Oncology Dose Finding A Case Study Intrapatient Dose

Oncology Dose Finding A Case Study: Intra-patient Dose Escalation Jonas Wiedemann, Meghna Kamath Samant & Dominik Heinzmann, p. RED Biostatistics, Valerie Cosson & Sylvie Retout, p. RED 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 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 q 2 w approach chosen • DCE-MRI* as angiogenic PD marker – values (Ktrans, Kep, AUC 90, Ve) directly related to: Ø Blood volume Ø Blood flow Ø Extracellular Extra-vascular Space - ESS Ø Rate of extravasation Ø 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: w. SD ~ 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, Win. Bugs, EDC, etc. feasible −> practical • 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 Ø Establish exposure – PD relationship for single agent Ø Identify the minimal PD effective dose Ø Confirm Mo. A Ø 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 14

Initial Test Cohort Study Overview Highest dose 6 -10 subjects DCE-MRI signal First intra-patient Dose Escalation Cohort 6 -10 subjects Adapted Intra-patient Dose Escalation Cohorts Terminate study non-interpretable DCE-MRI signal 6 -10 subjects pr cohort Allows timing of PD/BM adjustment dose scheme adjustment Adapted Confirmatory Parallel Fixed Dose Cohorts Allows Further adjustment of timing and no of assessments 6 -10 subjects pr cohort Up to 50 subjects will be evaluated in total 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 IC 50 (both assumed to be Gaussian distributed with mean and precision) With • E the DCE-MRI parameter, i. e. Ktrans, Kep, Ve, Vp and i. AUC, • E 0 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), • IC 50 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 IC 50 (and Imax) Observed PD data ~ + A posterior mean value and precision Bayesian 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 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 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 anticancer agents, Invest New Drugs, 2009 23

Thanks! Contact info: Jonas. wiedemann@roche. com 24

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