Download Intra-patient Dose Escalation

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
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 - ESS
 Rate of extravasation
 In addition, low within-patient variability
* Dynamic Contrast Enhanced-Magnetic Resonance Imaging
10
ml/ml/min
DCE-MRI methodology – Excellent reproducibility
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 doseresponse
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
Dose - DCE-MRI inhibition
 Confirm MoA
 Confirm feasibility of DCE-MRI
Inhibition of Ktrans (%)
120
100
80
60
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 Cohort
Study Overview
Highest dose
6-10 subjects
DCE-MRI signal
DCE-MRI signal
First intra-patient Dose
Escalation Cohort
6-10 subjects
Adapted Intra-patient Dose
Escalation Cohorts
6-10 subjects pr cohort
Adapted Confirmatory Parallel Fixed
Dose Cohorts
6-10 subjects pr cohort
Up to 50 subjects will be evaluated in total
Terminate study
non-interpretable DCE-MRI signal
Allows
timing of
PD/BM adjustment dose scheme
adjustment
Allows
Further
adjustment of timing and no of
assessments
Parallel Fixed Dose
Cohorts
6-10 subjects pr cohort
Tumor Biopsy
Evaluation Cohort
10 subjects on lowest
efficacious dose
15
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)
With

I max  Cp 

E  E 0  1 
IC50  Cp 

•
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
17
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
IC50 ~
1
N ( IC50
,  1IC )
+
Bayesian estimation
A posterior mean value and
precision
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
• Requires high number of samples (5000 – 10000) => time consuming
koutP chains 1:2
0.06
0.04
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: [email protected]
24
We Innovate Healthcare
25