NUEVOS DISEÑOS DE ENSAYOS CLINICOS EN … · conformation of ATP pocket ... & RECIST Week 6...

ANDRES CERVANTES

NUEVOS DISEÑOS DE ENSAYOS CLINICOS EN FASE TEMPRANA

LoRusso P M et al. Clin Cancer Res 2010;16:1710-1718

CANCER DRUGS TESTED IN CLINICAL TRIALS OR UNDER U.S. FDA REVIEW BY YEAR

• Safety

• Tolerability

• Pharmacokinetics

• Pharmacodynamics

• To document any evidence of antitumor effect

• To determine a recommended dose for a phase II trial

AIMS OF A PHASE I (FIRST IN HUMAN) TRIAL

Maximum tolerated dose

(cytotoxic agents)

Versus

Optimal or effective dose

Relevant level of target modulation

AIMS OF A PHASE I (FIRST IN HUMAN) TRIAL

Garraway LA, Verwey J, Ballman K. J Clin Oncol 2013

GENOMICS DRIVEN CANCER MEDICINE

SCHEDULING OF TUMOR BIOPSIES AND THE OPORTUNITIS FOR GENOMIC ANALYSIS

Dienstmann R, Rodón J, Tabernero J. J Clin Oncol 2013

TREATMENT OF REFRACTORY TUMORS AFTER THEIR MOLECULAR PROFILLING

Von Hoff D, et al. J Clin Oncol 2010

ATTRITION RATE IN ONCOLOGY DRUG DEVELOPMENT

• Failure rate:

– Phase III:

45% (all) vs 59% (Onc)

– Registration:

23% (all) vs 30% (Onc)

• Causes:

– Lack of efficacy (30%)

– Safety (30%)

– Pharmacokinetic (10%)

– Other (30%)

Kola et al, Nat Rev Drug Discover 2004

Big ten: 1991-2000

ATTRITION RATE IN ONCOLOGY DRUG DEVELOPMENT

1995-2007 period: 800 oncology drugs, 150 kinase inhibitors

Walker et al, Nature Rev Drug Discover 2009

Oncology drugs Ph I Ph II Ph II Ph III Ph III Market

Attrition rate (Transition probability)

All 0.8 0.49 0.59 77%

Kinase inhibitors 0.88 0.75 0.83 45%

Evolution: 95% 77% 45% (kinase inhibitors)

Causes:

• Clinical trial design

• Patient stratification

• More representative preclinical animal models

• Use of biomarkers

HOW TO REDUCE ATTRITION IN ONCOLOGY DRUG DEVELOPMENT?

• Strong proof of concept evidence:

– Target, target relevance, target dependency

• Minimize toxicity:

– Gene knockouts, RNAi, preclinical toxicology

• Appropriate animal models:

– Genetic (transgenic or knockout animals) and “xenopatients” rather than xenograft models

• Identification of biomarkers:

– Phase I: POC studies, correct dosing/schedule

– Phase I/II: Target “population”

• Appropriate phase I, phase II and phase III designs

• Early discontinuation for “commercial” reasons

BIOMARKERS IN DRUG DEVELOPMENT

• Pharmacodynamic/Mechanism of Action Biomarkers

– Inform about a drug’s pharmacodynamic actions

– Most relevant to early development

• Dose and schedule selection

• Define pharmacological behaviour in patients

• Goal: Improve efficiency of early development

• Predictive Biomarkers

– Identify patients who will/will not respond to treatment

– Most relevant to mid/late development

• Basis for stratified/personalized medicine

• Develop co-diagnostic biomarker assays

• Goal: Enrich treatment population to maximize benefit

The biomarker hypothesis

• Increase probability of registrational success through increased scientific understanding of the drug, target and pathway:

– Proof of mechanism of action

– Proof of mechanism of resistance (primary and secondary)

– PD exploration: right schedule and dose

• Permit focused clinical studies with higher probability of demonstrating benefit:

– Adaptative study designs

– Prospective screening of patients for enrolment

Early investment (phase I-II) in biomarkers will accelerate development time lines and reduce costs

TRADITIONAL ONCOLOGY PHASE I STUDY DESIGN

• Pharmacokinetic and toxicity monitoring throughout the study

• Standard dose escalation up to dose limiting toxicity (DLT) level

• Expansion at a dose level below the DLT level defines the MTD

• MTD is the recommended Phase II dose for further study

Dose Escalation Cohorts

Starting

Dose

Level

“DLT”

“MTD”

Maximum

Tolerated

Dose

Recommended

Phase II

Dose

Expansion

Cohort

Provided by Chris Takimoto

BIOMARKER DEVELOPMENT IN DRUG APPROVAL TIMELINES

Phase I Phase II Phase III Registrational Preclinical

Drug approval time lines

Phase I Phase II Preclinical

MoA/PD Biomarkers

Validation, standardization

Phase I Phase II Phase III Preclinical

Predictive Biomarkers

Validation, standardization

• Ph. II trials are the 1st opportunity for correlative studies with sufficient

patients exposed to a RD

• Novel markers discovered in late ph. II will delay ph. III entry

Anti-EGFR/HER3 Dual-action Fab: MEHD7945A

• Affinity-matured, human IgG1

• Dual binding specificity:

– Each Fab binds to either EGFR or

HER3 with high affinity

– Simultaneously blocks ligand-

binding to EGFR and HER3

• Binding affinity to EGFR: Kd = 1.9 nM

• Binding affinity to HER3: Kd = 0.4 nM

• Inhibits signaling by all major

ligand-dependent HER-family

dimers

• Mediates ADCC Fc

Light

Chain

Heavy

Chain

HER3

EGFR

Antigen-binding

fragment

MEHD7945A: A novel, first in class, two in-one antibody

Schaefer et al., Cancer Cell, 2011.

FIRST-IN-HUMAN PHASE I STUDY DESIGN (DAF4873G)

• Eligibility: Patients with relapsed/refractory epithelial tumors

• Endpoints: PK, safety, DLT, objective response, exploratory PD

– PD markers: FDG-PET, tumor biopsies (IHC/RPPA for pRAS40, pRbS6, and pERK),

plasma biomarkers (e.g., amphiregulin, IL-8) Cervantes A, et al. ASCO 2012

1 mg/kg (n=3)

4 mg/kg (n=3)

10 mg/kg (n=6)

22 mg/kg (n=6)

30 mg/kg (n=6)

Dose Escalation

(N=30)

Relapsed/refractory

epithelial tumors

q2w infusions

3+3 design

DLT window 28 days

Dose cohorts ≥

10mg/kg were

expanded to a total of 6

patients for added

safety/PK assessment

Expansion

14 mg/kg (q2w)

(N=36)

Relapsed/refractory

CRC

NSCLC

SCCHN

Pancreatic

15 mg/kg (n=6)

Baseline C3, D8 (at week 5, after 3 infusions) C5,D1 (at week 8, after 4 infusions)

Cetuximab-relapsed SCCHN of the

Larynx, Invading Tracheostomy Site

Line of Therapy Treatment Best Response

Dx (T4N2M0) Nov-2007 - -

Induction therapy Taxotere/platinum/5-FU (Nov-Dec 2007) (Completed Regimen)

Concurrent chemo with radiation RT 70Gy + carbo qw (Jan-Mar 2008) CR

1L Cetuximab (Oct 2009-Jun 2010) SD (then PD)

2L Cetuximab/carbo (Jul-Sep 2010) PD

3L Cetuximab/paclitaxel (Oct 2010-Mar 2011) SD (then PD)

4L Capecitabine (March-May 2011) PD

5L DAF 14 mg/kg (July 2011-present) C2D2: better phonation, less pain, FDG-PMR C3D8: appreciable shrinkage of visible tumor

C4D8: CT-PR (70% reduction in SLD)

ANTI-HER3/EGFR ACTIVITY IN SCCHN PATIENT (1)

Cervantes A, et al. ASCO 2012

ANTI-HER3/EGFR ACTIVITY IN SCCHN PATIENT (2)

Baseline Pre-C5, D1 (CT at week 8, after 4 infusions)

SCCHN of the tongue, diagnosed in 1994, ost recently metastatic to the lung

Prior therapies include multiple surgeries and chemoradiation

MEHD7945A at 14 mg/kg IV q2w since 09/11

Confirmed PR and clincial improvement (regained ability to swallow)

Remains active on study (> 6 months)


ANTI-TUMOR ACTIVITY IN SCCHN PATIENTS WITH HIGHEST TUMOR EXPRESSION OF HRG

SCCHN-cPR SCCHN-cPR

First diagnosis 2007 1994

Tumor location Larynx Tongue +

pulmonary

mets

Prior anti-EGFR Cetuximab 3x

(± chemo)

None

MEHD7945A

Line of treatment

DOR (weeks)

5L

+26

2L

+18

SCCHN-cPR

SCCHN-cPR


THE PHARMACOLOGICAL AUDIT TRAIL

• A series of sequential questions or benchmarks to

evaluate in early drug development

– Likelihood of failure decreases as each successive

benchmark is addressed

• Stepwise approach to proof of principle

– Modulation of the intended target results in clinical benefit

• Organize strategic thinking about early development

assets

– Allows for critical decision making based upon biomarker

and clinical endpoints

• Groundwork must begin early in preclinical

development

Workman, Mol Cancer Therapy 2003

Yap et al, Nature Rev Cancer 2010

PHAT AND MODEL-BASED DRUG DEVELOPMENT

• Model-Based Drug Development

– Preclinical PK/PD/biomarker models with direct

relevance to clinical setting

• Requires extensive resource investment

preclinical pharmacology studies

– Discovery Research – Clinical Pharmacology

– Biomarkers – Clinical/Translational Medicine

• Essential for evaluation of the PhAT benchmarks

in first-in-human Phase 1 clinical trials

THE PHARMACOLOGICAL AUDIT TRAIL (PHAT)

Is the target

expressed or

activated?

Adequate drug

dose &

schedule?

Active

concentrations

in plasma?

Active

concentrations

in tumour?

Active against

the molecular

target?

Modulation of

downstream

pathway?

Biological effect

achieved?

Clinical

response or

benefit?

Predictive

biomarkers of

activity?

Weak

Unknown Established

Strong

Provided by Chris Takimoto, modified from Workman et al, Mol Cancer Therap 2003

Preclinical PK-PD Modeling of cMET Inhibition

Plasma

Tumor

Sacrifice a subset at 1,4,8, and

24 h (n = 3 per time point)

pMET cMET

Dose at 3.1, 6.3, 12.5,

25, and 50 mg/kg

Assay Tumour PD Biomarker

Plasma PK Analysis

Tumour Growth Inhibition

Yamazaki et al, Drug Met Dispos 2008

UNIFIED PRECLINICAL PK-PD BIOMARKER MODELS

Plasma

PK

Tumour

PK

Biomarker

Change

Antitumor

Activity

Yamazaki et al, Drug Met Dispos 2008

A NEW APPROACH

• Translational Phase I study with Biomarker

Defined Endpoints

– A new study design for targeted oncology agents

• PD/MoA biomarkers are formal study endpoints

– Biologically effective dose (BED): biomarker defined

– Maximum tolerated dose (MTD): toxicity defined

– Recommended Phase 2 dose range: toxicity and

biomarker defined

• Allows for the objective evaluation of the PhAT

benchmarks

TRANSLATIONAL PHASE I STUDY WITH BIOMARKER-DEFINED ENDPOINTS

• Biologically effective dose (BED) defined in by

– Prespecified change in biomarker seen in a defined fraction of patients, or

– Any clinical antitumor activity

• Maximum tolerated dose (MTD) defined in standard manner

• Expansion cohorts have mandatory tumour biopsies

• Phase 2 dose range defined by BED in tumour biopsies and by MTD

Target biomarker effect in

surrogate tissues or if any

clinical activity

“BED”

Dose Escalation

with biomarker monitoring

in surrogate tissue

Starting

Dose

Level

Tumour biopsy cohorts for

biomarker evaluation

Potential

Phase 2

Dose

Range

Expansion

Cohort 3

Expansion

Cohort 1

Expansion

Cohort 2

“MTD”

Maximum

Tolerated

Dose

“DLT”

Provided by Chris Takimoto

AZD0530: anilinoquinazoline

AZD0530 – A POTENT, SELECTIVE INHIBITOR OF SRC FAMILY KINASES

• Reversible, competitive binding at active conformation of ATP pocket

• Favorable PK and bioavailability

– Suitable for once-daily oral dosing

– t½ in healthy volunteer studies ~40 hours

N

N

O

N O

O

Cl

O

O

N

N

Isolated protein kinase IC50, nM

cSrc 2.7

cYes 4

Lck <4

Lyn 5

c-Fyn 10

v-abl 30

c-kit 200

Csk 843

PDGFR β >5,000

PDGFR α >10,000

Baselga J, Cervantes A, et al. Clin Cancer Res 2010

STUDY DESIGN AND OBJECTIVES

• To investigate the MTD and DLT of once-daily, oral AZD0530 in patients with advanced solid cancers

• To develop methodology for demonstrating Src inhibition in human cancers

Once-daily dosing

Day 21

Follow-up

& RECIST

Week 6

Follow-up Week 9

Follow-up

& RECIST

Day 1

DLT assessment period

Dose, mg Patients

60 5

125 6

175 5

200 7

250 7

Part A

Dose, mg Patients

50 16

125 16

175 19

Tumor biopsy for biomarker assessment

Part B

Once-daily dosing

Day 8 Day 28

Follow-up

& RECIST

Day 1

Single dose

Follow-up

(every 3 weeks)

RECIST

(every 9 weeks) • To evaluate the effect of AZD0530 on Src activity

in human tumor biopsies at three doses

• To evaluate PK and preliminary efficacy (Parts A and B)

Washout

Calu6 xenografts stained

with anti-FAK pY861

Control

AZD0530 50 mg/kg • Src phosphorylation of FAK and paxillin is critical for the migratory phenotype

• Methodologies using FAK pY861 and paxillin pY31 antibodies have been validated in preclinical models

• Src inhibition by AZD0530 decreases phosphorylation of FAK and paxillin in preclinical models

P-FAK AND P-PAXILLIN – BIOMARKERS OF SRC INHIBITION

FAK = focal adhesion kinase

Cadherins

Migration

Invasion

Cadherins

Integrins

GF

Src GF receptor

P P

Growth factor

induced

mitogenesis Osteoclast

function Promotes

G1/S

Survival

FAK

Paxillin

Actin

cytoskeleton


PRE AND POST AZD0530 TREATMENT

p-FAK p-paxillin

Day −1

Day 28


0

−100

−200

−50

−150

−250

CHANGES IN P-FAK MEMBRANE H-SCORE

Individual patient results

grouped by dose

50 mg 125 mg 175 mg

Ch

an

ge f

rom

baselin

e

50

0

−50

−100

−150

−200

−250

0 100 200 300

Baseline

Ch

an

ge f

rom

baselin

e


NEW PHASE I STUDY DESIGN REQUIREMENTS

• Validated/qualified PD/MoA biomarker assay

– Robust and reproducible

• Measurable signal in normal and malignant tissues

– Surrogate tissues: skin, buccal mucosa, PBMCs, hair

follicles, etc.

– Tumour biopsies, CTCs, cfDNA, ...

– Imaging

• Pre-study definition of a positive biomarker signal

– What change is associated with antitumor activity?

• Phase I centres and study support staff comfortable

with tissue biopsies and imaging

The shift

Past


The shift

Past

Present &

Future


The shift

Past

Present &

Future

Vision &

Investment


CONCLUSIONS

• The attrition rate in Oncology drug development is high but lowering with appropriate clinical trials design

• Biomarkers in phase I-II have to be standardized and validated ready for early phase III incorporation

• The PhAT can help organize strategic thinking for the early development of molecularly targeted therapies

• Clinical evaluation of PhAT benchmarks requires substantial preclinical laboratory studies – PK-PD Model-based drug development

• Novel study designs are required for the optimal implementation of this strategy – Example: Translational Phase I study with biomarker-defined

endpoints

• Implementation of this approach in our early development programs is ongoing

UNIDAD DE ENSAYOS FASE I

HOSPITAL CLÍNICO UNIVERSITARIO DE VALENCIA

SERVICIO DE HEMATOLOGÍA Y ONCOLOGÍA MÉDICA

• Radiología Intervencionista: Jorge Guijarro, Ximo Gil, Juanma Sanchis

• Patología: Samuel Navarro, Cristina Mongort, Antonio Ferrándis, Octavio

Burgés.

• Laboratorio polimorfismos y mutaciones: Javier Chaves, Charo

Abellán.

• Laboratorio Genética Oncología: Maider Ibarrola, Gloria Ribes

• Oncología Médica: Desamparados Roda, Alejandro Pérez Fidalgo,

Susana Roselló, Ana Bosch, Paloma Martín, Amelia Insa, Juanmi

Cejalvo, Inés González, Valentina Ganbardella.

• Enfermeras de Investigación: Inma Blasco, Amparo Domingo

• Data Manager: Julia Peláez

• Personal administrativo: Yolanda de la Cruz, Gabriela Pérez, Jessica

Fraile

• Jefe de Servicio: Ana Lluch

GRACIAS

NUEVOS DISEÑOS DE ENSAYOS CLINICOS EN … · conformation of ATP pocket ... & RECIST Week 6...

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