1

From Animal Scale-Up

to First-In-Human

Clinical Studies

{Chapters 32 & 33}

Jerry M. Collins, Ph.D.

Developmental Therapeutics Program

Division of Cancer Treatment and Diagnosis, NCI

Chapter 32

Section: Animal Scale-Up

Slides Supplied by:

Robert L. Dedrick, Ph.D.

Founder and Former Chief

Chemical Engineering Section, NIH

In a Chemical Plant, kilograms

of materials are made –

somehow linked to a test tube

process on a scale of milligrams

How do you get

from milligrams

to kilograms?

“SCALE-UP” How would “Scale-Up”

happen in BIOLOGY?

2

Many Biological Processes are Scaled by Body Weight

3

Allometric Chart

Convert Equations

to Log-Log Graph

Log-Log Graph

Physiologic-Based

Pharmacokinetics

“PB-PK”

Dedrick, RL, et al.

Biochem. Pharmacol, 1972

Compartmental Model for

Ara-C Pharmacokinetics

4

Core Principle of Physiologic-Based PK

Prediction, not Curve-Fitting

dose-normalized

concentrations in

4 mammalian species

(without metabolism)

Khor et al, Cancer Chemother Pharmacol, 1997

“Complex Dedrick Plot”

adjust x-axis for relative time

5

Rat Data

Scale-Up in vitro to in vivo:

cells culture to whole body

Human Data

Log-Log Graph

Ideas Borrowed from Bob Dedrick

Conversation between a Biologist and

an Engineering Consultant

[1] What are the similarities? (engineers)

[2] What are the differences? (biologists)

[3] How do you get from one set of facts

and circumstances to another?

● “Extrapolation”

● “Scale-Up”

6

//nihroadmap.nih.gov //nihroadmap.nih.gov

Cover: July 2011 issue

… This will speed the delivery of new drugs, diagnostics and medical devices to patients.

Note: NIAID, NHLBI, NCI, and other NIH units also have therapeutics-related programs

Not a new task for NCI:

Developmental Therapeutics Program Was Established by Congress in 1955

DTP.CANCER.GOV

NEXT.CANCER.GOV

Providing Services to Facilitate

Turning Discoveries into Medicines

7

First-In-Human (FIH)

Clinical Studies

<Chapter 33>

Phase 1 Clinical Studies

“First-in Human”

Jerry M. Collins, Ph.D. Developmental Therapeutics Program

Division of Cancer Treatment and Diagnosis, NCI

Re-Engineering Phase I (FIH) Trials

1. Pipeline/Funnel Pressure:

combinatorial/HTS, new Sponsors

2. To Phase I Faster, Less Preclinical Work

3. Fewer patients, homeopathic doses

4. More patients “near-Phase 2” doses

5. “Value-Added” factors

PK only: variability, metabolism/pharmacogenetics

PD: Decisions to Drop/Continue

8

Design of Phase 1 (FIH) Trial

Among all design features,

some choices remain essential

Starting Dose

Escalation Scheme

For Both Elements, Conflict Between

Caution/Safety vs. Efficiency/Efficacy

Pre-Defined

BIBLIOGRAPHY / COLLINS / PHASE 1

J.M.Collins, D.S.Zaharko, R.L.Dedrick, B.A.Chabner.

Potential roles for preclinical pharmacology in Phase I trials.

Cancer Treat. Rep. 70:73-80, 1986.

** Message: we do a lot of preclinical pharm studies;

- - what do we learn?

- - how is it used?

** Initial proposal for customized dose escalation.

J.M. Collins, C.K. Grieshaber, B.A. Chabner.

Pharmacologically-guided Phase I trials based upon

preclinical development.

J. Natl. Cancer Inst. 82:1321-1326, 1990.

** Note that title does not say “PK”

Intended as an overall platform

Summarizes mostly retrospectively

ADAPTIVE DESIGN

9

PK-PD Hypothesis:

When Comparing

Animal and Human Doses,

Expect Equal Toxicity for

Equal Drug Exposure

Concentration of Drug as

a Biomarker or Endpoint

Bridges Between Preclinical

and Clinical Development

Preclinical Clinical

Pharm/Tox Phase 1 Trials

--------------- -------------------

Mouse MTD Starting Dose

Blood Levels Blood Levels

Escalation Strategy

Acute Toxicity of Anticancer Drugs

Human versus Mouse

Dose Ratio AUC Ratio

10

Conclusion:

Hypothesis has merit.

Follow-Up:

What is underlying reason for

interspecies differences?

S.Markey, 8-Nov-01, <more general discussion, pp.169-170>

Additional Effects on Drug Metabolism

Species Differences

• Major differences in drug metabolism in different

species have been recognized for many years

both in gut microflora and CYP proteins

• Example: phenylbutazone half-life is:

3 h in rabbit

6 h in rat, guinea pig, dog

3 days in humans

Metabolism as the

Principal Confounding Factor

for First-in-Human Trials

11

major human metabolite

major rat metabolites

terfenadine/SELDANE®

fexofenadine/ALLEGRA®

parent versus metabolite

antihistaminic potency

about equimolar

cardiac ion channel potency

10,000-fold different

(parent is more toxic)

X

Pharmacodynamic Approach:

Target-Guided Dose Escalation

Preclinical Pharm/Tox Clinical Phase 1 Trials --------------------------------- ---------------------------------

Safety Factor

Reference Animal Dose Starting Human Dose

Stop or Escalate?

Define Target Goal Assess Target Impact

12

Guidance for Industry, Investigators, Reviewers

Exploratory IND Studies

FDA January 2006

Categories of Studies Include:

[1] Molecular Proof-of-Concept (pharmacologic concentrations)

[2] Functional Imaging

FDA’s Exploratory IND

enables NCI’s Phase Zero

“Historical” Phases of Human Evaluation

Phase 1: Safety, early signs of activity

Phase 2: Is activity promising?

Phase 3: Improve current therapy?

Phase 0: Mechanism of Action

Articulate and Answer the Key Question

Key question can be as simple as whether drug candidate is absorbed from GI tract

Readily Answered

Key Question for Phase Zero PARP Project:

Can DNA Repair Enzyme Be Inhibited?

(Need Tumor Sample and Suitable Assay!)

13

0

0.2

0.4

0.6

0.8

1

1.2

0 4 8 12 16 20 24

Time (hours)

Pla

sm

a C

on

ce

ntr

ati

on

(u

M)

10 mg (N = 3)

25 mg (N = 3)

50 mg (N = 7)

0.21 µM target

Veliparib Phase Zero Plasma PK

Target Concentration

S.Kummar, ASCO 2007

First NCI Phase Zero Project

PARP enzyme inhibitor

Goals

Can Target Plasma Concentration Be Achieved Orally?

Outcomes

YES

Can Tumor Biopsy Provide Definitive

Results?

PAR Inhibition in Tumor Biopsies 3-6 Hours Post Dose

0

20

40

60

80

100

120

Pe

rce

nt

of

Ba

se

lin

e

Baseline Post-Dose

Pt 4

Pt 5

Pt 6

Pt 7

Pt 10

Pt 11

S.Kummar, T.A.T. 2008

14

First NCI Phase Zero Project

PARP enzyme inhibitor

Goals

Can Target Plasma Concentration Be Achieved Orally? - - - - - - - - - - - - - - - - - -

Can Tumor Biopsy Provide Definitive

Results?

Outcomes

YES

YES

PK

PD

Inhibition by dose and time

Functional Imaging via PET:

Biomarkers for Treatment Evaluation

Does treatment impact the desired target?

What is the minimum/maximum dose?

How to select interval between courses?

CONTEXT:

Individual Patient, or New Agent Development

MAO-B

Inhibition by

Lazabamide

J.Fowler,BNL

Neurology(93)

15

First-In-Human Trials

Identity Crisis?

What is Inherent in

First-In-Human Trials?

<surprise!>

FDA

NIH

Pittsburgh

Indianapolis NIA/NIDA/Baltimore

Dartmouth

U

C

L

A

DUKE University