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									Oncology Dose Finding
A 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
                                                    2
Oncology Dose Finding

    - Intra-patient Dose Escalation – Pros & Cons


Why is This of Interest?

Imaging Study

Statistical Methodology

Lessons Learned & Further Development
                                                    3
Oncology Dose Finding
Overview

Several different approaches are more or less commonly seen:

• Conventional rule based “3+3”

• 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


                                                                       4
FDA point of view
A 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
                                                                             5
Accelerated Titration Designs
A direct comparison to “3+3”

• In 2008 Penel et. al. compared the performance of ATD and “3+3” in
  270 (1997–2008) 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 “3+3”
                                                                          6
Intra-patient Dose Escalation
Pros & 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 dose–response effects

• The succession of dose levels is not necessarily determined
  completely by choices made before the onset of the trial

                                                                           7
Intra-patient Dose Escalation
Pros & 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.)
                                                                        8
Oncology Dose Finding

     - Intra-patient Dose Escalation – Pros & Cons


Why is This of Interest?

Imaging Study

Statistical Methodology

Lessons Learned & Further Development
                                                     9
   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 -
      Rate of extravasation
     ESS

       In addition, low within-patient
      variability                                                       10
* Dynamic Contrast Enhanced-Magnetic Resonance Imaging
            DCE-MRI methodology – Excellent reproducibility
ml/ml/min




            2 paired pre-treatment scans (Ktrans: wSD ~ 0.10-0.11)   11
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 −>
  alternative approach needed

• Modeling and simulation methods explored and tools in place, i.e.
  Bayesian, WinBugs, EDC, etc.   −>    practical feasible

• By introducing large dose-escalating steps / relatively short half life
  −> faith in observed Toxicity/PD dose-response


                          Phase I intra-patient dose escalation
                          imaging study to establish PD dose-
                          relationship measured as DCE-MRI                  12
Oncology Dose Finding

     - Intra-patient Dose Escalation – Pros & Cons


Why is This of Interest?

Imaging Study

Statistical methodology

Lessons Learned & Further Development
                                                     13
Imaging Study
Overall target
 Establish exposure – PD
  relationship for single agent

 Identify the minimal PD effective                                                     Dose - DCE-MRI inhibition

  dose                                                                  120




                                             Inhibition of Ktrans (%)
                                                                        100
 Confirm MoA                                                           80

                                                                        60
 Confirm feasibility of DCE-MRI                                        40

                                                                        20

                                                                         0
                                                                          0.01   100 0.1 250    1   750     10 2500   100 3000 1000
                                                                                                Dose (mg/kg)
                                                                                                 Dose (mg)




                 - by applying intra-patient dose escalation with 3 initial dose steps

                 - by applying a Bayesian approach                                                                               14
                                  Initial Test
Study Overview                    Cohort
                                                             Highest dose

                                       6-10 subjects
                      DCE-MRI signal                   DCE-MRI signal



      First intra-patient                                      Terminate study
       Dose Escalation
            Cohort
          6-10 subjects                non-interpretable DCE-MRI signal


     Adapted Intra-patient       Allows
                                                              Parallel Fixed
       Dose Escalation           timing of PD/BM              Dose Cohorts
           Cohorts               adjustment dose scheme       6-10 subjects pr
                                 adjustment                       cohort
      6-10 subjects pr cohort

    Adapted Confirmatory               Allows
                                       Further adjustment
     Parallel Fixed Dose               of timing and no of
           Cohorts                     assessments            Tumor Biopsy
      6-10 subjects pr cohort                                  Evaluation
                                                                 Cohort
   Up to 50 subjects will be evaluated in total                 10 subjects on     15
                                                              lowest efficacious
Oncology Dose Finding

     - Intra-patient Dose Escalation – Pros & Cons


Why This Interest?

Imaging Study

Statistical methodology

Lessons Learned & Further Development
                                                     16
Primary PK/PD Modeling
Bayesian 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)

                                                     I m ax  Cp 
                                      E  E 0  1 
                                                                 
                                                    IC50  Cp   
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 (0<Imax<1),

•     IC50 the drug concentration at which 50% of max inhibition is reached.

                                                                               17
*   If possible, an exploratory indirect model to investigate time delay in
Primary PK/PD Modeling
Bayesian approach – General principles
- unknown parameters are interpreted in terms of
probability
 Prior distribution on IC50 (and Imax)                      Observed PD data

                         IC 50 ~   N ( IC 50 ,  1 )
                                          1
                                                 IC



                                                       +



                                                           A posterior mean value
   Bayesian                                                and precision
   estimation

                                                                                    18
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
             koutP chains 1:2

        0.06
      • 0.04Requires high number of samples (5000 – 10000) => time consuming
           0.02

            0.0

                  4001   4500    5000
                                iteration
                                            5500   6000
                                                                               19
Oncology Dose Finding

     - Intra-patient Dose Escalation – Pros & Cons


Why This Interest?

Imaging Study

Statistical methodology

Lessons Learned & Further Development
                                                     20
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
                                                                              21
Further Development
Current 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

                                                                        22
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 3+3 design” versus “accelerated titration
  designs”: analysis of 270 phase 1 trials investigating anti-cancer
  agents, Invest New Drugs, 2009                                           23
                     Thanks!




Contact info: Jonas.wiedemann@roche.com

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