The Preclinical Pathway to a Phase 0 Clinical Trial

The Preclinical Pathway to a Phase 0 Clinical Trial

Accelerating Cancer Diagnosis and Drug DevelopmentAccelerating Cancer Diagnosis and Drug Development

DCTDDCTD Division of Cancer Treatment Division of Cancer Treatment and Diagnosisand Diagnosis

Joseph E. Tomaszewski, PhDJoseph E. Tomaszewski, PhDDeputy Director, DCTD, NCIDeputy Director, DCTD, NCISeptember 5, 2007September 5, 2007

Joseph E. Tomaszewski, PhDJoseph E. Tomaszewski, PhDDeputy Director, DCTD, NCIDeputy Director, DCTD, NCISeptember 5, 2007September 5, 2007

DCTD Phase 0 WorkshopDCTD Phase 0 Workshop

Can A New Path For Cancer Drug Development Be Charted? (Nov

2003)Toward an initial clinical experience /

development paradigm NOT driven by toxicity

Instead by predefined / predictable -pharmacological endpoints (plasma

concentrations) in humans -pharmacodynamic endpoints (in

surrogate or tumor tissue)

Goal: Preclinical studies shift from causing toxicity to assessing PK / PD relationships

Drive for drugs leads to baby clinical trials. Nature 2006, 440:406-407.

Drive for drugs leads to baby clinical trials. Nature 2006, 440:406-407.

Slow Start to Phase 0 as Researchers Debate Value. JNCI 2006 98: 804-806.

Slow Start to Phase 0 as Researchers Debate Value. JNCI 2006 98: 804-806.

January 2006Pharmacology/

Toxicology

3. Clinical Studies of Mechanism of Action (MOA) Related to Efficacy

FDA will accept alternative, or modified, pharmacologic and toxicological studies

Short-term modified toxicity or safety studies in 2 species to achieve a clinical PD endpoint

Incorporate PD endpoints in toxicity studies

Possible use of single, relevant species

Doses based on efficacy, MED and safe BEDs, not MTDs

Compressing Drug Development Timelines In Oncology Using Phase ‘0’

Trials

NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 131-139

Shivaani Kummar, Robert Kinders, Larry Rubinstein, Ralph E. Parchment, Anthony J. Murgo, Jerry Collins, Oxana Pickeral, Jennifer Low, Seth M. Steinberg, Martin Gutierrez, Sherry Yang, Lee Helman, Robert Wiltrout, Joseph E. Tomaszewski and James H. Doroshow

Abstract | The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase ‘0’ trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future.

What Does a Phase 0 Trial Involve?

Pre-Clinical to Clinical Transition

Assay development in vitro and in vivoAssay development in vitro and in vivo

Development of pre-clinical system on which Development of pre-clinical system on which to model tissue acquisition, handling, and to model tissue acquisition, handling, and processingprocessing

Demonstration of drug target or biomarker Demonstration of drug target or biomarker effect and PK-PD relationships in vivoeffect and PK-PD relationships in vivo

Drug biodistribution and binding using novel Drug biodistribution and binding using novel imaging technologiesimaging technologies

Innovative statistical designsInnovative statistical designs

Limited sample sizeLimited sample size

PD and PK as primary endpoints, rather than MTDPD and PK as primary endpoints, rather than MTD

How Can Phase 0 Trials Improve Efficiency and Success of Subsequent

Trials?

Eliminating an agent very early in clinical Eliminating an agent very early in clinical development because of poor PD or PK development because of poor PD or PK propertiesproperties e.g., lack of target effect, poor bioavail., rapid e.g., lack of target effect, poor bioavail., rapid

clearanceclearance ““Fail Fast, Fail Early” Fail Fast, Fail Early”

By informing subsequent trialsBy informing subsequent trials Validating a PD assay for assessing target Validating a PD assay for assessing target

modulationmodulation Developing a reliable SOP for tissue acquisition, Developing a reliable SOP for tissue acquisition,

handling, and processinghandling, and processing Determining dose and time course that yields a Determining dose and time course that yields a

required target effectrequired target effect Intensively evaluating PK, providing a closer Intensively evaluating PK, providing a closer

approximation to a safe, but potentially effective approximation to a safe, but potentially effective starting dose and support for limited sampling in starting dose and support for limited sampling in subsequent trialssubsequent trials

TISSUE HANDLING & PROCESSING

Clinical team

Interventional Radiology

Translational laboratory

Study Effect of tissue& biologic fluid handling on target

Develop SOPs for tissue & biologic fluid handling

TISSUE ACQUISITION

IRB approved protocol to obtain peripheral blood samples from healthy volunteers to develop assay

IRB approved protocol to obtain peripheral blood samples and tissues from cancer patients to optimize assay prior to analyzing samples from the clinical trial

ASSAY DEVELOPMENT LABORATORY

ANIMAL MODELS

Animal facility with an experienced veterinarian:

to conduct drug effect studies in xenografts

provide samples for assay analysis

mirror the clinical tissue acquisition SOP in animal models to determine effect of tissue handling on target

Summary: PD Assay Development Before Initiation of Phase 0 Clinical Trials

REGULATORY AGENCY

CLINICAL LABORATORY

Trial Monitor

IND Sponsor

•National Cancer Institute

•Pharmaceutical Industry

•Investigator

Laboratory for Pharmacodynamic (PD) Analysis

Laboratory for Tissue Handling and Processing

Laboratory for Pharmakinetic (PK) Analysis

Interventional Radiology

Drug Development Clinic

Research Imaging

Bioethics

Schedule tumor biopsies: coordinate with times for drug administration

Review imaging studies, determine feasibility of obtaining biopsies

Research Nursing

Medical Oncologists

Clinical Nursing

Data Managers

Social Workers

Patient Education

Documentation of patient understanding of the nature of the clinical trials

Pathology Laborator

y

Repository

Integrated Phase 0 Research Team

NCI’s First Phase 0 Study

Abbott Laboratories Abbott Laboratories

PARP Inhibitor, ABT-888PARP Inhibitor, ABT-888

Poly (ADP-

Ribose) Polymerase (PARP)

Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388.Copyright ©2007 American Association for Cancer Research

ABT-888 History with NCI

July 2004: CTEP brings in Abbott’s July 2004: CTEP brings in Abbott’s PARP inhibitor for developmentPARP inhibitor for development

Early 2005: PK/Toxicology issues Early 2005: PK/Toxicology issues identified with lead development identified with lead development candidatecandidate

August 2005: Abbott decides to August 2005: Abbott decides to pursue development of back-up pursue development of back-up molecule (ABT-888)molecule (ABT-888) IND filing delayed until late 2006/early IND filing delayed until late 2006/early

20072007 CTEP & Phase 0 team selects ABT-888 for CTEP & Phase 0 team selects ABT-888 for

first Phase 0 trialfirst Phase 0 trial

Rationale for ABT-888 Phase 0

Exploratory IND candidateExploratory IND candidate No anticipated toxicity at low dosesNo anticipated toxicity at low doses Pharmacodynamic marker studies possiblePharmacodynamic marker studies possible CMC, Non-GLP pharm/tox studies availableCMC, Non-GLP pharm/tox studies available Phase 1 IND filing delayedPhase 1 IND filing delayed

Phase 0 candidatePhase 0 candidate PD assay required optimizationPD assay required optimization Assay development would support Phase 1 Assay development would support Phase 1

studiesstudies PK and PD data from Phase 0 would PK and PD data from Phase 0 would

accelerate Phase 1 combination studiesaccelerate Phase 1 combination studies

ABT-888 ± TMZ (U87MG Glioma Xenograft):

Pre-clinical Starting Point for Choosing Dose and Schedule for Clinical Protocol

28 Days of Dosing ABT-888 Treatment Schedule

CP : CTumor

PD1, PD2, PD3

Data supplied by Abbott Labs

Copyright ©2007 American Association for Cancer Research

Donawho, C. K. et al. Clin Cancer Res 2007;13:2728-2737

Efficacy and PARP Inhibition: (ABT-888, bidx5, Oral, 2Hr Post Dose)

TMZ

TMZ

ABT-888 p.o., b.i.d.x5

0

1000

2000

3000

4000

5000

PA

R (

pg

/ml p

er

100

g

pro

tein

)

TUMORS

**vs. vehicle

*vs. all groups

TREATMENT GROUPS(harvested 2 hrs after the last dose)

VEH 12.5 mkd 5 mkd 1 mkd 0.3 mkd 0.1 mkd

A-861695

* ** p < 0.05

PAR Inhibition: (ABT-888 alone, bidx5, Oral, 2Hr Post Dose)

PA

R

Data supplied by Abbott Labs

B16F10 syngeneic melanoma in mice

0

250

500

TREATMENT GROUPS(harvested 2 hrs post dose)

TUMORS

VEH

ABT-888 p.o., b.i.d. dose given once

tumors frozen prior to lysate preparation

ABT-888

25 mkd 12.5 mkd 6.25 mkd 3.125 mkd 1.56 mkd

* p < 0.05 Veh vs. 25 and 12.5 mkd only

** p < 0.05 25 and 12.5 mkd vs. 3.125

CP = 570nM

CP = 210 nM

PAR Inhibition: (ABT-888, Dx1, Oral, 2Hr Post Dose)

Human Equiv Dose 60-70 mg 30-35 mg

PA

R

VEH 12.5mg/kg 6.25mg/kg 3.13mg/kg 1.56mg/kg 0.78mg/kg

Data supplied by Abbott Labs

Veh vs 12.5 and 6.25 mg/kg only

12.5 and 6.25 vs 3.13

Therapeutic Window for ABT-888

Predicted human Cmax

Steady state (OMP) concentration required for efficacy

Animal Toxicity

Therapeutic Window7.3 – 12.8 x

Time (hours)

Pla

sm

a C

on

cen

trati

on

0 12 24

First Phase 0 – How Did We Get There?

Efficacy – Work backward1. Schedule: 28 Day, ip, combination. PAR

inhibition related to tumor regression, stasis

2. Reduced schedule to Dx5, po, bid; PAR inhibition at p <0.05 level for 5 dose levels

3. Reduced schedule to Dx1, po; PAR inhibition at p <0.05 level for 2 top dose levels

4. Determined CP and CT in all studies to establish target levels for clinical study

Pharmacology1. Developed and validated PK assay2. Developed and qualified PD assay

New Model Summary

Perform studies in animal models prior to initiating clinical trials to:Select appropriate endpoints to evaluate

in man Interrogate and validate PD target or

biomarker assaySimulate human tissue acquisition,

handling, processing and storageDemonstrate drug target or biomarker

effect in tumor and/or surrogate tissues/samples

Determine PK-PD relationshipsEvaluate drug biodistribution and

binding using imaging technologiesEnable conducting Phase 0 clinical trials

The Next Speaker is:

Dr. Shivaani Kummar