1. 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
picture placeholder

2. Outline Oncology Dose Finding Why is This of Interest? Imaging Study
- Intra-patient Dose Escalation – Pros & Cons
Why is This of Interest?
Imaging Study
Statistical Methodology
Lessons Learned & Further Development

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

4. 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

5. 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
In 2004 the Critical Path Initiative was developed to address the growing concern that many of the new basic science discoveries made in recent years may not quickly yield more effective, more affordable, and safe medical products for patients. The Critical Path Initiative proposed the development of a toolkit which would contain powerful new scientific and technical methods, including new clinical evaluation techniques to improve the efficiency and effectiveness of the clinical trial process, including trial design, endpoints, and analyses. In the 2006 Critical Path Opportunities List, the Adaptive Trial Design was specifically proposed.

6. 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”

7. Intra-patient Dose Escalation Pros & cons
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

8. Intra-patient Dose Escalation Pros & 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.)

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

10. 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

11. DCE-MRI methodology – Excellent reproducibility
ml/ml/min
2 paired pre-treatment scans (Ktrans: wSD ~ )

12. 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

13. Oncology Dose Finding
- Intra-patient Dose Escalation – Pros & Cons
Why is This of Interest?
Imaging Study
Statistical methodology
Lessons Learned & Further Development

14. Imaging Study Overall target
Establish exposure – PD relationship for single agent
Identify the minimal PD effective dose
Confirm MoA
Confirm feasibility of DCE-MRI
Dose (mg)
by applying intra-patient dose escalation with 3 initial dose steps
by applying a Bayesian approach

15. Study Overview Initial Test Cohort
6-10 subjects
Study Overview
Highest dose
DCE-MRI signal
DCE-MRI signal
First intra-patient Dose Escalation Cohort
6-10 subjects
Terminate study
non-interpretable DCE-MRI signal
Adapted Intra-patient Dose Escalation Cohorts
6-10 subjects pr cohort
Parallel Fixed Dose 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

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

17. 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)
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.
* If possible, an exploratory indirect model to investigate time delay in DCE-MRI

18. 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 ~
A posterior mean value and precision
Bayesian estimation

19. 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) => time consuming

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

21. 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

22. 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

23. 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

24. Thanks!
Contact info:

25. We Innovate Healthcare