Dr Christophe Massard Journées annuelles de l’Association des Internes d’Hématologie 25 au 27 Septembre 2009 – Nantes Current challenges in phase I trials

Dr Christophe Massard

Journées annuelles de l’Association des Internes d’Hématologie25 au 27 Septembre 2009 – Nantes

Current challenges in phase I trials

Les médecins sont des hommes qui prescrivent des médicaments dont ils connaissent peu de choses… pour guérir des maladies qu’ils connaissent encore moins… chez des êtres humains dont ils ne connaissent rien.

Voltaire (1694-1778)

We have several problems…

More than 900 compounds in development

More than 8000 early clinical trials (I/II)

Increasing cost of drug development (0,6 billon to 1,2 billon USD) and limited ressources (patients, time)…

Old fashioned drug development

The revolution of molecular biology is not integrated

The Stages of Development of a New Anticancer Agent(The Conventional Approach)

Discovery

Formulation

Evaluation of activity (in vitro and in vivo)

Pharmacology

Toxicology

Phase I (dose-finding trial)

Phase II (efficacy trial)

Phase III (comparison with standard agent trial)

Introduction into general medical practice

Current challenges in phase I What are the real objectives of phase I trials ?

What are the best tools to search for efficacy ?

How do we integrate biology and molecular knowledge in phase I trials ?

How do we evaluate and manage toxicity in the era of molecular targeted agents

Molecular targeted agents

Current challenges in phase I

What are the real objectives of phase I trials ?Do we define “success” of a Phase I trial on

identification of a MTD and a well defined PK profile ?

Is proof of concept and early evaluation of activity an important objective of phase I trials ?




Old paradigm for Early Clinical Trials Administration of anti-neoplastic agents to

participants, based on safety and potential for efficacy established in in vitro and animal studies.

Objectives: Assessment of safety and tolerability Identification an appropriate dose for further studies. Toxicity Profile Pharmacokinetics

But MTD and Safety are not the only endpointsfor physicians and patients

Benefits of Phase I Studies 1991-2002 (Horstmann et al, 2005)

Overall response rate of 10.6%Stable disease rate of 34.1%

Studies with MTTDisease control rate of around 48.2% (SD: 41%; PR; 7.2%)Clinical benefit even at low dosesStabilisation of disease for periods close to 4 monthsMedian PFS and OS currently achieved in the selected

phase I pop is similar to approved agents in 2nd or 3rd line

Horstmann et al, NEJM 2005; Italiano et al, Annals Oncol 2007;

Postel-Vinay et al, BJC 2009


What are the best tools to search for efficacy ? Traditional emphasis on…

• RECIST (complete or partial responses)• Progression Free & Overall Survival (PFS & OS)

New emphasis on…

• Stable Disease

– Growth Modulatory Rate• Quality of life / Symptom Improvement



10

LES ESSAIS DE PHASE I SONT-ILS DES ESSAIS THERAPEUTIQUES ?

Une réponse doit-elle être vu dans une PHASE I ?

A ce jour, tous les produits approuvés pour une

utilisation en oncologie clinique, ont montré au moins

une réponse dans les essais de PHASE I.

Week32

1-Shrinkage (RECIST) 2-Central Necrosis (limits of RECIST)

Week0

Week12

Base

line

Day 1

, cy

cle

2D

ay 1

, cy

cle

3

Tumor growing in AVE

-60

-40

-20

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

Time

Tu

mo

r g

row

ing

dif

fere

nc

e (

%)

1

2

3

4

5

6

9

10

SPIDER plot

Kinetics before, during and after treatment

Gomez-Roca et al, ASCO 2009

Kinetics of TG: SD as true responses…or indolent diseases



How do we integrate biology and molecular knowledge in phase I trials ? Proof of concept, PD read out Patient selection Trial design


Biology-driven phase I trials

Biology-driven phase I trials

Pre-treatment biomarkersPrognostic factors to stratify patientsDefine a subpopulation of pts who will benefit or not

from therapyBaseline PD markers

Post-treatment biomarkersPharmacodynamic markers+++Follow the drug until it reaches its targetDefine effects at the tumor site

Proof of concept and biomarker use

>>>Inclusion of surrogate biomarker

>>>Functional imaging, Blood, Tumor or skin biopsies, Circulating tumor cells…

The molecular portrait performed on

material at time of diagnosis

JC Soria

The molecular portrait performed on

material at time of diagnosis

JC Soria

Does not predict for the molecular portrait

of the current disease

IGR sequential Biopsies program

I)

……

2Gene i

……

0.5Gene 1

Ratio

(D0/D21)gene

Biopsy (D0)Before treatment

Biopsy (D21)After treatment

RNAPurification

Labeling Hybridization

Image Analysis

Bioinformatic’ Analysis

Gene regulated by treatment

Patient I

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

Patient I

Patient IX

Patient III

Patient XI

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

……

1Gène

n

2gène i

……

0.5gène

1

Ratio

(post/préTTT)gène

Patient X

Patient II

Patient VIII

PatientIV

Gene regulatedfor patient

with response/toxicity

Gene regulatedfor patient

without response/toxicity

Statistical AnalysisGenes associated

to response or toxicity

upGene nf

downGene

ga

downGene

bd

upGene lq

upGene ij

Ratio

(R / NR )gene

Biostatistic' Analysis

II)

1Gene

n

Patient I

I ) Biopsy before treatment and Biopsy after treatment II) Comparison with clinical observations (response,

toxicity).

Avoid inter-individual variability

Lazar et al : AACR-NCI-EORTC, 2007

An example IGR’s Team Experience

Enrichissement

Pantel et al. Nat Cancer Rev. 2008

Liquid biospy: Isolation of CTC in peripheral blood

Potential Applications for detection of Micrometastatic Tumor Cells (CTCs)

Marker of recurrence (prognosis and stratification)

Marker of response to therapy (surrogate marker)

More readily available source of tumor to mesure target modulation (biological therapies)

Source of material to study biology of metastasis

Prediction of prognosis and real-time monitoring of the efficacy of systemic therapies

Patient selection in phase I is a key-issue

- Population enrichment on the basis of the target can be potentially very misleading- Sunitinib/Sorafenib and RCC- Gefitinib and NSCLC without EGFR mutation

- Limiting the number of previous Ct lines when using targeted agents is debatable while the kinetics of the tumor is much more important

- Area of unmet medical need- Rare tumors (sarcoma, neuroendocrine…)- Glioma, brains mets

Clinical benefit and patient selection?

Clinical benefit and patient selection?

ATHLETE patients….

38162848729312517121224013556789101213

0,0

0,2

0,4

0,6

0,8

1,0

0 2 4 6 8 10 12 14 16 18 20 22Months

137162653105162244

111113468914

0,0

0,2

0,4

0,6

0,8

1,0

0 2 4 6 8 10 12 14 16 18 20 22Months

Treatment group

No CNS metastases

CNS metastases

Patients included n=258

Patients screened

n=267 Not included

due to CNS metastases

n=9

Patients with primary CNS

lesionsn=2Patients

without CNS Metastases

n=244

Patients with CNS

Metastasesn=14

PFS

OS

Patients with Brain mets enrolled in phase I: IGR experience

Delamotte et al, TAT meeting 2009

27

Case Study (54F; NSCLC [adenocarcinoma] PS 1; mTOR inhibitor + erlotinib)

Lesion 1

Screening Week 12 CR Week 42 CR

Lesion 2

This non-smoking pt is stillalive at week 82 and free of cerebral disease (she was withdrawn of the phase I at week 42 for pulmonary PD)

She never received cerebral RT

Pathology-based therapycytotoxic

Molecular classification

and Target-oriented therapy

Ashworth A, JCO 2008; Fong et al, NEJM 2009

Synthetic lethal concept

ALK translocationALK translocationALK translocationALK translocation

FISH

Selective inhibitor ATP-dependant

(PF-02341066) c-MET and ALK

Phase I, antitumoral activity Myofibroblatic inflammatory sarcoma NSCLC (translocation EML4-ALK)

New target in NSCLC: ALK kinaseTranslocation EML4-ALK

,

First in Human, First in class ALK inhibitor

Efficacy in ALK dependant tumor+++

New design of phase I>>> III

ASCO 2009, Kwak EL et al., abstract 3509

Before After 2 ycles

48 year-old Female with NSCLC ALK positive




How do we evaluate and manage toxicity in the era of molecular targeted agents Chronic dosing => chronic toxicities with new DLT ! New organ toxicities (skin, ophtalmological…)

MTT toxcities managment (acute/chronic phase)

CutaneousGut and liverCardiovascularHematologicalNeurologicalLungBone and arthririsEndocrinologyOphtalmological

- Side effects are the testominy of biological activity,

- ON or OFF target

- Learning to deal with side-effects is a key-issue>>>long term toxicity

-High response rate: 1 CR and 12 PR (RR=52%)

-MTD defined

-But high degree of HYPERTENSION and VASCULAR Pb

- Not recommanded +++ because of late toxicitiesFeldman DR et al, JCO 2009

Collaborations IGR

and AP-HP

Saint Antoine

Antoine Beclere

Pitié-Salpétrière

Henri Mondor Kremlin Bicêtre

IGR

Nephrological

Nephrological CardiacCardiac

Gut, liverGut, liverENTENT

My vision of Phase I trials in 5 years…Patient with advanced Cancer referred to SITEP

UnitScreening for exclusion/inclusion criteria

Pre-treatment tumor evaluation(biopsy/CTCs/DNA blood/functional imaging)

FDA approved test (CellSearchTM)

PronosticBreast, prostate

and colon cancer…

CEC, apoptosis marker

Molecular profilMolecular characterization

FISHIHC

SequencingRNA/DNA arrays

My vision of Phase I trials in 5 years…

Patient with advanced Cancer referred to SITEP UnitScreening for standard exclusion/inclusion criteria

Pre-treatment tumor evaluation(biopsy/CTCs/DNA blood/functional imaging)

Post-treatment tumor evaluation (sensitivity/resistance/drug penetration)

Clinical benefit and quality of Life+++

Inclusion in phase I protocols according

to molecular alterations

Inclusion in phase I protocols according

to molecular alterations

Thank you for your attention

AcknowledgementsAcknowledgements

Pr Soria

SITEP collaborators

…and Discussion

Documents

Dr Christophe Massard Journées annuelles de l’Association des Internes d’Hématologie 25 au 27 Septembre 2009 – Nantes Current challenges in phase I trials