sviluppo di disegni sperimentali: esperienze e...

Sviluppo di disegni sperimentali:

esperienze e proposte

Gianluca Fincato

Medical Director

BU Oncology

Novartis Farma SpA

ISS – Roma, 17/11/2017

BU ONCOLOGY

This material, and all contents cited within, is intended to provide free medical

information for physicians. The objective is to share scientific data allowing

each HCP to draw autonomous conclusions and make autonomous decisions

from the material provided.

The scientific information may include data/information on investigational uses

of compounds/drugs that have not been approved by regulatory authorities.

Efficacy and safety have not been established. There is no guarantee these

compounds will become commercially available.

This material may contain recommendations outside the approved labeling of

Novartis products, but it is not intended to promote or recommend any

indication, dosage, regimen or any claim not covered

in the licensed product information (SPC).

Use of This Slide Deck

From R&D strategy to trial design

Our strategy is defined by patient selection, novel

combinations and understanding resistance

Pathway analysis

and drug sensitivity

Patient preselection

with genetic and

pathway biomarkers

Genetic analysis of

responders and

non-responders

New targets and

combinations

Clinical trial

design

Understanding

resistance

Patient selection is critical for efficient,

successful cancer drug development

Drives:

• Improved patient benefit

• Increased probability of success

• Faster time to market with lower development cost

• Highest social benefit

All early development conducted with patient selection

Companion diagnostics underway for all relevant full development programs (Genoptix)

Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

Novartis drug development model

Target selection

Compoundselection

IND-enablingstudies

First humanstudies

Proof of Concept

Full Development

Registration

NIBR

TCO

GDD


NIBR = Novartis Institute for BioMedical Research

TCO = Translational Clinical Oncology

GGD = Global Drug Development

Patient selection can markedly shorten

development timelines

Phase I FPFV

45 monthsAUY922 POC

18 monthsBKM120 POC

5 moLGX818 POC

LDK378 POC (April 24)11 months

18 monthsLDE225 POC

Selection at FPFV

Selection at MTD

No selection

6 moTasigna POC

60 monthsHCD122 POC

65 monthsTKI258POC


Alternative trial design: adaptive

studies

Types of adaptation in clinical

trials

Chow and Chang (2007)

Motivations and definition

• Motivations

• Increase the probability of success for identifying the clinical

benefit of the treatment under investigation.

• Reduce costs of drug development programs through more

efficient study designs.

• Definition and Features

– Adaptive design is defined as a study that includes a

prospectively planned opportunity for modification of one or

more specified aspects of the study design and hypotheses

based on analysis of data (usually interim data) from subjects in

the study (FDA, 2010).

– Aim to enhance the trial, not a remedy for inadequate planning


Phase I/II in oncology: Novartis

approach

From the Traditional 3+3 design...

New cohort at a new dose

level: Enroll 3 patients

Go to next higher dose level

or same dose if highest dose

level

Enroll 3 additional pts

at the same dose level

Go to next lower dose level

or declare MTD at next lower

dose level if 6 pts already tested

(never re-escalate)

DLT >1/3DLT =1/3

DLT =0/3

DLT =1/6 DLT >1/6

Go to next higher untested

dose level ordeclare MTD otherwise

Go to next lower dose level

or declare MTD at next lower

dose level if 6 pts already tested

(never re-escalate)


...to a Bayesian model: combination of

clinical and statistical expertise

Informed decisions: clinical data, historical knowledge and

Statistics

DLT rates

p1, p2,...,pMTD,...

(uncertainty!)

Historical

Data

(prior info)

Model based

dose-DLT

relationship

Trial Data

0/3,0/3,1/3,...

Clinical

Expertise

Dose

recommen-

dations

DecisionsDose Escalation

Decision


Phase I/II: adaptive study: a Novartis

example combining phase I bayesian

and two stage phase II

Phase I

Phase II

https://clinicaltrials.gov/ct2/show/NCT00526045?term=auy922&cond=Solid+Tumor&phase=04&rank=4


Primary objective - dose escalation arm

• To determine the MTD of AUY922 as a single agent when administered IV on a

once weekly schedule to adult patients with advanced solid tumors, whose

disease has progressed despite standard therapy or for whom no standard

therapy exists.

Phase I/II: adaptive study



Primary objective - breast cancer dose expansion arm

• At the MTD two further arms will be expanded to assess response (according to a two

stage multinomial design) in the following breast cancer patient populations:

1. Patients with HER2 positive inoperable locally advanced or metastatic breast cancer

must have:

• History of trastuzumab resistance, defined as either local or systemic disease

progression on treatment with at least 8 weeks of a trastuzumab containing

regimen.

• Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or

lapatinib in combination with other agents) and up to 2 lines of cytotoxic therapy

for advanced disease.

• Patients who develop metastases while receiving adjuvant or neo-adjuvant

trastuzumab are eligible.

2. Patients with ER positive inoperable locally advanced or metastatic breast cancer

whose disease has progressed on at least one and up to 3 lines of standard sequence

endocrine therapy and who received up to 2 lines of ct for adv. disease.




Secondary objectives

• To characterize the safety and tolerability of AUY922 treatment.

• To characterize the pharmacokinetic (PK) profiles of AUY922

• To assess changes in target and downstream PD markers in pre- and post- AUY922 dosing in

PBMCs as a measure of HSP90 inhibition, including such markers as HSP70, CDK4, and HSP90/p23

complex dissociation.

• To assess changes in target and downstream PD markers in pre- and post AUY922 dosing in tumor

tissue biopsies (where available and accessible) as a measure of HSP90 inhibition, including such

markers as HSP70, AKT, pAKT, and CDK4.

• To assess changes in relevant client proteins in pre- and post- AUY922 dosing in biopsies of tumor

tissue (where available and accessible). These client proteins may include HER2 and ER

• To assess changes in cellular response markers in pre- and post- AUY922 dosing in tumor tissue

biopsies (where available and accessible), including (Ki67) for proliferation and cleaved caspase 3

and M30 for apoptosis.

• To asses changes in cellular response markers in pre- and post- AUY922 dosing in peripheral blood

including M30 and M65 for apoptosis.

• To quantitate the number of circulating tumor cells (CTC) and analyze either a pharmacodynamic

marker (HSP70) or client protein expression (HER2) in pre- and post AUY922 therapy peripheral blood

of patients with locally advanced or metastatic breast cancer




Selection criteria

9 inclusion criteria 18 exclusion criteria

MBC HER2+/HR+

Tumor tissue

sample

1-2 anti HER2 o 1

hormono previous

treatments

Other selection

criteria

mBC patients

Eligible patients

Phase I/II: adaptive study -> need for patient selection



Our colleague Tom Marsilje – the acknowledged discoverer of Zykadia (ceritinib),

died Tuesday afternoon of colon cancer at a hospital in San Diego.

He was 45.

1

Although he had already begun his battle

with colon cancer, he was continuing his

drug research efforts. He could view his

role both as a researcher and as a patient.

So today, as you dash off that e-mail, make that presentation, arrange that

meeting, please pause and take a moment to remember Tom, his family and the

effort he put forth to make life better for patients and their families.

• LDK378 exhibits potent antitumor

activity in ALK+ NSCLC, including in

patients previously treated

with CRZ

• CNS activity of LDK378 was seen in

NSCLC patients with brain metastases

• Response rates in patients treated

with LDK378 ≥400 mg/day:

• Median duration of response

(patients with ≥1 PR [n=44])

was 7.4 months

– Duration of response was

≥6 months in 71% of patients

– Data to be updated at ASCO 2013

LDK378: a successful example of

adaptive design and pts selection -> a

phase I “efficacy” study (130 pts)

CNS, central nervous system; CR, complete response; PR, partial response; uPR, PR documented only once to date.

Shaw AT, et al. ESMO 2012; Abstr 440O.

Patients CR

n (%)

CR + PR

n (%)

CR + PR + uPR

n (%)

NSCLC, ≥400

mg/d (n=59)1 (2) 24 (41) 42 (71)

NSCLC + prior

CRZ, ≥400

mg/d (n=45)

1 (2) 21 (47) 36 (80)

Shaw, A., NEJM, 370(13), 1189-1197

LDK 378: FDA Breakthrough Designation

Phase I Study (LDK 378 X2101) 80 % of objective responses in 70 NSCLC pats

Activity found also on brain metastasis

Phase II studies: • LDK378 A2201 (≥3L, after CT & crizotinib)

• LDK378 A2203 (≥2L, after CT)

Phase III study: • LDK378 A2301 (1L, pts naïve)

• LDK378 A2303 (3L, after CT & crizotinib)

1. Leukapheresis: patient’s T cells are

collected1-3

2. T cells are genetically transduced

ex vivo with a lentiviral vector

encoding the anti-CD19 CAR1,3

3. CTL019 cells undergo ex vivo

expansion on magnetic antibody-

coated beads1-3

4. Lymphodepleting chemotherapy:

the patient may receive a preparative

lymphodepleting regimen before T cell

infusion1-3

5. CTL019 cells are infused into the

patient1-3

1. Porter DL, et al. N Engl J Med. 2011;365:725-733; 2. Porter DL, et al. J Cancer. 2011;2:331-332; 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73.

Image from Levine BL. Cancer Gene Ther. 2015;22:79-84.

Overview of CTL019 Therapy in

the Clinic

Copyright © Novartis Corporation

Business Use Only23

Adaptive design in phase I/II: need for

new approaches

Recent advances in molecular biology have led to the development of a

myriad of anticancer agents that specifically target aberrant pathways and

other proteins that are relatively specific for tumor cells. The number of

agents available for testing dictates that a more efficient system aimed at

quickly and accurately identifying promising agents for phase III testing

be developed. This will allow investigators to efficiently discard non

efficacious agents and devote time to the development of the more

promising agents, thus conserving financial and human resources.

A barrier to achieving this goal is the lack of good surrogates of true patient

benefit, which in oncology is improvement in overall survival. In addition to

identifying good surrogates, which could be imaging biomarkers or

biochemical, genetic, or molecular biology biomarkers, novel approaches to

phase II study design need to be tested.

Alex A. Adjei, Clin Cancer Res 2009

Until recently, the phase II trial in oncology generally took the form of the

single-arm two-stage design, for which the typical end point was objective

tumor response (by RECIST)

A two-stage design was frequently constructed to distinguish between a

study-level response rate felt to indicate a lack of promise and a response

rate that would indicate promising activity . The dominant use of this design

was based on the premise that an agent that could not produce a tumor

response was not likely to produce a clinically meaningful overall survival

(OS) or progression-freesurvival (PFS) benefit in subsequent phase III

testing.

The recent rapid evolution in oncology drug development has challenged

these previously accepted paradigms. Target agents not always are likely to

produce or improve tumor response rates; rather that such agents will

improve PFS or OS.Larry Rubinstein, Clin Cancer Res 2009

Adaptive design in phase I/II: need for

new approaches

Benefits and disadvantages of

adaptive design

• Benefits

– Increase of information value given the same number of patients

– Less patients needed compared to classical non-adaptive

designs

• Hurdles

– Adaptations at an interim analysis may lead to operational bias,

thus resulting in a slight change of the study population.

– Statistical inferences such as confidence interval and/or p-

values on the treatment effect of the test treatment under study

may not be reliable.

Introduction to Pharmaceutical Statistics | IIS China | Adaptive Clinical Trials

Practical issues: regulatory

perspective

• Regulatory requirements for adaptive designs in Phase I or II trials

are very different to those for Phase III trials

• It is mandatory to control the overall Type I error rate in the strong

sense and maintain trial integrity for Phase III trials

• EMEA Reflection Paper (2007) on

Methodological issues in confirmatory clinical trials

planned with an adaptive design

• FDA Draft Guidance for Industry (2010) on

Adaptive design clinical trials for drugs and biologics

Summary and conclusions

• The potential advantages offered by adaptive designs should be

viewed in balance against any perceived risks or complexities.

• Strict control of processes for handling interim data and

restricting information, and documentation that are followed, will

be critical.

• Some types of adaptations convey limited information for which it

seems difficult to envision how the trial might be compromised.

• Others convey more information, but perhaps we can implement

extra steps to mitigate the risk.

Introduction to Pharmaceutical Statistics | IIS China | Adaptive Clinical Trials

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