Jeffrey S. Barrett, Ph.D., FCP The Children

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Jeffrey S. Barrett, Ph.D., FCPThe Childrens
Hospital of PhiladelphiaDivision of Clinical
Pharmacology and TherapeuticsThe University of
Pennsylvania Medical SchoolDepartment of
Pediatrics
Actinomycin-D / Vincristine in Pediatric Oncology
Trials COG Effort
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Outline

• Introduction
• Clinical Setting for AMD / VCR in Pediatric
  Oncology
• Missing Data and the Impact on Pharmacotherapy
• Grant Overview
• Objectives and Goals
• Project Descriptions
• Current Status
• Project Plan Update
• Overall Milestones Achieved to Date
• By Project Review
• Critical Activities
• Next Steps

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Introduction

• In August of 2002, the Childrens Oncology Group
  (COG) suspended 3 active protocols for pediatric
  rhabdomyosarcoma after 4 chemotherapy-associated
  deaths from VOD.
• No subsequent evaluation as to the cause of these
  devastating side effects or correlation between
  toxicity and drug exposure.
• Primarily by the limited pharmacokinetic
  knowledge of AMD.
• Because AMD is crucial to soft tissue sarcoma
  therapy, its use as an anti-neoplastic agent
  continues clinical evaluation vital.

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Introduction

• June 24, 2004 NIH requests that the COG responds
  to an RFP focused on enhancing the safety and
  effectiveness of AMD and VCR administered to
  children with cancer.
• July 21, 2004 COG provide LOI with 4 project
  proposals
• August 11, 2004 Full proposal submitted to NIH /
  NCI
• October 1, 2004 Award made to COG
• March 31, 2005 Results of initial MS activities
  presented to NIH/NCI at COG meeting initial
  requirements gathered for Simulation Plan
• October 20, 2005 Update on grant progress to FDA
  Pediatric Oncology Subcommittee

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Introduction Clinical Setting Historical
experience in children
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Introduction Clinical Setting Historical
experience in children
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IntroductionImpact of Missing Data on
Pharmacotherapy

• No analytical methodology for AMD
• PK largely unknown No idea about dose-exposure.
• PD largely unknown.
• AMD Dose-toxicity relationship qualitative at
  best
• VCR PK not well defined in pediatric populations
• Exposure-response (toxicity) not well defined.
• PGx component to PK and/or clinical outcomes
  suspected but not defined.
• Dose-limiting vs manageable toxicity unclear
• Dose adjustments empirically based
• No basis for age / size modification
• No basis for special populations (e.g., renal
  impairment)
• No guidance on drug interactions

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Grant OverviewObjectives and Goals
Project 1 To conduct a retrospective analysis of
historical data from Wilms tumor (NWTS-IV and
NWTS-V) and rhabdomyosarcoma (IRS-IV and IRS-V)
studies in which vincristine and actinomycin-D
were administered to various pediatric
subpopulations in order to define
exposure-toxicity relationships.   Project 2 To
develop a dosing and pharmacokinetic sampling
procedure for actinomycin and vincristine
utilizing a single lumen central venous catheter.
  Project 3 To construct PK/PD models based on
actinomycin-D and vincristine exposure-response
relationships that incorporate physiologic-based
and mechanistic expression when possible, and
simulation to extend such relationships into a
clinical trial paradigm in which trial outcomes
may be predicted.   Project 4 To conduct a
prospective PK/PD/outcome trial of vincristine
and actinomycin-D in children, primarily less
than 3 years of age, receiving these drugs as a
component of their therapy.
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Grant OverviewInterdependencies
Overall success highly dependent on project
management and communication
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Grant OverviewProject Descriptions Project 1
Aim 1 To describe vincristine and actinomycin D
dosing for patients on NWTSG 4 and 5 and IRSG IV
and V Aim 2 Correlate dosing data from Aim 1
with efficacy, particularly in children less than
3 years of age Aim 3 Correlate dosing data from
Aim 1 with toxicity, particularly in children
less than 3 years of age Aim 4 Analyze the
combined NWTSG and IRSG datasets with
classification and regression tree methodology to
provide background data for the clinical trial
simulation described in Project 3
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Grant OverviewProject Descriptions Project 1
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Grant OverviewProject Descriptions Project 2
Aim 1 To examine the recovery of actinomycin-D
and vincristine in common catheter configurations
which would be utilized to administered these
agents via a central venous line. Aim 2 To
assess the in vitro equivalence of catheter
configurations utilized for sampling
purposes Aim 3 To develop procedures for dosing
and sampling to ensure robust sampling equivalent
to a separate sampling line Aim 4 To validate
the procedure proposed in Aim 3 via clinical
testing to the target patient population
(children with cancer)
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Grant OverviewProject Descriptions Project 2
Determine cytochrome P450s involved in the
metabolism of Act-D
Develop and validate a single LC/MS/MS assay to
quantify both Act-D and VCR
Optimize plasma sampling techniques for PK
studies in children
Create a pilot PK study of Act-D and VCR in
children
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Grant OverviewProject Descriptions Project 3
Aim 1 Develop PBPK models for actinomycin and
vincristine from historical pharmacokinetic data
for the prediction of plasma pharmacokinetics and
exposure in organs and tissues. Aim 2
Incorporate dose/toxicity data from the
historical literature and Project 1 into the PBPK
models to associate specific organ exposures to
toxicity outcomes. Aim 3 Conduct a pilot study
in pediatric patients using extensive plasma
sampling to further define AMD and VCR
pharmacokinetics and inter-subject variability
for model refinement. Aim 4 Perform Clinical
Trial Simulations for the design of the
prospective PK/PD trial proposed in Project 4.
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Grant OverviewProject Descriptions Project 3
Dose Exposure Relationships
Exposure Response Relationships
Data Sources

• PBPK Model in the Dog
• Define in NONMEM
• Add precision estimate

• Dose AE Model
• Pooled from Literature
• Define response profile

• Literature Priors
• Animal and human PK
• Variance in physiology
• Scaling principals
• In vitro binding data
• Cellular partitioning
• Clinical trial summaries (AE/SAE)

• PBPK Model in the Adult
• Scale Dog to Human
• QC plasma exposure

• Mechanistic PK/PD Model
• Map transduction process
• Biophase concentration
• Correlate with in vitro data

• PBPK Model in the Child
• Scale CL allometrically
• QC plasma exposure

Individual AE Data (COG)

• Clinical Response Model
• AE vs Pred. Exposure(dose)
• Add variance components
• Add covariate structure

• Pilot PK Study
• Dose Finding Trial

• PBPK Pediatric Pop Model
• Add variance components
• Add covariate structure

Dosing Guidance for Pediatric Cancer Patients
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Grant OverviewProject Descriptions Project 4
Aim 1 Develop and finalize a clinical protocol
based on the observed toxicity-dose response
(Project 1) and the clinical trial simulation
results (Project 3) utilizing a single lumen
catheter procedure defined by Project 2. Aim 2
Evaluate AMD/VCR dose-exposure relationships via
nonlinear mixed effect modeling incorporating
covariates that explain sources of variation
including size, age, heritable and non-heritable
sources. Aim 3 Create PK/PD models (based on
Aim 2) that correlate toxicity findings and
clinical outcomes from the prospective trial CTS
results and catheter experiment results
(procedures defined by Project 2) Aim 4
Propose dosing guidance for actinomycin-D and
vincristine based on clinical utility (maximizing
therapeutic outcome and minimizing therapeutic
risk) suitable for label recommendations
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Current StatusProject Plan
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Current StatusMilestones Achieved

• Analytical method for AMD/VCR quantification in
  pediatric plasma samples validated and published
• Procedure for AMD/VCR dosing/sampling from
  central catheter has been developed (awaiting
  clinical validation)
• Pilot PK study initiated 3 (8 planned) enrolled
• PBPK models for AMD and VCR developed and scaled
  to project pediatric exposures
• PK models refined for CTS application
• CTS Plan completed CTS ongoing
• Draft clinical protocol circulated to NIH and
  select COG phase 1 sites

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Current StatusBy Project Review Project 1

• NWTS database created
• Data errors and inconsistencies continue to be an
  issue and are being resolved
• Data entry of non-electronically available data
  delayed
• SAP finalized

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Current StatusBy Project Review Project 2
AMD/VCR method validated, published and continues
refinement (with LOD lt 0.1 ng/mL probable)
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Current StatusBy Project Review Project 2
AMD/VCR method validated, published and continues
refinement (with LOD lt 0.1 ng/mL probable)
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Current StatusBy Project Review Project 2
In vivo performance of analytical method already
demonstrated in pilot study patients
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Current StatusBy Project Review Project 2
Clinical procedure and apparatus for dosing /
sampling from a central venous catheter developed
Flush Volume
Catheter Size (French) Residual Blood Sample Concentration (ng/mL mean SD) Residual Blood Sample Concentration (ng/mL mean SD)
Catheter Size (French) Act-D VCR
6.6 0.40.2 lt LOD
7 0.40.2 lt LOD
9 0.30.1 lt LOD
6.6 Port-A-Cath 0.40.1 lt LOD
1. Cook 5 french 27cm catheter fragment 2. 200
µL pipette tip 3. Cook catheter connector 4.
Medex 3-way stopcock 5. 3 mL syringe for sample
collection 6. 5 mL syringe for waste collection
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Current StatusBy Project Review Project 3
PBPK Models developed for AMD and VCR Scaled to
pediatric populations
PLASMA FLOW

• Model Elements AMD and VCR
• Flow-limited PBPK models derived from dog
• Human physiologic parameters inserted and
  rescaled allometrically for pediatric subjects
• Moderate variation in physiologic and PK
  processes assumed to date
• Models expressed in NONMEM and TS2
• Initial simulations agree with historical data in
  children based on plasma exposure

PLASMA
HEART
HEPATIC ARTERY
SPLEEN
LIVER
BILE
KIDNEY
URINE
BONE MARROW
MUSCLE
CARCASS
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Current StatusBy Project Review Project 3

• Good agreement with Veal et. al. (n31)
• and CHOP pilot PK study (n2)

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Current StatusBy Project Review Project 3
Models refined based on pediatric data obtained
from UKCCSG (Veal et. al.)

• Model developed using the First-Order Conditional
  Estimation method in NONMEM
• 165 plasma concentrations collected from 33
  pediatric patients administered 0.70 to 1.50
  mg/m2 AMD
• A three-compartment model with first-order
  elimination was chosen as the structural model
• Random effects to describe the inter-subject
  variability were included for V1 and CL

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Current StatusBy Project Review Project 3
Simulation plan completed (available for review)

• Simulation Scenarios
• Previous IRS and NWTS Trials
• Dosing Modifications in Infants
• BSA vs BW Dosing
• Dose Capping
• Clinical Study Designs and Sampling
  Considerations
• Adverse Event Rates for Prospective Study
• Clinical response for Prospective Study

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Current StatusBy Project Review Project 3
Uncertainty in Var CL
Novelty of MS Approach
Uncertainty in Mean CL
Residual Variability
Interindividual Variability CL
Ct D/Ve-CLi/Vt et
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Current StatusBy Project Review Project 3
Novelty of MS Approach

• Pharmacometric Solution
• Global sensitivity analysis
• Plot the MPE and RMSE against the population
  means (with uncertainty) for each simulation
  scenario
• Identify study designs that produce minimal bias
  and high precision over the range of possible
  parameters

• Clinical Reality
• Discrepancy across studies
• Population, dosing, treatment diversity exists as
  well as compliance with targeted regimens /
  exposures
• Correlation with toxicity difficult to assess
  from conventional analyses
• Guidance for prospective study based on
  historical data difficult

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Current StatusBy Project Review Project 4
Clinical Protocol Draft Circulated
PROSPECTIVE PHARMACOKINETIC/PHARMACODYNAMIC AND
OUTCOME TRIAL OF ACTINOMYCIN-D AND VINCRISTINE IN
CHILDREN WITH CANCER  
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Critical Activities

• Completion of pilot PK study and in vivo
  validation of central venous catheter
  dosing/sampling procedure
• Completion of data entry / assembly for
  historical AE/tox data from IRS and MWTS trials
• Correlation of tox with dosing metrics
• Completion of key CTS scenarios

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Critical Activities

• Revision and finalization of clinical protocol
• Investigator solicitation and education
• Data collection strategy, data management plan
  for prospective trial
• SAP for prospective study
• Label exercise based on CTS output

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References
Barrett JS, Skolnik J, Gastonguay MR and Adamson
PC. The Value of Priors and Prior Uncertainty in
Clinical Trial Simulation Case Study with
Actinomycin-D in Children with Cancer.
Presented, 2004 Population Approach Group Europe
Meeting, Uppsala, Sweden, June 17-19, 2004.
Skolnik J, Barrett JS, Shi H, and Adamson PC.
Pre-clinical Studies in Support of the Clinical
Pharmacologic Evaluation of Actinomycin-D in
Children with Cancer. American College of
Clinical Pharmacology Meeting, Phoenix, AZ,
October 3-5, 2004. Mondick J and Barrett JS. A
Physiologically-based Pharmacokinetic Model to
Predict Tissue Distribution of Actinomycin-D in
Humans. American College of Clinical Pharmacology
Meeting, Phoenix, AZ, October 3-5, 2004.
Skolnik JM, Paccaly DA, Barrett JS, Adamson PC.
Mechanisms to enhance enrollment in pediatric
trials An in vitro procedure to clear residual
chemotherapeutics from indwelling catheters. J.
Clin. Pharmacol 2005 45 1085 (Abstr. 76).
Barrett JS, Mondick JT, Skolnik J, Adamson PC.
Clinical trial simulation in an academic research
setting Engaging the clinical team and
generating the simulation plan. J. Clin.
Pharmacol 2005 45 1087 (Abstr. 85). Skolnik,
JM, Barrett, JS, Hsi, H, Adamson, PC A liquid
chromatography-tandem mass spectrometry method
for the simultaneous quantification of
actinomycin-D and vincristine in children with
cancer. Cancer Chemotherapy and Pharmacology
Sep 271-7 Epub ahead of print
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