Medical Students 2010 - Slide 5 - J.B. Vermorken - Introduction to Clincial Trials

Introduction to Clinical Trials

Jan B. Vermorken, MD, PhDDepartment of Medical Oncology

Antwerp University HospitalEdegem, Belgium

ESO student course, Ioannina, 2010

Outline

• Cancer treatment today• Drug development• The bridge to the clinic• Phase I and II trials• WHO vs RECIST criteria• Phase III trials for efficacy• Ethical aspects• Studies with non-cytotoxics• Conclusions

Cancer Treatment Today

• Surgery

• Radiation therapy

• Systemic treatment: – Cytotoxic chemotherapy– Hormone therapy– Immunotherapy– “Targeted therapy”

Long Term Survival (%)

1970 2008• Leukemia in children 0 80• Leukemia in adults 0 45• Bone cancer 5 60• Testicular cancer 0 80• Breast cancer 40 85• Non-small cell lung cancer 0 15• Colon cancer 30 60• Hodgkin’s disease 10 85

From Lab….. To Clinical Trials…. To Standard Practice

Laboratory data Effective Therapy

Drug Development

• Identification of new agents• Preclinical requirements:

efficacy, toxicology (ICH)• Formulation, manufacturing• Regulatory (government) review

(IND submission)• Phase I, II, III clinical trials• Regulatory (government) review

(NDS = new drug submission)

Anticancer Drug Discovery

• Mechanism-based– Rational synthesis or discovery of agents

targeting mechanisms of malignant behavior. Then test in lab models

• Screening/Compound-based– Screen new chemical entities for activity in

cancer models in the laboratory.

Then discover mechanisms of action.

Screening/CompoundBased Discovery

• Majority of available anticancer drugs have been identified by screening

• Sources: plants (vincas, taxanes)microbes (doxorubicin)chemicals (cisplatin)

• Most act by interfering with molecular process of cell division, thus many normal tissues affected.

Preclinical Requirements

A new drug must have the following completed prior to patient testing:

• Demonstrated efficacy in tumor models• Toxicology: 2 species (rodent and non-rodent)• Formulation and manufacturing• Animal pharmacokinetics; mechanism of action

studies

Preclinical Evaluation of Cytotoxic Agents

IN VITROIN VITRO IN VIVOIN VIVO

Mechanism of actionMechanism of action Stage IStage I Stage IIStage II

Target level Maximum tolerated dose Spectrum of activity

Cellular level Dose-limiting toxicities Schedule dependency

Efficacy Route of administration

Cross resistance

Combination therapies

Human Tumor in Nude Mouse

Moving a New Therapy from the Lab to the Clinic

ClinicalClinicalEvaluationEvaluation

LaboratoryLaboratoryExperimentsExperiments

River of UnknownsRiver of Unknowns

Clinical Trials

• Phase I

• Phase II

• Phase III

Phase I Design:Selection of Starting Dose

• Based on mouse toxicity:– 0.1 Mouse Equivalent LD10 (MELD10)

• In instances where dog toxicity show this dose to be toxic, 1/3 Toxic Dose Low (TDL) in dogs is selected as starting dose

Phase I Trials

• Find highest safe dose (1 level below MTD)• Identify side effects

3 pts

3 pts

3 pts

3 pts

3 pts

3 pts

Dose

Severe toxicity

Recommended dose

Dose escalating by modified Fibonacci

Modified Fibonacci Escalation

Dose Level Theory Example

starting Dose x 1

level 2 2 x level 1 2

level 3 1.67 x level 2 3.3

level 4 1.5 x level 3 5



level 7 1.33 x level n-1 -

Phase II Trials

• Screen drug for activity in cancer patients

• Use recommended dose

• Test it in 15-30 patients with same tumor type

• Look for objective tumor shrinkage: Partial or Complete Response

Adapted from World Health Organization, 1980.

Complete Response: WHO

PrimaryPrimaryTumorTumor

NodesNodes

MetastasesMetastases

Disappearance of all clinical,Disappearance of all clinical,radiologic and biologicradiologic and biologic

signs of tumorsigns of tumor

TreatmentTreatment

TreatmentTreatment

Decrease of the multiple of twoDecrease of the multiple of twotumor diameters by at least 50%tumor diameters by at least 50%

Partial Response: WHO


Increase of the multiple of twoIncrease of the multiple of twotumor diameters by at least 25%tumor diameters by at least 25%

Progression: WHO


TreatmentTreatment

Example CalculationBaseline Week 8 Week 16 Week 24

Lesion 1234

3.2 x 42.7 x 23.5 x 52 x 2.1

1.5 x 21.3 x 1

2.8 x 2.91 x 1.7

1 x 1.21 x 1

2.5 x 2.8 x 1.1

1.6 x 1.21.2 x 1.32.9 x 2.71.2 x 1.3

Sum Products

39.9( PR < 19.9)

14.1 (PR) 8.1 (PR) 12.9 (PD)

PD calculated from lowest sum on study

RResponse esponse EEvaluation valuation CCriteria riteria iin n SSolid olid TTumors umors (RECIST)(RECIST)

Therasse et al JNCI 2000Therasse et al JNCI 2000

• Intended for use in clinical trials with primary endpoint of objective response

• Measurable lesion >= 20 mm (10 if spiral CT)• Unidimensional assessment: Tumor burden assessed by

summing longest diameters of all measurable lesions up to 10 (5 per organ)

• Four categories of response: CR*, PR*, SD, PD• RECIST widely adopted by cooperative groups, industry,

academia

* Required confirmation

RECIST Guidelines:Response Criteria

• Target lesions ( LD / LD baseline)– CR– PR: 30% (50% surf. area and 65% volume)– SD– PD: 20% (44% surf. area and 73% volume)

• Non-target lesions– CR (including markers)– Non-CR– PD

Example Calculation

Baseline Week 8 Week 16 Week 24

Lesion 1234

3.2 x 4 2.7 x 2 3.5 x 5 2 x 2.1

1.5 x 2 1.3 x 1

2.8 x 2.9 1 x 1.7

1 x 1.2 1 x 1

2.5 x 2 .8 x 1.1

1.6 x 1.2 1.2 x 1.3 2.9 x 2.7 1.2 x 1.3

Sum Products

39.9( PR < 19.9)

14.1 (PR) 8.1 (PR) 12.9 (PD)

Sum Longest Diameter

13.8(PR < 9.7)

7.9 (PR) 5.8 (PR) 7.1 (PD)

PD calculated from lowest sum on study

Unidimensional vs. WHO Criteria: Response Rates in 4,613 Patients from 14 Studies/Data Sets

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12 13 14 total

WHO New

New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guidelines

(verion 1.1)

E.A. Eisenhauer, et al.

European Journal of Cancer 2009; 45: 228-247

What What HAS NOTHAS NOT changed in RECIST 1.1 changed in RECIST 1.1

• Measurable lesions defined by unidimensional measurement

• Tumor burden based on sum of diameters• Categories of response:

– CR– PR (30% decrease in sum from baseline)– SD– PD (20% increase in sum from nadir)

Courtesy of E.A. Eisenhauer

For example: Response classification same…For example: Response classification same…

Time point Response: Patients with Target (+/- non-target) Disease:

Target lesions Non-Target lesions New Lesions Overall response

CR CR No CR

CR Non-CR/Non-PD No PR

CR Not evaluated No PR

PR Non-PD or not all evaluated No PR

SD Non-PD or not all evaluated No SD

Not all evaluated Non-PD No NE

PD Any Any PD

Any PD Any PD

Any Any Yes PD

Summary:Summary:What What HASHAS changed in RECIST 1.1 changed in RECIST 1.1

RECIST 1.0 RECIST 1.1

Measuring tumor burden

10 targets5 per organ

For response: 5 targets(2 per organ)

Lymph node Measure long axis as for other lesions. Silent on normal size

Measure short axis. Define normal size.

Progression definition 20% increase in sum 20% increase and at least 5 mm absolute increase

Non-measurable disease PD

“must be unequivocal” Expanded definition to convey impact on overall burden of disease. Examples.

Confirmation required Required when response primary endpoint—but not PFS

New lesions -- New section which includes comment on FDG PET interpretation

New Lesions (1)New Lesions (1)

• Must be unequivocal: not attributable to different scanning technique or non tumor (e.g. “new” bone lesions may be flare)

• When in doubt continue treatment, repeat evaluation

• If scan showing new lesion is of anatomical region which was not included in baseline scans, it is still PD

Courtesy of E.A. Eisenhauer

New Lesions (2)New Lesions (2)

• FDG-PET: sometimes used by investigators to complement CT. If so:

– Negative FDG-PET at baseline and a positive FDG-PET at follow-up means PD

– No FDG-PET at baseline and a positive FDG-PET at follow up: • It is PD if it corresponds to a new site of disease on

CT• It is equivocal if no new site of disease on CT.

Repeat CT to see if new site apparent next scan: if so, PD date will be that of the initial abnormal FDG-PET scan

• It is not PD if corresponds to a pre-existing site of disease on CT that is not progressing on the anatomic images

What is Efficacy?

• Response Efficacy

• Efficacy is improved:– Cure rates– Survival – Quality of life: i.e. meaningful symptom palliation

• “Response” is a measure of biologic effect which may be a marker for efficacy

Phase III Trials

Once a new agent has shown activity in phase II, comparative trials are usually designed.

New agent can be given alone or in combination

• Objectives: Compare “new” to “standard”

• Endpoints: Survival, toxicity, quality of life.

• Sample Size: 200-2000 patients

Phase III Trials: Definitive Tests of Efficacy

• Large studies to detect “significant” differences in outcomes of interest: – Cure, survival, quality of life

• Randomized design: – Allows unbiased assessment of treatment effect

• Sample Size: – Determines power with which one can detect

postulated differences

How Much Improvement in Efficacy?

• Critical question which drives:– Trial design and sample size– Eventual change in practice

• Patients and physicians (staff) differ on degree of improvement which must be seen to choose a more toxic therapy.

• If patients views are accepted: many trials are too small (underpowered).

Survival Advantage at 3 years Required by Patients vs Staff to Accept Toxic Treatment

02468

1012

<0 1 3 5 10 20 30 40 >50

Patients Staff

% Survival Advantage Threshold

Nu

mb

er

of s

ub

ject

s

From Brundage et al, 1997

Acceptance Thresholds: By 50% or More of Staff

months

0.8-

0.6-

0.4-

0.2-

0.0-

1.0-

'12

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p = .000

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Acceptance Thresholds: By 50% or More of Patients

months

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Studies with non-Cytotoxics

“Targeted therapy”

Non-Cytotoxics (“Targeted Therapy”)

General term to describe agents which do not directly target DNA.

Includes agents having targets which are: Cellular

Growth factors and their receptors Signaling pathways

Extracellular Matrix Vasculature

Moving a New Therapy from the Lab to the Clinic

ClinicalClinicalEvaluationEvaluation

LaboratoryLaboratoryExperimentsExperiments

River of UnknownsRiver of Unknowns

Differences between cytotoxic and non-cytotoxic agents

Preclinical Data: Cytotoxic Agent

Dose

Eff

ec

t

-- anti-tumor

toxicity --

Antitumor Effect: Tumor Regression

Time

tum

or

Siz

e control

increasing doses new agent

The Bridge to the Clinicfor Traditional Cytotoxics

• Dose-Toxicity and Dose-Effect relationships: often parallel

• Cause regression of established tumors

• Traditionally:

– phase I trials: endpoint is toxicity

– phase II trials: endpoint is response

• These have allowed dose determination and selection of many agents found in randomized trials to be effectiveeffective i.e. prolong survival

Preclinical Data: Non- Cytotoxic

Effe

cttarget-

toxicity-

- antitumor

Effe

ct

target-

toxicity-

- antitumor

Antitumor Effect: Growth DelayTu

mor

Siz

e control

increasing doses new agent

The Bridge to the ClinicFor Novel Non-Cytotoxics

• Dose-Toxicity and Dose-Effect relationships: may not be parallelmay not be parallel

• May notMay not cause regression of established tumors

• Thus, for newer agents:

– phase I trials: endpoint is uncertain

– phase II trials: endpoint is uncertain

Ethical Committee: Roles and Function

• To safeguard the rights, safety and well-being of trial subjects

• Documented procedures

• At study start assess:– Scientific justification for proposed research and use of human

subjects– Weigh potential benefits/risks– Consent document and process– Qualifications of investigator and team

• Ongoing review

Summary

• Journey from the laboratory to clinical practice requires several steps

• Promising new therapies must undergo evaluation in patients:– Phase I: find dose, side effects– Phase II: look for hints of activity– Phase III: definitive tests of efficacy

• All trials must have ethical committee review and patient consent

Declaration of Helsinki: Sample Statements

• It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject

• Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation

• Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected

• The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol

Ethics and Consent

• History:

– War Crimes– Tuskagee syphilis study– Jewish Chronic Hospital study– Willowbrook study

Complex signalling pathways in oncology

Hanahan D, Weinberg RA. Cell 2000;100:57–70

DR4, DR5

Difficult to target

Src

IGF-II, HGF, Ang2

Growth factor receptors

Growth factorreceptor ligands

51v3

EGFR, ErbB2, VEGFR-2,IGF-1R, MET, KIT, RET, Tie2

RResponse esponse EEvaluation valuation CCriteria riteria IIn n SSolid olid TTumours umours

RECIST guidelinesRECIST guidelines

Wilhelm S, et al. Clin Cancer Res 2004;64:7099–109

Sorafenib: targets both tumour cell and vascular compartments

Tumour cell Endothelial cell or pericyte (vascular)

Angiogenesis:differentiationproliferationmigrationtubule formation

Raf

VEGFR-2PDGFR-

MEK

Apoptosis

Proliferation

PDGF

VEGF

Survival

Ras

Nucleus

Ras

ERK

Raf

MEK

Apoptosis

ERK

PDGF VEGFParacrine stimulation

Sorafenib

KIT/Flt-3/RET

Mitochondria

MitochondriaMcl-1

HIF

Sorafenib

Sorafenib

Sorafenib

Nucleus

HIF = hypoxia inducible factor; VEGF = vascular endothelial growth factor VEGFR = VEGF receptor; PDGF = platelet-derived growth factor PDGFR = PDGF receptor; Mcl-1 = myeloid cell leukaemia-1

• A multi-kinase inhibitor of– serine/threonine kinases: C-Raf (Raf-1) and B-Raf-1– receptor tyrosine kinases: VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, and c-KIT

Codes of Conduct: International Standards

• Nuremberg Code• Declaration of Helsinki• Good Clinical Practice

• Adopted by most nations

Elements of Informed Consent

• Purpose of the trial and that it involves research

• Treatment and how it is assigned. Number of subjects planned

• Duration of study and procedures involve

• Experimental aspects

• Possible benefits and likely risks

• Voluntary nature

• Alternative treatment

• Access to data and confidentiality

Summary (2)

• Some drugs showing activity in animal studies or phase II turn out to be inactive in phase III

• New agents are now exploiting the scientific discoveries of the last decades:– Targeting differences between cancer and normal cells– Targeting blood vessels that support cancer growth

• Many such new agents now being investigated in clinical trials in several areas of the world

Documents

Medical Students 2010 - Slide 5 - J.B. Vermorken - Introduction to Clincial Trials