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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.

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hcc journal club september 2009 statistical topic phase i studies

HCC Journal ClubSeptember 2009Statistical 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
Phase I studies
  • What are the goals?
    • Dose-finding
    • Safety
    • PK and PD
  • How are they designed?
  • What is the rationale for dose-selection?
fong et al
Fong et al.
  • Stated goals: Determine the following—
    • Safety
    • adverse-event profile
    • dose-limiting toxicity
    • maximum tolerated dose (MTD)
    • Dose at which PARP is maximally inhibited
    • PK profile
    • PD profile
study design
Study Design
  • “modified accelerated titration”
  • Not at all!
  • TRUE Accelerated titration design:
    • Treat 1 person per dose until either
      • 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:
    • 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
Back to basics: Acceptable toxicity
  • What is acceptable rate of toxicity?
    • 20%?
    • 30%?
    • 50%?
  • What is toxicity????
    • 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
‘3+3’ Design
  • “Standard” Phase I trials (in oncology) use what is often called the ‘3+3’ design (aka ‘modified Fibonacci’):
  • 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 K
  • If 0 patients experience dose-limiting toxicity (DLT), escalate to dose K+1
  • If 2 or more patients experience DLT, de-escalate to level K-1
  • If 1 patient experiences DLT, treat 3 more patients at dose level K
    • If 1 of 6 experiences DLT, escalate to dose level K+1
    • If 2 or more of 6 experiences DLT, de-escalate to level K-1
this is actually better than most
This is actually better than most
  • Most studies treat only 3 or 6 at each dose level
  • With 0 of 6 DLTs:
    • Estimated DLT rate = 0%
    • 95% CI for DLT rate = [0%, 45%]
  • With 1 of 6 DLTs:
    • Estimated DLT rate = 17%
    • 95% CI for DLT rate = [0%, 64%]
why do we use it all the time
Why do we use it all the time?
  • It is terribly imprecise and inaccurate in its estimate of the MTD
  • Why?
    • MTD is not based on all of the data
    • Algorithm-based method
    • Ignores rate of toxicity!!!
  • Likely outcomes:
    • 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
We could use smarter designs!
  • 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:
    • Accurate selection of dose (range) which hits target
    • Relatively few patients are treated
    • Relatively few patients are exposed to ineffective doses
this trial
This trial
  • 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
Novel Designs
  • Why not impose a statistical model?
  • What do we “know” that would help?
    • Monotonicity (often)
    • Desired level of DLT
  • Statistical models improve:
    • Prediction
    • Efficiency
  • Accelerated Titration: incorporates model (next slide)
  • Example: CRM (continual reassessment method)
    • 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)
how would crm have worked in this study
How would CRM have worked in this study?
  • 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 dose-finding.
discussion
Discussion
  • Phase 0 trials
    • PK and PD
    • single dose
    • 6-10 patients
  • Goals:
    • 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:
    • 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