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Introduction to Clinical Trials
Jan B. Vermorken, MD, PhDDepartment of Medical Oncology
Antwerp University HospitalEdegem, Belgium
ESO student course, Ioannina, 2010
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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
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Cancer Treatment Today
• Surgery
• Radiation therapy
• Systemic treatment: – Cytotoxic chemotherapy– Hormone therapy– Immunotherapy– “Targeted therapy”
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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
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From Lab….. To Clinical Trials…. To Standard Practice
Laboratory data Effective Therapy
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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)
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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.
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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.
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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
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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
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Human Tumor in Nude Mouse
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Moving a New Therapy from the Lab to the Clinic
ClinicalClinicalEvaluationEvaluation
LaboratoryLaboratoryExperimentsExperiments
River of UnknownsRiver of Unknowns
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Clinical Trials
• Phase I
• Phase II
• Phase III
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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
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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
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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 5 1.4 x level 4 6.7
level 6 1.33 x level 5 8.8
level 7 1.33 x level n-1 -
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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
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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
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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
Adapted from World Health Organization, 1980.
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Increase of the multiple of twoIncrease of the multiple of twotumor diameters by at least 25%tumor diameters by at least 25%
Progression: WHO
Adapted from World Health Organization, 1980.
TreatmentTreatment
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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).
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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
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Acceptance Thresholds: By 50% or More of Staff
months
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Acceptance Thresholds: By 50% or More of Patients
months
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Studies with non-Cytotoxics
“Targeted therapy”
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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
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Moving a New Therapy from the Lab to the Clinic
ClinicalClinicalEvaluationEvaluation
LaboratoryLaboratoryExperimentsExperiments
River of UnknownsRiver of Unknowns
Differences between cytotoxic and non-cytotoxic agents
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Preclinical Data: Cytotoxic Agent
Dose
Eff
ec
t
-- anti-tumor
toxicity --
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Antitumor Effect: Tumor Regression
Time
tum
or
Siz
e control
increasing doses new agent
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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
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Preclinical Data: Non- Cytotoxic
Effe
cttarget-
toxicity-
- antitumor
Effe
ct
target-
toxicity-
- antitumor
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Antitumor Effect: Growth DelayTu
mor
Siz
e control
increasing doses new agent
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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
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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
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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
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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
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Ethics and Consent
• History:
– War Crimes– Tuskagee syphilis study– Jewish Chronic Hospital study– Willowbrook study
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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
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RResponse esponse EEvaluation valuation CCriteria riteria IIn n SSolid olid TTumours umours
RECIST guidelinesRECIST guidelines
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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
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Codes of Conduct: International Standards
• Nuremberg Code• Declaration of Helsinki• Good Clinical Practice
• Adopted by most nations
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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
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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