pharmacodynamic paradigms in early-phase cancer clinical trials workshop phase 0 trials in oncologic...

Pharmacodynamic Paradigms in Early-Phase Cancer Clinical Trials

WorkshopPhase 0 Trials In Oncologic Drug

Development

Hilary CalvertNorthern Institute for Cancer Research

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

1. 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

2. 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

3. Continual Reassessment (O’Quigley)– 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

4. 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

Classical Methodology for Phase I and Translational Trials


1. 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

2. 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

3. Continual Reassessment (O’Quigley)– 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






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

N N

OH O NNH

OH

NHOH

Foster et al, Br J Cancer 28(213):463-469, 1992

Recommended Phase II dose

Target AUC








intervals





3. 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





dose/toxicity relationship• Little data at lower dose levelsO'Quigley J et al: Biometrics, 46, 33-48, 1990

Comparison of mCRM1 Method with Traditional Method - Pemetrexed

Proc ASCO 1997, Abs no 733

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, 19992. Rinaldi DA et al: Journal of Clinical Oncology 13 (11): 2842-2850, 19953. McDonald AC et al: Clinical Cancer Research 4 (3): 605-610, 19984. Faries D: J Biopharm Stat 4:147-164, 1994








intervals





3. Continual Reassessment (O’Quigley)– 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






Simon R et al: Journal of the National Cancer Institute 89 (15): 1138-1147, 1997

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


• Continual Reassessment (O’Quigley)– 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


• Accelerated Phase I Design (Simon)– Starting dose– Single patient dose doubling– Increase patients per cohort and




SLOW AND STEADY

HARD TO GET

FAST AND LOOSE

CHEAP AND CHEERFUL

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

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

PARP Inhibitor – Clinical Plan

Single agent PARP Inhibitor

PARP Inhibitor + temozolomide 50%

PD Assays - surrogate PD Assays - surrogate

Stage 1 – Phase 1 patients – dose escalation of PARP inhibitor

Single agent PARP Inhibitor

PARP Inhibitor + temozolomide

PD Assays - surrogate PD Assays - tumour

PARP Inhibition achieved: Stage 2 – Melanoma - dose escalation of temozolomide

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

Median RTV

0 10 20 30 40 50 60 700.0

2.5

5.0

7.5

10.0

12.5

Control

TM 136

TM 68

TM 68 + 699 0.1

TM 68 + 699 1.0

699 10

TM 68 + 699 10

Day

Med

ian

RT

V(SW620 xenografts)

Plasma and tumour [447] and tumour PARP activityafter 1.0 mg/kg

30 min 6 hr 24 hr0

20

40

60

80

100

120

140

[Plasma]

PARP activity

[Tumour]

0

20

40

60

80

100

Time after injection

[699

] n

g/m

lP

AR

P activity: %

Co

ntro

l

PARP immunoblot assay with grateful thanks and credit to Alex

Bürkle and Ruth Plummerpermeabilised cell suspension

expose to NAD+ and oligonucleotide for 6 min

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

PAR formed

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

Schedule: 28 day cycle

-10 to -4 1 4 8 15 22 28

↑ ↑ ↑

PK PK PK

PD PD PD

PK PK

Comet Comet

:Temozolomide

:AG014699

Day:

Biopsy Biopsy in Part 2 (melanoma patients) only

PK (plasma) and PD (lymphocytes) in Part 1 (any tumour) and 2 (melanoma)First cycle only

Part 1 Part 2

Number 17 15

Male:female 3:4 8:7

Mean age (range) 56 (31-72) 48 (32-68)

Performance status 0:1:2

7:10:0 9:6:0

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

Patient Demographics

Dosing and toxicityCohort 699 dose

(mg/m2)TMZ dose (mg/m2)

n DLT

Part 1(n=18)

1 1 100 3 None

2 2 100 4 None

3 4 100 4 None

4 8 100 4 None

5 12 100 3 None

Part 2(n=15)

6 12 135 3 None

7 12 170 3 None

8 12 200 3 None

9 18 200 6 1/6 plus 3 C2 dose delays

DN04 - PBL PARP activity after AG014699 3.72mg (2 mg/m2)

31 271 14630

10

20

30

40

50

60

70

80

90

100

110

120

33 273 1463 30 270 1467

day -7 day 1 day 4

time after start of infusion (minutes)

PA

R f

orm

ed p

er 1

06 P

BL

(p

mo

l m

on

om

er)

AH27 - PBL PARP activity after AG014699 27.8 mg (12 mg/m2)

39 281 14410

100

200

300

400

500

600

700

800

900

1000

38 242 1602 45 283 1448 Day 8

day -7 day 1 day 4 day 8

time after start of infusion (minutes)

PA

R f

orm

ed p

er 1

06 P

BL

(pm

ol

mo

no

mer

)

4 mg/m2 12 mg/m2 18 mg/m2

0

5

10

15

20

25

PA

RP

act

ivit

y as

% o

f p

re-t

reat

men

tMean tumour PARP activity at 6 hours

after a single dose of AG014699

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?

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

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 A

MTD

of

Dru

g B

Toxic AntagonismToxic Additivity

Toxic Synergy

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 0.620.40 0.22 0.30 0.37 0.49 0.60 0.680.60 0.30 0.40 0.49 0.60 0.70 0.770.80 0.40 0.51 0.60 0.70 0.79 0.840.95 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

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:

Data derived from single agent Phase I Studies

Data estimated from mechanistic knowledge and experience

CRM Method – Illustration with Completed Trial

• OSI 211 in combination Phase I with carboplatin

OPt

OO

O

H3N

H3N

OSI211 – Liposomal LurtotecanCarboplatin

O

O N

N

NMe

NO

O

OEtHO

Combination Continual Reassessment Method of OSI 211 + Carboplatin.Probabilities of Dose Limiting Toxicity (DLT) Based on Priors

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

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

5 0.29 0.37 0.47 0.57 0.66 0.74 0.84


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 first 6 patients

Carbo OSI 211 DLT?

4 1.6 0/3

4 2.0 0/3

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

Decreasing Risk of DLT Increasing Risk of DLT

Carboplatin AUC is

expressed in µg/ml × min

Confidence intervals were calculated but are not shown

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

4 mg/m2 12 mg/m2 18 mg/m20

5

10

15

20

25

PA

RP

act

ivit

y as

% o

f p

re-t

reat

men

t

Mean Tumour PARP Activity at 6 Hoursafter a Single Dose of AG-014699

0

20

40

60

80

100

0 5 10 15 20 25

AG014699 Dose (mg/m2)

Tum

ou

r PA

RP A

ctiv

ity (

% p

re-

treatm

ent)

▲

▲▲

Predicted curve

95% Confidence intervals

Instead of this

We want this

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

Agouron/PfizerHeidi SteinfeldtZdenek HostomskyRaz DwejiGerrit LosCancer Research UK

NewcastlePatientsResearch nursesRuth PlummerNicola CurtinHerbie NewellRoger GriffinChris JonesAlan BoddyBarbara DurkaczBernard GoldingPlus the other clinical investigators

Acknowledgements

pharmacodynamic paradigms in early-phase cancer clinical trials workshop phase 0 trials in oncologic...

Documents

dose dose doubling

dose single patient

dose mtd

traditional starting

probability of dlt vs

target auc

accelerated phase

pks disadvantages