Oncology Early Clinical Trials’

Designsand their Challenges

Pamela N Munster, MD

TICR4-18-2012.

Phase ISafety/Phase

II dose

Phase IIICompare new vs. standard

Phase IVlong term safety

FDA Approval

IND granted

Cell culture, signaling studies, combinations, xenografts and animal models

Animal Tox

Molecular Screens

2554 Phase I trials currently accruing

Historical Drug Development Snapshot

3908 NCI listed

1872 NCI listed

Phase 0

Phase IIEfficacy/Tox

Testing of a novel strategy/compound– New single agent

• First in Man, Proof of Concept • New formulations, schedules or doses

– Combinations of novel agents with existing agents• X combined with chemotherapy• X combined with hormonal therapies

– Novel agent as biological response modifier• Inhibition of Histone deacetylase, • Inhibition of DNA repair (e.g. PARP, Chk1, wee1) • Inhibition of chaperone proteins, (e.g. HSP90)

Types of Treatments in Phase I Clinical Trials (I)

Testing of a novel strategy/compound– Different Modalities

• Small molecules• Immune modifiers• electroporation of inhibitory genes• siRNA, • anti-sense

Types of Treatments in Phase I Clinical Trials (II)

Terms and Definitions

– Safety, Toxicity and Tolerability

– Dose limiting toxicities (DLT)

– Maximally Administered Dose (MAD)

– Maximally Tolerated Dose (MTD)

– Recommended Phase II dose (RPTD)

– Dose Escalation Rules

– Pharmacokinetics and Pharmacodynamics

Early Phase Clinical Trials’ Design

Terms and Definitions– Safety, Toxicity and Tolerability

Standard toxicity assessment by Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0

1) Grading» 0-5

2) Causality determination: » treatment-emergent vs treatment-related

Early Phase Clinical Trials’ Design

Example: Toxicity Assessment

Presentation:A 47 year old Caucasian male starts an investigational agent on 4-1-11,Four days later he presents with a new rash over his entire right arm with itching. He continues to have mild fatigue, but now has an unquenchable thirst. He is able to do his daily chores. His fasting blood glucose is 271 mg/dL.

Baseline criteria included Grade I fatigue, but otherwise no symptoms.

Assessment: Grading and Relatedness (CTCAE IPhone App, or (ctep.cancer.gov/protocoldevelopment/electronic.../ctcaev3.pdf)Fatigue: Rash:Fasting Blood Glucose:

Example: Toxicity Assessment

Presentation:A 47 year old Caucasian male starts an investigational agent on 4-1-11,Four days later he presents with rash over the arms and chest, fatigue, and unquenchable thirst. He is able to do his daily chores and has otherwise no symptoms.His fasting blood glucose is 271.Baseline criteria included Grade I fatigue, but otherwise no symptoms.

Assessment:

Example: Toxicity Assessment

Presentation:A 47 year old Caucasian male starts an investigational agent on 4-1-11,Four days later he presents with rash over the arms and chest, fatigue, and unquenchable thirst. He is able to do his daily chores and has otherwise no symptoms.His fasting blood glucose is 271.Baseline criteria included Grade I fatigue, but otherwise no symptoms.

Assessment:Fatigue: Grade 1, not relatedRash: Grade 2, relatedFasting Blood Glucose: Grade 3, related

Terms and Definitions

Dose limiting toxicities (DLT) within window (usually 3-4 weeks)– Grade 3 non-hematological toxicities

– Grade 4 hematological

– Protocol-specific definitions• E.g. allow for grade 3

– Diarrhea despite optimal care, – Nausea despite optimal care– Hyperglycemia (with treatment for more than 14 days) (PI3k, mTOR) – Hypertension (VEGF inhibitors, VEGFR inhibitors)

Classical Phase I Clinical Trials’ Design

Terms and Definitions– Maximally Administered Dose (MAD)

• Highest administered dose (>2/6 pts with DLT)

– Maximally Tolerated Dose (MTD)• Highest tested dose where 0/6 or 1/6 patients

experienced DLT

– Recommended Phase II dose (RPTD)• The dose to be tested in phase II

Classical Phase I Clinical Trials’ Design

Dose escalation designs

Leonardo di Pisa (ca.1202)(Fibonacci)First mentioned in Pingala (200 BC)

Dose escalation designs

– Fibonacci (0, 1, 1, 2, 3, 5, 8, 13, 21, …)

– Modified Fibonacci

– Dose doubling Designs

– Adaptive Designs• real time pharmacokinetics, • statistical adaptations

– Combinations of designs

Early Phase Clinical Trials’ Design

Dose escalation

Cohorts Fib Modified

Fib

Percent increase

Example

(mg)

1 D D ------ 1

2 2 x D 2 x D 100% 2

3 3 x D 3.3 x D 66% 3.3

4 5 x D 5 x D 50% 5

5 8 x D 7 x D 40 % 7

6 13 x D 9 x D 29% 9

7 21 x D 12 x D 33 % 12

8 34 x D 16 x D 33 % 16

Fibonacci and modified Fibonacci Dose escalations

Dose escalation

Cohorts Dose Dose Increase

1 2 mg D

2 4 mg 2 x D 100%

3 8 mg 4 x D 100%

4 (1/6 DLT) 16 mg 8 x D 100%

5 24 mg 12 x D 40%-50%

6 36 mg 18 x D 40%-50%

Dose doubling

Dose escalation with fixed tablets: e.g. 100 mg tablets

Cohorts Dose % Increase Mod Fib

1 100 mg ------

2 200 mg 100% 100%

3 300 mg 50% 66%

4 400 mg 33% 50%

5 500 mg 25% 40 %

6 600 mg 20% 29%

7 700 mg 17% 33%

Other Dose Escalation schemes

Adaptive Dose escalation with fixed tablets: e.g. 100 mg tablets

Cohorts Dose Increase

1 100 mg qd

2 100 mg bid 100%

3 100 mg tid 50%

4 200 mg qd 25%

5 200 mg bid 100%

6 200 mg tid 50%

Adaptive Designs (Example)

Cohort Size

Patient Escalation 1+1 (occ. used for lowest doses) 3+3 (most common) 6+6

Cohorts and Sample Size

– Dose Escalation Rules

• PRE-DEFINED CONDITIONS FOR DOSE ESCALATION

– (standard and specific to the individual protocol)

Early Phase Clinical Trials’ DesignTerms and Definitions

Dose Escalation Rules (3+3 design)

# patients with DLT at a Given Dose Level

Escalation Decision Rule

0 out of 3 Dose escalate to next higher dose level

>2 out of 3 Dose escalation will be stopped. This dose level will be declared the maximally administered dose (highest dose administered). The next lower cohort will be expanded to 6 patients. If no DLTs are seen consider an intermediate dose level between this dose and the MAD dose.

1 out of 3 Enter at least 3 more patients at this dose level. If 0 of these 3 patients experience DLT, proceed to the

next dose level. If 1 or more of this group suffer DLT, then dose

escalation is stopped, and this dose is declared the maximally administered dose.

<1 out of 6 at highest dose level below the maximally administered dose

This is the recommended Phase II dose.

If 0 out of 3 at the highest dose

Consider protocol amendment to dose escalate further

Dose expansion

Purpose:• Estimation of toxicities in larger sample set• Estimation of PK and PD markers• Preliminary Efficacy

Sample size • Minimum 6• General 12-15

Dose expansion

Purpose:• Estimation of toxicities in larger sample set• Estimation of PK and PD markers• Preliminary Efficacy

Sample size • Minimum 6• General 12-15

Pharmacokinetics

and Pharmacodynamics

“Drug Behavior in the Subject”

Pharmacokinetics

Pharmacokinetics

Free Drug Plasma ↕ Metabolites

Bound Drug

TARGET SITE(Receptor)

Free Drug ↕ Bound Drug

TISSUE SITE

Free Drug ↕ Bound Drug

Metabolism

Absorption

Pharmacokinetics

Elimination Excretion

Polymorphism

P. Munster

MeasurablesRoutinely done: albeit often limited

•Half-life (t1/2) •Distribution volume•Peak concentrations (Cmax)•Time to peak concentration (Tmax)•Area under the curve•Food effects

Not routinely done•Polymorphisms •Drug-drug interactions•PK-PD interactions

Pharmacokinetics

Example of PK sampling in Phase I trial

Heparinized blood samples (10 mL) will be collected on Day1 at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after the first dose of LY335562 Day 15 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s doseDay 57 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose.

Single blood samples for pharmacokinetic studies for the desmethyl metabolite were also collected on days 8, 15, 22, 29, 43, 71, and 85.

Example: Plasma concentration: dose escalations

ASCO 2008, J Infante

Munster et al CCR 2009

VPA dose level (mg/kg/day)

VPA level (μg/ml)

0.25 h

24 h

48 h

168 h

Epi

rubi

cin

leve

l (ng

/ml)

C

0.01

0.1

1

10

100

1000

10000

0 50 100 150 200 250 300

Example: Plasma Concentrations – Drug Interactions

Metabolism and Polymorphism

[Kirchheiner, 2003]

Polymorphisms in the CYP2D6 gene changes Metabolizers status

PM: Poor metabolizersIM: Intermediate metabolizerEM: Extensive metabolizerUM: Uebermetabolizer

Pharmacodynamics

Pharmacodynamics

“Drug Effects on the subjects and tumors”

• Symptoms• Signs• Changes in Lab values (e.g effects on glucose metabolism)• Molecular and Biological effects

Munster P et al. Clin Cancer Res 2009;15:2488-2496©2009 by American Association for Cancer Research

Pharmacodynamics: Effects on Lab ParametersDIRECT EFFECTS

Copyright © American Society of Clinical OncologyMunster, P. et al. J Clin Oncol; 25:1979-1985 2007

Fig 1. Valproic acid (VPA) effects on epirubicin-associated toxicities

Indirect effects

Pharmacodynamics: Effects on Lab ParametersINDIRECT EFFECTS

HORMONERECEPTORSTATUS

HER2STATUS

VISCERADISEASE

PRIOR AROMATASEINHIBITORS

PRIORTAMOXIFEN

ACET-H4

DOSEMOD

Patients with Partial Response: 8/43 (19%)Pt 1Pt 2Pt 3Pt 4Pt 5Pt 6 Pt 7Pt 8

ER+ / PR+ER+ / PR+ER+ / PR+ER+ / PR-ER+ / PR+ER+ / PR+ER+ / PR+ER+ / PR+

Not amplNot amplNot amplNot amplNot amplNot amplNot amplNot ampl

YesYesYesYesNoYesYesNo

LetrozoleAnastrozole, ExemestaneAnastrozole, ExemestaneLetrozole, Exemestane AnastrozoleLetrozole, ExemestaneAnastrozole, ExemestaneLetrozole

TamoxifenTamoxifen Tamoxifen

YesYesNoYesYesYes-Yes

300200300300

Patients with Stable Disease > 24 weeks: 9/43 (21%)Pt 1Pt 2Pt 3Pt 4Pt 5Pt 6Pt 7Pt 8Pt 9

ER+ / PR-ER+ / PR+ER+ / PR-ER+ / PR+ER+ / PR-ER+ / PR-ER+ / PR+ER+ / PR+ER+ / PR+

Not amplNot amplNot amplNot amplNot amplNot amplAmplNot amplNot ampl

NoYesYesNoYesYesNoYesNo

Letrozole, AnastrozoleLetrozole, Exemestane,Anastrozole, LetrozoleLetrozoleAnastrozoleAnastrozole, LetrozoleLetrozole, ExemestaneLetrozoleLetrozole

TamoxifenTamoxifen

Tamoxifen TamoxifenTamoxifen

YesYes-YesYesYesYesYesYes

200200300300

Pharmacodynamics: PD effects (histone acetylation) and Responses

H4 acetylation occurred only in 58% of treated patients%

cha

nge

in h

isto

ne a

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n

Acetyl-H4

Day 1 Day 8

H3 and H4 acetylation more commonly seen in patients with clinical benefits

% c

hang

e in

his

tone

ace

tyla

tion

0

10

20

30

40

50

ALL R NR

% c

hang

e in

ace

tyl-H

4

*

P=0.022, n=36

Correlative studies: Histone acetylation

biomarker in responders vs non-responders

Ch

an

ge

in H

4 h

isto

ne

ace

tyla

tion

(%

)

Ch

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ge

in H

4 h

isto

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tion

(%

)

All R NR

-50

0

50

100

150

200Non-responders

Responders

% c

han

ge

in h

isto

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• No clear relationship between dose and toxicity • No definite threshold toxicity (DLT)• No clear relationship between efficacy and dose• No clear target modulation• Unrecognized down-target effects

– Activating or inhibitory

• Efficacy not likely

Difficult to choose dose or schedule in these circumstances

Emerging Challenges

• Imaging– PET scanning

• Tissue Perfusion • Blood Volume• Glucose metabolism• Estrogen metabolism

– DCE-MRI• Pharmacodynamic Studies

– Target inhibition in end-organ• Tumor biopsies• Circulating tumor cells

– Target inhibition in surrogate tissue• Peripheral Blood Mononuclear Cells

• Pharmacokinetics– Targeted Drug Levels:

• Serum Markers

Alternative and/or Additional Endpoints

• Traditional Phase I designs are valid for novel chemotherapy drugs and for some novel agents but….

• Many targeted agents require careful assessment and incorporation of correlative endpoints or novel imaging modalities to decide the dose, schedule, and optimal therapeutic partners

• Availability of real-time PK and PD (biomarkers)

• Validation of endpoints in larger studies with enriched populations

Conclusion

Thank you