Pharmacodynamic Paradigms in Early-Phase Cancer Clinical Trials

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Pharmacodynamic Paradigms in Early-Phase Cancer
Clinical Trials

• Workshop
• Phase 0 Trials In Oncologic Drug Development

Hilary Calvert Northern Institute for Cancer
Research
2
Methodology for Phase I and Phase 0
(translational) Trials

• Develop trial methodology designed for targeted
  agents in trials with pharmacodynamic endpoints
• The use of pharmacodynamic or toxic endpoints
  present similar problems magnitude,
  reproducibility, variability
• Endpoints
• To develop methods that utilise continuously
  variable (scalar) endpoints rather than yes/no
  (Boolean) endpoints
• To extend these techniques to combination Phase I
  trials

3
Classical Methodology for Phase I and
Translational Trials

• Traditional
• Starting dose
• Modified Fibonacci escalation
• Maximum Tolerated Dose (MTD) as an endpoint
• Disadvantages
• Patient inefficient
• Many patients at ineffective doses
• Safety risk as MTD is approached
• No built-in confidence intervals

• Pharmacokinetically-guided (Collins)
• Establish Target Area Under the Curve (AUC) from
  preclinical studies
• Monitor Pharmacokinetics at starting dose
• Escalate in large increments to achieve target
  AUC in patients
• Inter-patient variability in PKs
• Disadvantages
• Assumes linearity
• Metabolites
• May not be feasible

• Continual Reassessment (OQuigley)
• Stochastic model to predict probability of DLT vs
  dose
• Starting dose
• Dose doubling
• Add data to model
• Predict dose with desired probability of DLT
• Disadvantages
• Methodologically complex
• Needs constraints for safety
• May take time to converge

• Accelerated Phase I Design (Simon)
• Starting dose
• Single patient dose doubling
• Increase patients per cohort and reduce dose
  increments when mild (Grade II) toxicity is seen
• Disadvantages
• Could be hazardous with a steep dose/toxicity
  relationship
• Little data at lower dose levels

4
Classical Methodology for Phase I and
Translational Trials

• Traditional
• Starting dose
• Modified Fibonacci escalation
• Maximum Tolerated Dose (MTD) as an endpoint
• Disadvantages
• Patient inefficient
• Many patients at ineffective doses
• Safety risk as MTD is approached
• No built-in confidence intervals

• Pharmacokinetically-guided (Collins)
• Establish Target Area Under the Curve (AUC) from
  preclinical studies
• Monitor Pharmacokinetics at starting dose
• Escalate in large increments to achieve target
  AUC in patients
• Disadvantages
• Inter-patient variability in PKs
• Assumes linearity
• Metabolites
• May not be feasible

• Continual Reassessment (OQuigley)
• Stochastic model to predict probability of DLT
  vs. dose
• Starting dose
• Dose doubling
• Add data to model
• Predict dose with desired probability of DLT
• Disadvantages
• Methodologically complex
• Needs constraints for safety
• May take time to converge

• Accelerated Phase I Design (Simon)
• Starting dose
• Single patient dose doubling
• Increase patients per cohort and reduce dose
  increments when mild (Grade II) toxicity is seen
• Disadvantages
• Could be hazardous with a steep dose/toxicity
  relationship
• Little data at lower dose levels

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CI-941 DMP-941 - Losoxantrone

• Similar to mitoxantrone
• Animal models
• Activity equal to or better than doxorubicin
• No or little cardiotoxicity
• One of 3 analogues submitted for clinical
  development by Warner Lambert
• Candidate for AUC-based dose escalation
• Preclinical pharmacology established target AUC
  and linearity up to 45 mg/m2

6
Target AUC
Recommended Phase II dose
Foster et al, Br J Cancer 28(213)463-469, 1992
7
Classical Methodology for Phase I and
Translational Trials

• Traditional
• Starting dose
• Modified Fibonacci escalation
• Maximum Tolerated Dose (MTD) as an endpoint
• Disadvantages
• Patient inefficient
• Many patients at ineffective doses
• Safety risk as MTD is approached
• No built-in confidence intervals

• Pharmacokinetically-guided (Collins)
• Establish Target Area Under the Curve (AUC) from
  preclinical studies
• Monitor Pharmacokinetics at starting dose
• Escalate in large increments to achieve target
  AUC in patients
• Disadvantages
• Inter-patient variability in PKs
• Assumes linearity
• Metabolites
• May not be feasible

• Continual Reassessment
• Stochastic model to predict probability of DLT
  vs. dose
• Starting dose
• Dose doubling
• Add data to model
• Predict dose with desired probability of DLT
• Disadvantages
• Methodologically complex
• Needs constraints for safety
• May take time to converge

• Accelerated Phase I Design (Simon)
• Starting dose
• Single patient dose doubling
• Increase patients per cohort and reduce dose
  increments when mild (Grade II) toxicity is seen
• Disadvantages
• Could be hazardous with a steep dose/toxicity
  relationship
• Little data at lower dose levels

O'Quigley J et al Biometrics, 46, 33-48, 1990
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Comparison of mCRM1 Method with Traditional
Method - Pemetrexed
Schedule Q21D2 WQ4x6W3 Dx5Q21D4
Escalation Method mCRM mCRM Traditional
Doses mg/m2 50-700 10-40 0.2-5.2
No. Dose levels 7 4 10
MTD 600 30 4
Months to MTD 9 12 29
Pts near Phase II dose 20/37 16/24 11/38

1. Rinaldi DA et al Cancer Chemotherapy and
   Pharmacology 44 (5) 372-380, 1999
2. Rinaldi DA et al Journal of Clinical Oncology 13
   (11) 2842-2850, 1995
3. McDonald AC et al Clinical Cancer Research 4
   (3) 605-610, 1998
4. Faries D J Biopharm Stat 4147-164, 1994

Proc ASCO 1997, Abs no 733
9
Classical Methodology for Phase I and
Translational Trials

• Traditional
• Starting dose
• Modified Fibonacci escalation
• Maximum Tolerated Dose (MTD) as an endpoint
• Disadvantages
• Patient inefficient
• Many patients at ineffective doses
• Safety risk as MTD is approached
• No built-in confidence intervals

• Pharmacokinetically-guided (Collins)
• Establish Target Area Under the Curve (AUC) from
  preclinical studies
• Monitor Pharmacokinetics at starting dose
• Escalate in large increments to achieve target
  AUC in patients
• Disadvantages
• Inter-patient variability in PKs
• Assumes linearity
• Metabolites
• May not be feasible

• Accelerated Phase I Design (Simon)
• Starting dose
• Single patient dose doubling
• Increase patients per cohort and reduce dose
  increments when mild (Grade II) toxicity is seen
• Disadvantages
• Could be hazardous with a steep dose/toxicity
  relationship
• Little data at lower dose levels

• Continual Reassessment (OQuigley)
• Stochastic model to predict probability of DLT
  vs. dose
• Starting dose
• Dose doubling
• Add data to model
• Predict dose with desired probability of DLT
• Disadvantages
• Methodologically complex
• Needs constraints for safety
• May take time to converge

Simon R et al Journal of the National Cancer
Institute 89 (15) 1138-1147, 1997
10
Methodology for Phase I and Translational Trials

• Pharmacokinetically-guided (Collins)
• Establish Target Area Under the Curve (AUC) from
  preclinical studies
• Monitor Pharmacokinetics at starting dose
• Escalate in large increments to achieve target
  AUC in patients
• Disadvantages
• Inter-patient variability in PKs
• Assumes linearity
• Metabolites
• May not be feasible

• Traditional
• Starting dose
• Modified Fibonacci escalation
• Maximum Tolerated Dose (MTD) as an endpoint
• Disadvantages
• Patient inefficient
• Many patients at ineffective doses
• Safety risk as MTD is approached
• No built-in confidence intervals

SLOW AND STEADY
HARD TO GET

• Continual Reassessment (OQuigley)
• Stochastic model to predict probability of DLT vs
  dose
• Starting dose
• Dose doubling
• Add data to model
• Predict dose with desired probability of DLT
• Disadvantages
• Methodologically complex
• Needs constraints for safety
• May take time to converge

• Accelerated Phase I Design (Simon)
• Starting dose
• Single patient dose doubling
• Increase patients per cohort and reduce dose
  increments when mild (Grade II) toxicity is seen
• Disadvantages
• Could be hazardous with a steep dose/toxicity
  relationship
• Little data at lower dose levels

CHEAP AND CHEERFUL
FAST AND LOOSE
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Use of Pharmacodynamic Endpoints

• Almost always useful as a secondary endpoint
• Clinical proof of principle of an effect on the
  target
• May be useful as a primary endpoint if
• Target is known, is single and is known to
  mediate the therapeutic effect
• Level of target suppression needed is known (50,
  90, 99?)
• Required duration of target effect is known
• It is possible to measure all of the above

• Methodology required for trials with a
  Pharmacodynamic endpoint
• Requires definition of a dose where an effect of
  sufficient magnitude is present for sufficiently
  long in a sufficiently high proportion of the
  patients
• Endpoint is scalar (e.g., 95) rather than
  Boolean (e.g., DLT present or not)
• Interpatient variability and confidence intervals
• Prediction of duration of effect

• Use of a scalar (continuously variable)
  methodology will also be of value where toxicity
  is used as an endpoint

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PARP Inhibitor Phase 1 (0.5?) Trial AG014699

• Potent inhibitor, IV administration
• Not expected to be active as a single agent (BRCA
  data not known at the time of design)
• Expected to potentiate monomethylating agents and
  Topoisomerase I active compounds
• Tumour biopsies required for PD endpoint
• Desire for single agent data on PARP inhibitor
• Combination study with temozolomide undertaken
• PARP inhibitors potentiate temozolomide
• Temozolomide active in melanoma
• Melanoma patients have multiple lesions, biopsies
  relatively easy
• Single dose of AG14699 scheduled 1 week before
  combo

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PARP Inhibitor Clinical Plan
Stage 1 Phase 1 patients dose escalation of
PARP inhibitor
Single agent PARP Inhibitor
PARP Inhibitor temozolomide 50
PD Assays - surrogate
PD Assays - surrogate
PARP Inhibition achieved Stage 2 Melanoma -
dose escalation of temozolomide
Single agent PARP Inhibitor
PARP Inhibitor temozolomide
PD Assays - tumour
PD Assays - surrogate
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PD End point

• PARP Inhibitory Dose (PID)
• Dose of AG-014699 causing 50 inhibition on
  PARP-1 ex vivo in peripheral blood lymphocytes 24
  hours after 1st dose, with a plateau in the
  degree of inhibition between dose levels.
• Validated quantified immunoblot using monoclonal
  antibody against PAR

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(SW620 xenografts)
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PARP immunoblot assay with grateful thanks and
credit to Alex Bürkle and Ruth Plummer
permeabilised cell suspension
expose to NAD and oligonucleotide for 6 min
PAR formed
stop reaction with ice-cold 12.5µM 699
blot known number of cells on to nylon membrane
probe with 1 anti-PAR antibody
probe with 2 HRP-conjugated antibody
expose to ECL and measure luminescence
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PARP Assay Validation

• Minimise / explain variability
• Enzyme stable with freezing??
• Inhibition stable with freezing
• Can inhibition be measured in PBMCs?
• Establish procedures for handling samples
• Does sampling and transport affect result?
• Consistency of assay reagents
• Provide standards for acceptability of results
• Control samples
• Intra- and inter-assay variability
• Thanks to Ruth Plummer
• Probably 1-2 person years

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Schedule 28 day cycle
Temozolomide
AG014699
-10 to -4 1 4 8 15 22 28
? ? ? PK PK PK PD PD PD PK PK Comet Comet
Day
PK (plasma) and PD (lymphocytes) in Part 1 (any
tumour) and 2 (melanoma) First cycle only
Biopsy Biopsy in Part 2
(melanoma patients) only
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Patient Demographics
Part 1 Part 2
Number 17 15
Malefemale 34 87
Mean age (range) 56 (31-72) 48 (32-68)
Performance status 012 7100 960
Tumour type Sarcoma 3 Melanoma 15
Melanoma 3 (13 cutaneous, 1 ocular, 1clear cell sarcoma of soft tissue)
Colorectal 3
Others 8
Previous treatment Pretreated but no DTIC/Temozolomide Chemonaive
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Dosing and toxicity
Cohort 699 dose (mg/m2) TMZ dose (mg/m2) n DLT
Part 1 (n18) 1 1 100 3 None
Part 1 (n18) 2 2 100 4 None
Part 1 (n18) 3 4 100 4 None
Part 1 (n18) 4 8 100 4 None
Part 1 (n18) 5 12 100 3 None
Part 2 (n15) 6 12 135 3 None
Part 2 (n15) 7 12 170 3 None
Part 2 (n15) 8 12 200 3 None
Part 2 (n15) 9 18 200 6 1/6 plus 3 C2 dose delays
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Mean tumour PARP activity at 6 hoursafter a
single dose of AG014699
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AG14699 Phase 0/1 TrialInterpretation

• 12 mg/m2 AG14699 causes profound inhibition of
  PARP in PBMCs and 90 inhibition in melanoma
• 12 mg/m2 AG14699 can be given with a full dose
  of temozolomide
• Protocol criteria have been met, but
• Might 18 mg/m2 with a dose-reduction for
  temozolomide work better?
• What would be the variability of the level and
  duration of tumour inhibition?
• Do we need a longer period of inhibition for
  single agent treatment of BRCA tumours?
• What might the effects on PARP homologues be?

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PARP Homologues

• PARP-1 most prevalent
• most of existing data relates to PARP-1
• PARP-2 responsible for residual PARP activity in
  PARP-1 knockouts
• PARP-2 knockouts are also viable
• Double knockouts not viable
• PARP-3 Unknown
• PARP-4 V-PARP - drug resistance
• PARP-5 Tankyrase 1 - involved in telomerase
  activity
• PARP-6 Tankyrase 2
• PARP 7.. upwards ? function

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Two Dimensional CRM MethodDeveloped in house by
James Wright

• New targeted agents will be used in combination
  with both traditional cytotoxics and other
  targeted agents
• Multikinase inhibitors
• For every single agent Phase I there will be many
  combination Phase Is
• Toxicities may potentiate or antagonise
• For any two drugs, there is a range of maximum
  tolerated dose pairs

MTD of Drug B
Toxic Antagonism
Toxic Additivity
Toxic Synergy
MTD of Drug A
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Two Dimensional CRM MethodDeveloped by James
Wright, PhD Student, 1997-2000

• CRM Methodology requires that the probability of
  DLT at each level is estimated before the start
  of the trial (priors)
• A model relating the probability of DLT to dose
  is created using the estimated data points
• As real data accumulate during the course of the
  trial they are used to modify the model
• A problem for single agent studies is that the
  initial estimates may be way out
• For combination Phase I studies, single agent
  data are already available, facilitating the
  estimation of priors
• Hypothetical example

D1 D2 0.00 0.25 0.4 0.6 0.8 0.95
0.00 0.00 0.16 0.22 0.30 0.40 0.48
0.25 0.16 0.24 0.30 0.40 0.51 0.62
0.40 0.22 0.30 0.37 0.49 0.60 0.68
0.60 0.30 0.40 0.49 0.60 0.70 0.77
0.80 0.40 0.51 0.60 0.70 0.79 0.84
0.95 0.48 0.62 0.68 0.77 0.84 0.88
Priors are constructed showing the probability of
dose limiting toxicity for each pair of doses
Data derived from single agent Phase I Studies
Data estimated from mechanistic knowledge and
experience
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CRM Method Illustration with Completed Trial

• OSI 211 in combination Phase I with carboplatin

OSI211 Liposomal Lurtotecan
Carboplatin
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Combination Continual Reassessment Method of OSI
211 Carboplatin.Probabilities of Dose Limiting
Toxicity (DLT) Based on Priors
Carboplatin AUC is expressed in µg/ml min
Initial Estimates Initial Estimates OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2)
Initial Estimates Initial Estimates 1.2 1.6 2.0 2.4 2.8 3.2 3.8
Carbo Target AUC 4 0.21 0.27 0.35 0.42 0.51 0.59 0.70
Carbo Target AUC 5 0.29 0.37 0.47 0.57 0.66 0.74 0.84
Increasing Risk of DLT
Decreasing Risk of DLT
After first 6 patients After first 6 patients After first 6 patients
Carbo OSI 211 DLT?
4 1.6 0/3
4 2.0 0/3
OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2)
1.2 1.6 2.0 2.4 2.8 3.2 3.8
4 0.025 0.05 0.10 0.19 0.33 0.51 0.76
5 0.29 0.37 0.47 0.57 0.66 0.74 0.84
After 17 patients After 17 patients After 17 patients
Carbo OSI 211 DLT?
4 1.6 0/3
4 2.0 0/3
4 2.4 2/5
5 1.2 0/1
5 1.6 0/3
5 2.0 2/2
OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2) OSI 211 dose (mg/m2)
1.2 1.6 2.0 2.4 2.8 3.2 3.8
4 0.04 0.08 0.16 0.29 0.47 0.65 0.85
5 0.14 0.27 0.45 0.65 0.80 0.90 0.97
Confidence intervals were calculated but are not
shown
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Proposed Enhancements of 2-Dimensional Phase I
Methodology

• Use a scalar rather than a Boolean endpoint
  (e.g., reduction in neutrophil count rather than
  MTD)
• Modify for use with Pharmacodynamic endpoints

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Mean Tumour PARP Activity at 6 Hoursafter a
Single Dose of AG-014699
100
We want this
80
60
Predicted curve
Tumour PARP Activity ( pre-treatment)
Instead of this
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95 Confidence intervals
?
20
?
?
0
0
5
10
15
20
25
AG014699 Dose (mg/m2)
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Methodology for Phase I and Translational Trials
- Needs

• Trial methodology designed for targeted agents in
  trials with pharmacodynamic endpoints methods
  that utilise continuously variable (scalar)
  endpoints rather than yes/no (Boolean) endpoints
• Extension of these techniques to combination
  Phase I trials
• Models to detect trends may be more appropriate
  than hypothesis-testing
• We need to use these methods where available and
  develop new mathematical models where they are
  not
• Early investment in PD assay development and
  validation

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Acknowledgements
Agouron/Pfizer Heidi Steinfeldt Zdenek
Hostomsky Raz Dweji Gerrit Los Cancer Research UK
Newcastle Patients Research nurses Ruth
Plummer Nicola Curtin Herbie Newell Roger
Griffin Chris Jones Alan Boddy Barbara
Durkacz Bernard Golding Plus the other clinical
investigators