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Rome, 28/3/2008
Clinical trials challenges
with
targeted agents
Paolo Bruzzi
Clinical Epidemiology, Dept. of Epidemiology and Prevention,
Istituto Nazionale per la Ricerca sul Cancro
Genoa - Italy
Trials: Rationale of Phases
1. Any new drug, when first used in man,
involves unknown risks, and has unknown
pharmacological and toxic properties:
PHASE I
Aims of of clinical trials
Phase I
Question: (How much, often, etc.) can (should) I
use the drug?
Aims of of clinical trials
Phase I
Question: How (much, often, etc.) can (should) I use the
drug?
Endpoints:
Toxicity,
Pharmacology
MTD
(Dose-response?)
Rationale of Phases
1.
Any new drug, when first used in man, involves unknown
risks, and has unknown pharmacological and toxic properties:
PHASE I
2. Before starting a long and expensive efficacy
trial, it is convenient to know if the drug has
the effects (ACTIVITY) that make its
efficacy plausible:
PHASE II
Activity vs Efficacy
• Efficacy: The benefit desired by the patient
Usually, quantity and/or quality of life
Activity vs Efficacy
• Efficacy: The benefit desired by the patient
• Activity: The direct effects (mechanisms) by
which the treatment is supposed to produce the
benefit
Activity vs Efficacy
• Efficacy: The benefit desired by the patient
• Activity:
–
–
–
–
–
Antihypertensive
Diuretic
Lipid Lowering
Antibacterial
Antiarythmic
Aims of of clinical trials
Phase I
Phase II
Question: Does the drug what it is supposed to
do to the disease (the organism)?
Aims of of clinical trials
Phase I
Phase II
Question: Does the drug what it is supposed to
do to the disease (the organism)?
Endpoints: Activity Endpoints (Changes in the
disease or in physiopathological parameters)
Rationale of Phases
1.
Any new drug, when first used in man, involves unknown
risks, and has unknown pharmacological and toxic properties:
PHASE I
2.
Before starting a long and expensive efficacy trial, it is
necessary to know if the drug has the effects (ACTIVITY)
that make its efficacy plausible: PHASE II
3. The EFFICACY of a treatment is not
warranted by its Activity: PHASE III
Activity = Mechanisms of action
Intervention
ACTIVITY
Antidiabetic
Reduction in
blood sugar
Antihypertens.
Reduction in
B.P.
Screening
Earlier
Diagnosis
Activity = Mechanisms of action
Intervention
ACTIVITY
EFFICACY
Antidiabetic
Reduction in
blood sugar
Red.mortality
Red.morbility
Antihypertens.
Reduction in
B.P.
Prev. CVD
Screening
Earlier
Diagnosis
Red. Mortality
Red. Incidence
Aims of of clinical trials
Phase I
Phase II
Phase III
Question: Does the drug do what the patient
expects from it?
Aims of of clinical trials
Phase I
Phase II
Phase III
Question: Does the drug do what the patient
expects from it?
Endpoints: Efficacy Endpoint(s)
Overall Survival - QoL
Surrogate endpoints
Note
• The rationale of trial phases has no implications
for their methodology
• The methodology of phases is related to:
–
–
–
–
Therapeutic paradigm
Characteristics of experimental therapy
Endpoints
Ethical Problems
Trials of Cytotoxic Drugs
Underlying Paradigm
1. Monotonic dose-effect relationship
(the more the better)
Trials of Cytotoxic Drugs
Underlying Paradigm
1. Monotonic dose-effect relationship
2. Direct cell killing
Trials of Cytotoxic Drugs
Underlying Paradigm
1. Monotonic dose-effect relationship
2. Direct cell killing
3. Constant proportion of tumor cells killed
(independent of the number of cells)
Consequences
PHASE I trials:
Aim: (The more the better ->) Finding the
Maximum Tolerated Dose (MTD) of the drug
(combination)
Note: MTD? (single dose, total dose, doseintensity, dose-density, mode of injection, etc.)
Consequences
PHASE I trials:
Toxicity: Specific
Uncontrolled phase I trials
Consequences
PHASE II trials:
Aim: (Direct cell killing ->) Assessing the
antitumor activity (ability to differentially kill
tumor cells)
Antitumor activity: Reduction of volume of tumor
mass
Primary= Objective Response (%)
Phase II: Implications
• Spontaneous tumor reduction (>50%) is rare
(<1%)No need for control groups
Phase II: Implications
• Uncontrolled Phase II trials
Phase II: Implications
• Uncontrolled Phase II trials
• Need to assess tumor reduction
– Patients with measurable lesions
– Unresectable cancers
– (Preoperative (primary) chemotherapy)
Phase II: Implications
• Uncontrolled Phase II trials
• Phase II trials in metastatic pts
Phase II: Implications
• Uncontrolled Phase II trials
• Phase II trials in metastatic pts
• Proportional reduction: Effects in metastatic
cancer  Micrometastatic disease
Phase II: Implications
• Uncontrolled Phase II trials
• Phase II trials in metastatic pts
• Phase III trials in disease-free (and metastatic)
patients
Development of cytotoxic drugs
Phase I: Uncontrolled, dose-escalation in heavily
pretreated pts
Phase II: Uncontrolled, response rate with MTD
in pts with measurable disease
Phase III: Large RCT‘s, OS (RFS/PFS) in
unselected, resected/metastatic pts
Development of cytotoxic drugs
Other peculiarities of phase III trials
• Unselected patients
– Site- and stage-specific
Development of cytotoxic drugs
Other peculiarities of phase III trials
• Unselected patients
– Site- and stage-specific
– Histology-specific? (e.g. NSCLC)
Development of cytotoxic drugs
Other peculiarities of phase III trials
• Unselected patients
• Pragmatic (EFFECTIVENESS)
Development of cytotoxic drugs
Other peculiarities of phase III trials
• Unselected patients
• Pragmatic (EFFECTIVENESS)
• Classical ‘Frequentist’ Statistics
– Test of significance, power
– Adjustment of p values for multiple looks
– Frequentist 95% CI
Development of a new cytotoxic drug
Phase I
Pre-treated pts
MTD
Phase II
Tumour A
Metastatic Pts
High response rate
Phase III
Metastatic Pts
Survival (PFS)
Tumour B
Metastatic pts
Low response rate
Phase III
Radically Resected Pts
Survival (RFS)
‘New’ Anticancer Therapies
•
•
•
•
•
•
•
•
Targeted Therapies
Biological Response Modifiers (e.g.IL-2)
Cancer Vaccines
Cell Therapy
Gene Therapy
Anti-angiogenetic drugs
Others
Associations?
Targeted therapies
Definition (NCI Dictionary)
targeted therapy (...THAYR-uh-pee)
A type of treatment that uses drugs or other
substances, such as monoclonal antibodies, to
identify and attack specific cancer cells without
harming normal cells.
Targeted therapies
• G. Sledge (JCO, 2005): ‘‘A targeted therapy
should attack a biologically important process
(usually, though not necessarily, a single
molecule), preferably one central to a hallmark
of cancer. The target should be measurable in
the clinic, and measurement of the target (in
either quantitative or qualitative terms) should
correlate with clinical outcome when the
targeted therapy is administered’’.
Targeted therapies
Working definition:
Drugs aimed at specific (functional) targets
of (some) cancer cells
Targeted therapies
Working definition:
Drugs aimed at specific targets of (some) cancer
cell
1° example: TamoxifenEstrogen receptors in
breast cancer cells
Recent examples (Targets)
Epidermal Growth Factor
Receptor (Anti-EGFR)
Vascular Endothelial Growth
factor (anti-VEGF)
Human epidermal growth factor
receptor (anti-HER2)
Protein products of oncogenes
(e.g. BRC/Abl)
Multitargeted agents
Other pathways/receptors
Recent examples (drugs)
Monoclonal Antibodies (xxxx…ab)
Tyrosine kinase inhibitors
(xxx…ib)
Other Inhibitors (mTOR, FTI,etc)
(xxxx….ib)
Others
Recent examples
Epidermal Growth Factor
Receptor (Anti-EGFR)
Monoclonal Antibodies (xxxx…ab)
Vascular Endothelial Growth
factor (anti-VEGF)
Tyrosine kinase inhibitors
(xxx…ib)
Human epidermal growth factor
receptor (anti-HER2)
Other inhibitors
(xxxx….ib)
Protein products of oncogenes
(e.g. BRC/Abl)
Multitargeted agents
Other pathways/receptors
Others
Common Issues
• Low toxicity? (interactions with CTX?)
Common Issues
• Low toxicity (interactions with CTX?)
• Direct cell killing?Reduction in tumor
size? Objective Response plausible?
Marginal effects
Common Issues
• Low toxicity (interactions with CTX?)
• Moderate/low anticancer activity (response
rate)
Common Issues
• Low toxicity (interactions with CTX?)
• Moderate/low anticancer activity (response rate)
• Dose-Response? Often Unlikely
Common Issues
•
•
•
•
Low toxicity (interactions with CTX?)
Moderate/low anticancer activity (response rate)
Dose-Response? Often Unlikely
Transient effect
– Treatment duration
– Resistance (partial, reversible)
Common Issues
•
•
•
•
•
Low toxicity (interactions with CTX?)
Moderate/low anticancer activity (response rate)
Dose-Response? Often Unlikely
Transient effect
Effect only in the presence of the target?
Common Issues
•
•
•
•
•
•
Low toxicity (interactions with CTX?)
Moderate/low anticancer activity (response rate)
Dose-Response? Often Unlikely
Transient effect
Effect only in the presence of the target?
Positive interaction with CTX/RTX?
Common Issues
•
•
•
•
•
•
•
Low toxicity (interactions with CTX?)
Moderate/low anticancer activity (response rate)
Dose-Response? Often Unlikely
Transient effect
Effect only in the presence of the target?
Positive interaction with CTX/RTX?
Activity independent of tumor size? (Yes?)
Consequences
Trials of novel therapies
• Phase I: Dose?
• Phase II: Activity?
• Phase III: Effectiveness?
New Methodology
Phase I trials of targeted therapies
MTD-Optimal Dose -Lowest effective Dose?
•
•
•
•
•
Safety
Dose-toxicity
Pharmacokinetics (e.g. saturation)
(MTD)?
Biologically Effective Dose
(Biologic endpoints from animal/human models)
• Dose/Activity (Phase I-II)
Phase I-II trials of targeted therapies
Study design (for dose-activity)
•
•
•
•
•
•
Larger size
Randomization? (e.g. different doses)
Patients?
Duration of treatment?
Single agent or + CTX?
Endpoint?
Phase II (or I-II) trials
Main Challenge
How to assess the activity of novel
therapies?
Design and conduct of phase II studies of targeted anticancer therapy:
Recommendations from the task force on methodology for the development
of innovative cancer therapies (MDICT) - Boot et al, Eur J Cancer 2007
Approach used in the development of
some novel anticancer therapies
• Phase IA: Safety, Toxicity
Biological Marker ?
• Phase III: Efficacy
Phase II (or I-II) trials
Reasons for phase II trials (Simon, JCO 2001):
• Economy: Insufficient resources to test all drugs
in all tumor types by phase III trials
Phase II (or I-II) trials
Reasons for phase II trials (Simon, JCO 2001):
• Economy
• Ethics: inappropriate to expose large numbers
of pts in a phase III trial to an agent with no
demonstrated activity.
Phase II (or I-II) trials
Reasons for phase II trials (Simon, JCO 2001):
• Economy
• Ethics
• Opportunity: chance to modify dose of the agent
or to better select the target population for the
phase III trials
Phase II (or I-II) trials
Reasons for phase II trials (Simon, JCO 2001):
• Economy
• Ethics
• Opportunity
• Science, i.e. statistics: Results of subsequent
phase III trial
– Positive: More convincing
– Negative: Can be interpreted
Phase II (or I-II) trials of targeted
therapies
1. Endpoint
2. Design
3. Selection of patients
Phase II (or I-II) trials
Activity
Endpoint
Design
Selection of pts
a) Endpoints of Phase II (or I-II)
trials
Activity endpoints
vs
Surrogate endpoints
Endpoints in phase II trials
Activity Endpoints:
Assess mechanisms, direct effects on the
disease/organism
Endpoints in phase II trials
Activity Endpoints:
Surrogate endpoints:
Intermediate events/markers/ parameters
that (are assumed to) reflect the effects of
the treatment on the true endpoint
Endpoints
Surrogate endpoints
Activity Endpoints
Activity endpoints may not be valid
surrogate’ endpoints
• Antiarythmic drugs
– Effects on arythmia  Effects on sudden
deaths
Cast trial: active antiarythmic drugs increased
SD mortality
Activity endpoints may not be valid
surrogate’ endpoints
• Screening tests
– Earlier diagnosis  Reduction in mortality?
Mayo clinic lung project: earlier diagnosis but no
decrease in mortality
Activity endpoints may not be valid
surrogate’ endpoints
• (Chemo)prevention
– Incidence  Mortality?
Tamoxifen in BC?
Plausible surrogate endpoints may not be
activity endpoints
Endpoint
Surrogate
Activity
Obj. response
yes ?
For cytotoxic
drugs
RFS
yes ?
No
PFS
yes ?
No
Endpoints in phase II trials
Phase II trials, if possible, should use
Activity endpoints
– Stronger rationale for phase III trials
– Smaller size
– Negative Phase III can be interpreted
Endpoints in phase II trials
Phase II trials, if possible, should use
Activity endpoints
If not possible, plausible (validated?)
surrogate endpoints are acceptable
Endpoints in Phase II (I-II) trials
1. Biological Activity
Tumor tissue markers, circ. tum. cells,
plasma/serum markers, metabolic imaging,
etc.
Endpoints in Phase II (I-II) trials
1. Biological
Example: The smallest dose that inhibited the
phosphorylation of CRKL, an adapter protein that is a
major substrate of the deregulated BCR/ABL tyrosine
kinase and is aberrantly tyrosine-phosphorylated in
chromosome Philadelphia-positive leukemia cells, was
400 mg.
(Rosa DD et al., Molecular-targeted therapies: Lessons from ...,
Cancer Treat Rev (2007), doi:10.1016/j.ctrv.2007.07.019)
Endpoints in Phase II (I-II) trials
1. Biological
Example: Results from a phase I study evaluating
cetuximab in patients with advanced solid tumours
expressing EGFR showed that it effectively abrogated
EGFR-mediated cell signalling, with no alteration in
total EGFR protein.
(Rosa DD et al., Molecular-targeted therapies: Lessons from ...,
Cancer Treat Rev (2007), doi:10.1016/j.ctrv.2007.07.019)
Biological endpoints
- Sensitivity and Specificity of the Endpoint
- Sensitive: Representative of the mode of
action of the treatment
- Specific: Does not show spontaneous
modifications
Biological Endpoints
Specific Target
-
Eligibility restricted
Stronger effect (Smaller sample size)
More convincing evidence
Biological Endpoints
Specific Target
Not specific (e.g. TLI)
-
Weaker effect (large sample size)
Need for a randomised control group
Less convincing evidence
Biological Endpoints
- Sensitivity and Specificity of the Endpoint?
(preclin. studies, studies in other cancers, with
similar treatments)
Wrong endpoint  effective treatment discarded
Biological Endpoints
- Sensitivity and Specificity of the Endpoint?
- Eligible patients
- Measurable target
- Patients amenable to multiple biopsies
- Organizational and clinical burden
Biological Endpoints
- Sensitivity and Specificity of the Endpoint?
- Eligible patients
- Sufficient evidence to start a phase III trial?
Endpoints in Phase II (I-II) trials
2. Clinical (surrogate) Endpoints
Endpoints in Phase II (I-II) trials
2. Clinical (surrogate) Endpoints
• Objective response
– Plausible?
– Specific (>50% reduction in tumor mass within few
months)
– Sensitive? If not observed, the treatment can be
discarded as inactive?
Endpoints in Phase II (I-II) trials
2. Clinical (surrogate) Endpoints
• Objective response
• Time to progression/relapse (median TTP, %
Progression- free at 6 months, etc.)
Endpoints in Phase II (I-II) trials
2. Clinical (surrogate) Endpoints
• Objective response
• Time to progression/relapse
–
–
–
–
Historical data unreliable (control group?)
Randomised?
2 stage designs?
Sample Size? (close to phase III trials)
Time to Progression/Relapse
Surrogate endpoint!
If a relevant effect on TTP is seen in a phase II
trial, is the randomised Phase III trial still
ethical?
Endpoints in Phase II (I-II) trials
2. Clinical Endpoints
• Objective response
• Time to progression/relapse
• Clinical Benefit (QoL, improvement in
symtoms, combined endpoints)
– Validated?
– Same problems of TTP
b) Designs in Phase II (I-II) trials
1. Single-arm designs
•
•
•
Absolute values (e.g. 50% resp. Rate)
Relative to Historical Controls
Before-after designs
–
–
–
Regression to the mean?
Natural history of the tumor?
Bias?
Designs in Phase II (I-II) trials
1. Single-arm designs: Can be used if
a) The endpoint is very specific
or
b) Historical data are very solid and stable
and
c) The endpoint can be assessed
objectively/unbiasedly
Designs in Phase II (I-II) trials
1. Single-arm designs
2. Non-comparative randomised trials
Used to select the most active drug(s) among a series
of drugs/combinations
Problems in the interpretation of results
Seldom used with novel therapies
Designs in Phase II (I-II) trials
1. Single-arm designs
2. Non-comparative randomised trials
3. Randomised comparative Phase II trials
• Necessary for non specific endpoints
• Sample Size < than in Phase III trials
• Various designs (e.g. random discontinuation)
Randomised Phase II (I-II) trials
Control arm
• Untreated ?
–
–
–
Responding/Stable pts after standard therapy
Patients not candidate to further therapies
To encourage pts to participate
•
•
If endpoint is TTP, cross-over after progression
If biological endpoint, cross over after its assessment
Randomised Phase II (I-II) trials
Control arm
• Untreated ?
• Standard (chemo)therapy?
–
–
Same chemotherapy also in exp. arm
Negative/positive interactions?
Randomised Phase II (I-II) trials
Reduced Sample Size
• Large Effect (esp. for biological endpoints)
• Relaxed significance level
–
–
•
0.10 (-23%)
0.20 (- 47%)
Stopping rules for evidence of futility (clearly
inactive treatment)
c) Selection of patients for Phase II
trials
– Bearing the (presumed) target
• Increased power
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
=0.05
=0-2
Frequency of the target
90
%
10
0%
80
%
70
%
60
%
50
%
40
%
30
%
182 patients
20
%
10
%
Power
Trial in Unselected patients - Response rate from
20% to 40% (in pts with the target)
Target?
• Not always a yes/no phenomenon (e.g. number
of copies of HER2)
• Reliability of assessement (technique, interintra-laboratory variability)
• Necessary but not sufficient (e.g. EGFR and Kras mutation)
• Sufficient but not necessary (e.g. multitargeted
agents)
c) Selection of patients for Phase II
trials
– Bearing the (presumed) target
• Increased power
• Only if strong biologic rationale
• Risk if wrong target
Phase II (I-II) trials
Selection of patients
– With the (presumed) target
– All patients
• Identification a posteriori of markers of
susceptibility (targets)
• Much larger sample size (if true target)
182
pts
300
pts
182 patients
All available pts
600
pts
Frequency of the target
100%
90%
80%
70%
60%
50%
40%
30%
900
pts
20%
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
10%
Power
Unselected patients
Phase II (I-II) trials
Selection of patients
– With the (presumed) target
– All patients
– ‘Enriched’ populations (unbalanced
sampling of pts with the target)
3-400 pts:
50% with the
mutation
300
pts
182
pts
182 patients
All available pts
600
pts
Frequency of the target
90
%
10
0%
70
%
80
%
60
%
50
%
30
%
40
%
900
pts
20
%
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
10
%
Power
‘Enriched’ populations
Efficacy Trials of Novel Therapies
• Standard RCT’s – Overall Survival
surrogates)
• Peculiarities
–
–
–
–
–
Selected patients (target present)
Organizational burden
Costs
Long-term toxicity
(smaller size/larger effect)?
(or
Development of a ‘novel’ therapy
Strong preclinical evidence of activity on the
target
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Phase I-II
Dose-response
Randomised
Comparison
Biological endopint Stop if no
activity – Unselected pts
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Phase I-II
Dose-response
Phase IIB
Randomised
Comparison
Biological endopint Stop if no
activity – Unselected pts
Surrogate endpoint (sel. Pts?)
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Phase I-II
Dose-response
Phase IIB
Randomised
Comparison
Biological endopint Stop if no
activity – Unselected pts
Surrogate endpoint (sel. Pts)
Efficacy (OS, PFS, RFS)
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Phase I-II
Dose-response
Phase IIB
Randomised
Comparison
Biological endopint Stop if no
activity – Unselected pts
Surrogate endpoint (sel. Pts)
Stop if no difference with
control arm (futility) or toxicity
Efficacy (OS, PFS, RFS)
Development of a ‘novel’ therapy
Strong preclinical evidence of activity
Phase IA: Safety
Phase I-II
Dose-response
Phase IIB
Stop random if
suff. evid. of
efficacy
Randomised
Comparison
Biological endopint Stop if no
activity – Unselected pts
Surrogate endpoint (sel. Pts)
Stop if no difference with
control arm (futility) or toxicity
Efficacy (OS, PFS, RFS)
Development of targeted therapies
Bayesian Statistics
1. To monitor study results for early stop
2. To use validated surrogate endpoints
3. To extrapolate results across cancers of
different sites bearing the same target
• A therapy targeted at a specific mutation in gene X has
been demonstrated in RCT’s to improve survival in
resected pts with the mutation (20%), (lung c. , colon
c., prostate c. and breast c.), with reductions in
mortality of 20-40%
• A therapy targeted at a specific mutation in gene X has been
demonstrated in RCT’s to improve survival in resected pts with
the mutation (10%), (lung c. , colon c., prostate c. and breast
c.), with reductions in mortality of 20-40%
• We want to show its efficacy (phase III trial) in
osteosarcomas with the same mutation
• A therapy targeted at a specific mutation in gene X has been
demonstrated in RCT’s to improve survival in reseted pts with
the mutation (10%), (lung c. , colon c., prostate c. and breast
c.), with reductions in mortality of 20-40%
• We want to show its efficacy (phase III trial) in osteosarcomas
with the same mutation
• Null Hypothesis? - Evidence needed to accept the
efficacy of the new treatment in osteosarcomas?
Test of significance?
Mortality
Other Tumors
N=12000
Osteosarcoma
N= 240
Nil vs B 15% vs 12.5%
P = 0.0007
Nil vs B
15% vs 8.3%
P = 0.11
Summary
• The assessment of the activity of a treatment is
critical in its development
• The methodology of trials derives from the
therapeutic paradygm
• A priority of modern cancer research is the
identification of efficient (sensitive and
specific) markers of activity for phase II trials
of novel drugs
Conclusions
•
Development of cytotoxic drugs
–
–
Fixed Standard Methodologies
Roles:
•
•
•
Phase I - Pharmacologist
Phase II – Oncologist (+Statistician/Simon‘s tables)
Phase III – Oncologist + Statistician (sample size and
analysis)
Conclusions
• Development of novel drugs
– Specific (original) methodology developed,
monitored and re-adjusted for each new drug
– Roles:
• Multidisciplinary teams
(Basic Researcher+Oncologist+Statistician)
working together in the design, conduct and
interpretation of all phases of development
Traditional Role of the Statistician
Tell me, Paolo, how many patients do I
need for…..?
..back to the PC….and…
…for alfa=0.0001 and power 99.999% you
need 806,913.8 patients!
New duties of the statistician
Learn about biology!
New duties of the statistician
Think!
New duties of the statistician
Listen, propose and discuss!
Think again!
Until you find a rational solution