(a.k.a. Phase I trials)
Dose Finding Studies
Dose Finding Dose finding trials: broad class of early development trial
designs whose purpose is to find a dose of treatment that is optimal with respect to simple criteria Toxicity Efficacy Low risk of side effects
Several dose related questions of interest in therapeutic development Dose-efficacy association Dose-safety association Schedule-efficacy association Interactions between therapies (i.e. combinations of
treatments)
Dose Finding Many possible dose optima
Minimum effective dose Maximum non-toxic dose Maximum tolerated dose Ideal therapeutic dose (hard to control)
General dose-finding question is complex, but tendency has been to focus on dose-safety association
Utilize some basic assumptions about the dose-safety association.
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Maximum Tolerated Dose (MTD) The classic objective of dose finding in oncology:
select the dose that yields a pre-specified frequency of toxicity.
Designs intended to be “dose titrations” of “optimizations” while allowing tolerable toxicity
Basic assumption of “more is better” leads to notion of “MTD”
Very prevalent approach, but obvious limitations with regard to the more general dose finding problem
With vaccine and other “non-toxic” treatments, MTD might not be an appropriate conceptualization of the desired outcome!
Idealized Dose Finding Design Randomly assign
subjects to one of a few doses.
Treat adequate number at each dose level
Fit plausible dose response model for interpolation
Get unbiased estimate of true dose-response probabilities.
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Ideal Design Not Feasible In human trials, we cannot randomize
patients to high doses until lower ones have been explored.
Instead, ‘sequential’ or ‘adaptive’ designs But,
we don’t want to treat many subjects at low, ineffective doses
We don’t want to use doses that are too high and produce frequent serious side effects
Commonly Seen Designs Up-down methods
Accelerated titration
Continual Reassessment Method (CRM)
Up-Down Designs Most common “Standard” Phase I trials (in oncology) use what is
often called the ‘3+3’ design
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.
Treat 3 patients at dose K1. If 0 patients experience dose-limiting toxicity (DLT), escalate to dose K+12. If 2 or more patients experience DLT, de-escalate to level K-13. 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+1B. If 2 or more of 6 experiences DLT, de-escalate to level K-1
Up-Down Design Considerations Number of patients per dose level: most
often 3, but can be any number of patients (usually between 1 and 6)
Choosing doses Equally-spaced (Modified) Fibonacci
“true” Fibonacci sequence is 1, 1, 2, 3, 5, 8, 13,… “golden ratio” properties where ratio of successive
numbers approaches 0.61803… Log-scale
Dose IncrementsDose step Equally
spacedModified Fibonacci
Log scale
1 1 1 1
2 2 2 (100%) 10
3 3 3.3 (67%) 100
4 4 5 (50%) 1000
5 5 7 (40%) 10000
6 6 9 (29%) 100000
7 7 12 (33%) 1000000
8 8 16 (33%) 10000000
Advantages of Classic Designs Simplicity of design, execution, inference Meet ethical needs of exploring low doses
first Provide simple, operational definition of
the target dose Considerable clinical experience and
comfort with their use They can be easily studied quantitatively
and possibly improved
Classic Designs in Practice Generally, not very accurate depiction of true
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Ideal stopping probabilities
True dose-toxicity probabilities
Operating characteristics of design
Additional Issues Require dose levels specified in advance Usually start far from target dose Don’t fully use information from previously
treated patients Don’t use information on ordinal response
(e.g. graded toxicity) Estimate of MTD is seriously biased or
invalid
Accelerated Titration Similar to traditional design with small
cohorts at low doses Attempts to use information in ordinal
toxicity responses at lower doses May reduce the number of patients
needed to reach MTD
Continual Reassessment Method
Allows statistical modeling of optimal dose: dose-response relationship is assumed to behave in a certain way
Can be based on “safety” or “efficacy” outcome (or both).
Design searches for best dose given a desired toxicity or efficacy level and does so in an efficient way.
This design REALLY requires a statistician throughout the trial.
Advantage is increased efficiency and precision, low bias compared to non-model-based methods
Disadvantage is sophistication
CRM history in brief Originally devised by O’Quigley, Pepe and Fisher
(1990) where dose for next patient was determined based on responses of patients previously treated in the trial
Due to safety concerns, several authors developed variants Modified CRM (Goodman et al. 1995) Extended CRM [2 stage] (Moller, 1995) Restricted CRM (Moller, 1995) and others….
Basic Idea of CRM
p toxic ity dose d a pj ja( | , ) exp ( )
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a= -2
a= -1
a= -0.5
a= 0
a= 0.5
a= 1
Model chosen by Mathew etal.
Many models to choose from….
Carry-overs from standard CRM Mathematical dose-toxicity
model must be assumed To do this, need to think about
the dose-response curve and get preliminary model.
More common to use a “logit” model
We CHOOSE the level of toxicity that we desire for the MTD (p = 0.30)
At end of trial, we can estimate dose response curve.
‘prior distribution’ (mathematical subtlety)
Modified CRM (Goodman, Zahurak, and Piantadosi, Statistics in Medicine, 1995)
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a= -2
a= -1
a= -0.5
a= 0
a= 0.5
a= 1
p toxic ity dose d a pj ja( | , ) exp ( )
Modified CRM by Goodman, Zahurak, and Piantadosi(Statistics in Medicine, 1995)
Modifications by Goodman et al. Use ‘standard’ dose escalation model until first toxicity is
observed: Choose cohort sizes of 1, 2, or 3 Use standard ‘3+3’ design (or, in this case, ‘2+2’)
Upon first toxicity, fit the dose-response model using observed data
Estimate a Find dose that is closest to toxicity of 0.3.
Does not allow escalation to increase by more than one dose level.
De-escalation can occur by more than one dose level. Dose levels are discrete: need to round to closest level
Starting the CRM Assume a=0 to start Want dose with DLT rate of 30%
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a = 0
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Observe first cohort 0 out of 6 treated at
30 mg/m2 had DLT Use statistical
model to find best estimate of a based on updated information:
”What value of a is most consistent with data, given our model?”
a = 0.74
Observe second cohort 3 out 4 treated at 45 mg/m2 had DLTs Combine with 1st cohort information to update a:
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a = 0.38
Observe third cohort 5 out 6 treated at 35 mg/m2 had DLTs Combine with other cohort information to update a:
a = -0.25
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Observe fourth cohort 3 out 6 treated at 30 mg/m2 had DLTs Combine with other cohort information to update a:
a = -0.34
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Here, they decided tostop and declare 30 mg/m2 the MTD
Why did they stop? Not completely clear Looks like their
model did not adequately describe toxicities
Too flat Perhaps a more
flexible model (2 parameter) would have been better
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Other possible modeling options
Pros and Cons of CRM Advantages
Estimation method is not biased Does not depend strongly on starting dose Efficient for finding target dose Encapsulates subjectivity of dose-finding designs Can use ordinal information Can incorporate PK data in dose escalation
Disadvantages/Criticisms If model choice is not flexible, might not escalate and
estimate efficiently Clinicians do not like complexity Some worry about treating patients at high dose levels
Summary Oncology dose finding tends to be very
narrowly focused methodology Classic dosing studies are deficient for
dose finding CRM is method of choice for finding
optimal dose Application of CRM can be improved by
careful planning Extensions exist for CRM and classic
designs for “dual dose” finding
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