Oncology Dose Finding A Case Study: Intra-patient Dose Escalation

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Oncology Dose FindingA Case Study Intra-patient
Dose Escalation

• Jonas Wiedemann, Meghna Kamath Samant Dominik
  Heinzmann, pRED Biostatistics, Valerie Cosson
  Sylvie Retout, pRED TRS
• F. Hoffmann-La Roche

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Outline

• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why is This of Interest?
• Imaging Study
• Statistical Methodology
• Lessons Learned Further Development

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• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why is This of Interest?
• Imaging Study
• Statistical Methodology
• Lessons Learned Further Development

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Oncology Dose FindingOverview

• Several different approaches are more or less
  commonly seen
• Conventional rule based 33
• Continual Reassessment Methodology (CRM)
• More advanced methods combining toxicity and
  efficacy
• Intra-patient Dose Escalation

Commonly acknowledged that more advanced and
innovative methods are needed using accumulated
information such as Bayesian methodologies
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FDA point of viewA need for innovative designs

• Increasing spending of biomedical research does
  not reflect an increase of the success rate of
  pharmaceutical development.
• Many drug products were recalled due to safety
  issues after regulatory approval.
• Critical path initiative
• In its 2004 Critical Path Report, the FDA
  presented its diagnosis of the scientific
  challenges underlying the medical product
  pipeline problems.
• Advancing innovative trial designs Use of prior
  experience or accumulated information in trial
  design
• Insufficient exploration of the dose-response
  curve is often a key shortcoming of clinical drug
  development

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Accelerated Titration DesignsA direct comparison
to 33

• In 2008 Penel et. al. compared the performance of
  ATD and 33 in 270 (19972008) published phase
  I trials
• ATD had been used in only 10 of the these
  studies
• ATD had permitted to explore significantly more
  dose levels (seven vs. five)
• ATD reduced the rate of patients treated at doses
  below phase-2 recommended dose (46 vs. 56,)
• Nevertheless, ATD did not allow a reduction in
  the number of enrolled patients, shorten the
  accrual time nor increase the efficacy

However, still support ATD as an effective
clinical trial design over a standard 33
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Intra-patient Dose EscalationPros cons

• Pros
• Intra-patient dose escalation designs are
  generally used in ethical grounds, i.e. to
  address the fact that in cancer research it may
  be unethical to only provide sub therapeutic
  doses to cohorts of patients
• Fewer patients needed, i.e. lower costs, faster
  study conduct
• Meaningful if no toxicity is expected
• If analyzed properly, they can provide
  information about inter-patient variability in
  doseresponse effects
• The succession of dose levels is not necessarily
  determined completely by choices made before the
  onset of the trial

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Intra-patient Dose EscalationPros cons

• Cons
• However, though appealing these designs are not
  commonly applied due to some theoretical and
  practical objections
• Successive observations in a single patient are
  correlated. Hence, difficult to know if toxicity
  is due to current dose or cumulative exposure
  (same potential issue for PD markers)
• May not be feasible due to the fact that most
  patients in phase 1 studies would only stay on
  drug for 2 to 3 cycles of therapy due to rapidly
  progressive disease
• Could potentially create some selection bias
  (prognostics, characteristics, etc.)

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• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why is This of Interest?
• Imaging Study
• Statistical Methodology
• Lessons Learned Further Development

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Why is This of Interest?Project overview

• Anti-body, angiogenesis inhibitor (inhibits
  growth of new blood vessels, especially by
  inhibiting vascular permeability)
• Tested in first-in-man multiple dose ascending
  study with a dose of up to 3 mg/kg, no observed
  toxicity, and a ½ life of 9 days
• Dose schedule simulated and a q2w approach chosen
• DCE-MRI as angiogenic PD marker values
  (Ktrans, Kep, AUC90, Ve) directly related to

• Blood volume

• Blood flow

• Extracellular Extra-vascular Space - ESS

• Rate of extravasation

• In addition, low within-patient variability

Dynamic Contrast Enhanced-Magnetic Resonance
Imaging
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DCE-MRI methodology Excellent reproducibility
ml/ml/min
2 paired pre-treatment scans (Ktrans wSD
0.10-0.11)
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Why is This of Interest?Decision to go for
intra-patient dose escalation

• Angiogenesis inhibition confirmed and DCE-MRI as
  angiogenic PD marker low within-patient
  variability
• No observed toxicity and tentative dose found in
  first-in-man study However, still uncertainty
  about actual therapeutic dose -gt alternative
  approach needed
• Modeling and simulation methods explored and
  tools in place, i.e. Bayesian, WinBugs, EDC, etc.
  -gt practical feasible
• By introducing large dose-escalating steps /
  relatively short half life -gt faith in
  observed Toxicity/PD dose-response

Phase I intra-patient dose escalation imaging
study to establish PD dose-relationship measured
as DCE-MRI
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• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why is This of Interest?
• Imaging Study
• Statistical methodology
• Lessons Learned Further Development

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Imaging StudyOverall target

• Establish exposure PD relationship for single
  agent
• Identify the minimal PD effective dose
• Confirm MoA
• Confirm feasibility of DCE-MRI

100 250 750
2500 3000
Dose (mg)

• by applying intra-patient dose escalation with 3
  initial dose steps
• by applying a Bayesian approach

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Study Overview
Initial Test Cohort 6-10 subjects
Highest dose
DCE-MRI signal
DCE-MRI signal
Terminate study
First intra-patient Dose Escalation Cohort 6-10
subjects
non-interpretable DCE-MRI signal
Parallel Fixed Dose Cohorts 6-10 subjects pr
cohort
Adapted Intra-patient Dose Escalation
Cohorts 6-10 subjects pr cohort
Allows timing
of PD/BM adjustment dose scheme adjustment
Adapted Confirmatory Parallel Fixed Dose
Cohorts 6-10 subjects pr cohort
Allows Further adjustment of timing
and no of assessments
Tumor Biopsy Evaluation Cohort 10 subjects on
lowest efficacious dose
Up to 50 subjects will be evaluated in total
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• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why This Interest?
• Imaging Study
• Statistical methodology
• Lessons Learned Further Development

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Primary PK/PD ModelingBayesian approach
Primary model

• A direct inhibitory Imax model
• Two unknown parameters to be estimated, i.e. Imax
  and IC50 (both assumed to be Gaussian distributed
  with mean and precision)
• With
• E the DCE-MRI parameter, i.e. Ktrans, Kep, Ve, Vp
  and iAUC,
• E0 the DCE-MRI parameter at baseline,
• Cp the drug concentration at the time of DCE-MRI
  assessment,
• Imax the maximum decrease of the DCE-MRI
  parameter (0ltImaxlt1),
• IC50 the drug concentration at which 50 of max
  inhibition is reached.

If possible, an exploratory indirect model to
investigate time delay in DCE-MRI
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Primary PK/PD ModelingBayesian approach
General principles
- unknown parameters are interpreted in terms of
probability
Prior distribution on IC50 (and Imax)
A posterior mean value and precision
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Bayesian Method

• Advantages
• Combines a priori knowledge, including
  uncertainty, with new data
• Allows an increase of that knowledge, even with a
  low number of subjects
• Basis for formal approach to incremental model
  building, parameter estimation and other
  statistical inference as knowledge and data are
  accumulated
• Implemented in Winbugs 1.4.3
• Issues
• Construction of prior distributions is a somewhat
  subjective process
• Apparently very sensitive to the choice of the
  priors
• Bayesian inference is based on Monte Carlo Markov
  Chain
• Iterative process which eventually converges to
  the posterior distribution
• Requires high number of samples (5000 10000) gt
  time consuming

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• Oncology Dose Finding
• - Intra-patient Dose Escalation Pros
  Cons
• Why This Interest?
• Imaging Study
• Statistical methodology
• Lessons Learned Further Development

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Lessons Learned - so far

• Regulatory feedback (EU)
• Study approved in 3 EU countries without major
  issues
• Validation of analytical methods required for
  future studies
• Concern about high dose for Initial Test Cohort
• Feedback from clinicians/operational
• Internal
• Open minded lead clinician could have been an
  issue!!!
• Some opposition from operational
• External
• Investigators very open and helpful in setting up
  study
• Status Study still ongoing 4 patients enrolled
  in Initial Test Cohort
• Status Good feedback on DCE-MRI data quality
• However, some issues with too large tumors since
  DCE-MRI here is less sensitive

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Further DevelopmentCurrent dilemmas?

• Phase Ib/IIa combination study planed in
  recurrent Glioblastoma (GBM)
• Target to estimate the treatment benefit of
  combined treatment (with launched anti-angiogenic
  agent)
• Endpoint Progression-free-survival
• DCE-MRI as PD and clinical marker?
• Future dose when moving into a combination
  treatment
• Should be based on a toxicity/efficacy trade off?
• Possibility to adjust the dose of the launched
  agent?
• Phase 3 gating?
• Further disease areas? difficulties in
  generalizing

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References

• Simon, R. Accelerated Titration Designs for Phase
  I Clinical Trials in Oncology, JNCI, 1997
• Orloff, J. The future of drug development
  advancing clinical trial design, NATURE, 2009
• Whitehead, J. Easy-to-implement Bayesian methods
  for dose-escalation studies in healthy
  volunteers, Biostatistics, 2001
• Thall, P. F., Dose-Finding Based on
  Efficacy-Toxicity Trade-Offs, Biometrics, 2004
• Chang, M. A Hybrid Bayesian Adaptive Design for
  Dose Response Trials, Journal of
  Biopharmaceutical Statistics, 2005
• Penel, N., Classical 33 design versus
  accelerated titration designs analysis of 270
  phase 1 trials investigating anti-cancer agents,
  Invest New Drugs, 2009

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• Thanks!
• Contact info Jonas.wiedemann_at_roche.com

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