Relatively few patients are exposed to ineffective doses
This trial
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Is MTD relevant?
What is the goal?
Should we be looking for hitting the
target?
Toxicity ~ Efficacy?
PK and PD data presented
Although argument made for MTD,
PARP inhibition is relatively constant
for the higher doses
Novel Designs
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Why not impose a statistical model?
What do we “know” that would help?
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Statistical models improve:
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Prediction
Efficiency
Accelerated Titration: incorporates model (next slide)
Example: CRM (continual reassessment method)
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Monotonicity (often)
Desired level of DLT
Originally devised by O’Quigley, Pepe and Fisher (1990)
dose for next patient was determined based on toxicity
responses of patients previously treated in the trial
Others out there (and variations of CRM)
0.8
0.6
0.4
0.2
0.0
Proportion of Patients with DLT
1.0
Another Accelerated Titration Feature: Model fit
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Dose Level
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CRM example
CRM software example
How would CRM have worked in this
study?
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Would have accelerated quickly
Would have iterated at a few doses
May not have treated so many patients
at MTD
Would likely have been a smaller study
Could have used PD data to help dosefinding.
Discussion
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Phase 0 trials
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Goals:
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Define dose range for Phase I
Improve chance of success in phase I and II
Better planning of phase I
New and exciting!
First in man, pre-Phase I
Messy though:
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PK and PD
single dose
6-10 patients
Phase 0 vs. Phase 1?
How will this change Phase 1 goals?
My humble opinion: the development of Phase 0 strongly
suggests that Phase I paradigm needs to be reconsidered