Download Phase 2 Trials

Clinical Research Design &
Methodology: Phase II and III
Trials
Ian Tannock, MD, PhD, DSc
Princess Margaret Cancer Centre &
University of Toronto,
Toronto, Canada
ICTW, Cordoba, Argentina
Learning Objectives
To understand:
• The sequence of clinical trials that is necessary to develop
an agent showing preclinical activity to become an
approved anti-cancer drug
• The hierarchy of evidence from clinical trials
• Basic principles underlying the design of Phase 3 clinical
trials
• Common problems relating to the design, analysis and
interpretation of Phase 3 clinical trials
• How the results of related clinical trials are combined in a
meta-analysis
ICTW, Cordoba, Argentina
Dr. Tannock
Anticancer Drug Development: Clinical
Phases
Phase 1: Evaluate toxicity
Study drug disposition (pharmacokinetics)
Determine dose for Phase 2
Phase 2: Estimate antitumor efficacy
Further define toxicity
Phase 3: Compare outcomes with usual standard of care
Phase 4 (after registration):
Additional post-marketing safety assessment
Confirm results from fast-track approval trials
ICTW, Cordoba, Argentina
Dr. Tannock
So Your Phase 1 Trial is Finished…
Miraculin is reasonably safe with manageable dose limiting toxicity
Miraculin achieves serum (or tissue) levels that are sufficient to
achieve effects in pre-clinical studies
Worldwide, a total of 15-25 patients have now been treated with
Miraculin ; 4-8 at the dose you plan to use in phase 2
Only two partial responses (PR) noted in phase 1 – one with bladder
cancer, one with heavily-treated breast cancer
No biomarkers used for patient selection in phase 1 although samples
were obtained for further study…
ICTW, Cordoba, Argentina
Dr. Tannock
MiraPharma Decides That They will Support Two
Phase 2 Trials of miraculin – In Patients with
Metastatic Bladder and Metastatic Breast Cancer
For bladder cancer they elect to support a single arm
study of patients who have progressed after one line of
cisplatin-based chemotherapy
For breast cancer they will support a randomized phase 2
trial in women with metastatic disease who have had
disease progression after receiving both anthracyclene
and taxane-based chemotherapy. They will compare
miraculin with capecitabine
How will you design these trials?
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 2 Trials
Phase 2 trials have the major goal of determining whether a new
treatment has sufficient evidence of anti-cancer activity to warrant
further testing in a phase 3 trial:
Phase 2 trials generally include people with a single type of cancer,
for whom there is limited “standard” treatment available.
The new agent can be tested alone, or in combination with standard
treatment.
Phase 2 trials are relatively small, and can be single-arm or
randomized.
The primary endpoint (outcome measure) is a measure of anticancer
activity (e.g. tumor response) and does not imply clinical benefit to
patients.
ICTW, Cordoba, Argentina
Dr. Tannock
Single Arm Phase 2 Trial
For people with metastatic urothelial cancer, cisplatinbased chemotherapy is known to prolong survival and
gives response rates (RR = CR + PR) of ~ 50%.
Second-line chemotherapy (e.g. with taxanes) is
associated with RR of < 20% with no known effects to
improve survival.
MiraPharma executives decide that they would be
interested in studying miraculin further if data were
consistent with RR ≥ 30%.
They plan a phase 2 trial that accepts all fit patients with
urothelial TCC that have received one line of prior platinbased chemotherapy with a maximum sample size of 40
patients.
ICTW, Cordoba, Argentina
Dr. Tannock
Single-arm Phase 2 Trial of Miraculin for
Patients with Metastatic Urothelial TCC
 Eligible subjects have adequate performance status (ECOG
PS 0-2) and organ function and have progressed on one
line of cisplatin or carboplatin-containing chemotherapy
 They have measurable disease (RR, is primary endpoint)
 Trial should only continue if there is reasonable probability
that true RR ≥ 30%)
 Hence abandon trial if ≤1 response in first 10 patients (RR =
10% with 95% confidence interval [CI] = 0% - 29%)
 Otherwise continue to 40 patients
 There will be uncertainty. For example if 10/40 patients
respond RR = 25% with CI = 12% - 38%
ICTW, Cordoba, Argentina
Dr. Tannock
Randomized Phase 2 Trial of Miraculin
for Women with Metastatic Breast Cancer
Eligible women will have metastatic breast cancer that
has progressed on prior treatment.
They must have had prior chemotherapy with an
anthracyclene and a taxane with at least one prior
regimen for metastatic disease. They may have had
multiple hormone treatments.
The plan is to randomize 80 women, as follows:
80 eligible
women
Capecitabine orally
in standard dose
Miraculin 70mg/m2 IV
every three weeks
ICTW, Cordoba, Argentina
The primary endpoint will be
progression-free survival
(PFS), and Mira-Pharma
will mount a phase 3 study
if median PFS appears >3
months longer with
miraculin
Dr. Tannock
Adaptive Designs in Phase 2 Trials
You might wish to test several new drugs against
standard treatment and “pick the winners” to continue in
a phase 3 trial.
Patients are randomized to several treatment arms, those
with promising results are retained, and new arms can be
added.
An example is
the STAMPEDE
trial for men
with prostate
cancer.
Sydes et al: Trials 2012:13, 168
© 2012 Sydes et al.;
licensee BioMed
Central Ltd.
ICTW, Cordoba, Argentina
Dr. Tannock
Biomarker-based Clinical Trial Design
Many new agents are designed to act only against tumors that
express a “biomarker”.
Examples are trastuzumab (for HER2+ breast cancer), vemurafenib
(BRAF-expressing melanoma) and crizotinib (ALK rearranged
NSCLC).
These agents would have minimal activity against unselected patients
with these diseases.
Hence phase 2 trials are undertaken only in patients whose cancer
expresses the appropriate biomarker.
In other phase 2 trials it is appropriate to evaluate potential
biomarkers to determine if they correlate with the activity of the new
drug.
ICTW, Cordoba, Argentina
Dr. Tannock
Common Errors in Design, Analysis and
Interpretation of Phase 2 Trials
– Phase 2 trials are seeking signals of activity that would warrant the
huge expense and other resources needed to mount a phase 3 study
– Their results are inexact and subject to uncertainty
– Their primary endpoint is usually a measure of anti-tumor activity (e.g.
tumor response or delay in progression) and NOT a measure of
benefit to patients
– There are many examples where encouraging phase 2 trials are
followed by negative phase 3 trials
– Randomized phase 2 trials are NOT small phase 3 studies – although
it is possible to design phase 2 trials that transition to phase 3 (e.g.
STAMPEDE)
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 1 & 2 Trials: Ethical Guideposts
Scientific goals should never take precedence over the patient’s best
interest
Patients eligible for Phase 1 trials are those for whom no effective
therapy exists.
Patients eligible for Phase 2 trials have usually received all
therapies known to have a beneficial effect.
Informed consent is obtained from every patient
No new agent can proceed through development without going
through Phase I clinical evaluation.
Phase 2 trials are important to detect sufficient evidence of activity
before committing the resources necessary for a phase 3 trial
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 3 Trials
Phase 3 trials have the goal of determining whether a new treatment
provides sufficient benefit to patients that it should replace (or add to)
current standard treatments.
Phase 3 trials generally include people with a single type of cancer,
with randomization between the new treatment and an accepted
“standard” treatment.
The new agent can be tested alone (i.e. standard vs. new treatment)
or in combination with standard treatment (i.e. standard + new
treatment vs. standard treatment).
They may be double-blind (e.g. standard + new treatment vs.
standard treatment + placebo)
ICTW, Cordoba, Argentina
Dr. Tannock
Hierarchy of Evidence Used to Decide if Results of
Clinical Trials Should Influence Clinical Practice
1. High quality randomized phase 3 trials, or metaanalyses
2. Small randomized trials
3. Non-randomized trials with concurrent controls
4. Non-randomized trials with historical controls
5. Expert committee review, case reports, retrospective
studies
Not included are large population-based outcome
studies that can assess the influence of a new
strategy on a less selected population.
ICTW, Cordoba, Argentina
Dr. Tannock
Asking a Good Question
Phase 3 trials require huge resources (collaborators,
patients, $$$$)
It is therefore important that:
– They address a clinically important question
– There is substantial evidence for effectiveness of a new
treatment in preclinical models
– There is evidence that the new treatment is safe and
tolerated (phase I)
– There is good preliminary evidence of anti-tumor activity
(phase II)
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 3 Trials
The primary endpoint (outcome measure) should be a measure of
patient benefit (e.g. overall survival [OS] or QL)
If other endpoints are used they should be shown to be surrogates for
OS or QL
Phase 3 trials are large (several hundred patients)
Entry criteria should be as broad as possible so that the results will
apply to the general population of patients with the type of cancer
under investigation
ICTW, Cordoba, Argentina
Dr. Tannock
DFS and PFS as Surrogate Endpoints in
Phase 3 Trials
–
When phase III trials show large early increases in
PFS, and there are few alternative treatments, ethical
considerations may require the new treatment be
given to patients randomized to the control arm. This
may make it difficult to detect an influence on
survival.
–
Examples include sunitinib for renal cell carcinoma
and vemurafenib for BRAF-mutated melanoma
–
This does not apply to treatments for (e.g.)
metastatic breast or ovarian cancer
ICTW, Cordoba, Argentina
Dr. Tannock
Evaluation of Toxicity
 Therapeutic benefit of a new treatment depends on
a balance of efficacy and toxicity
 All new agents add toxicity
 Toxicity is usually reported and graded as per NCI
CTC criteria, with rigid requirements for reporting
serious (grade 3-4) toxicity
 However toxicity is both under-recognized and underreported in phase III trials – and chronic toxicity
associated with many targeted agents may only
become apparent after the trial is completed
ICTW, Cordoba, Argentina
Dr. Tannock
Principles of Design of Phase 3 Trials
Sample size depends on ....
 The expected level of survival in the control arm
 The difference in survival (δ) between arms that you wish to
detect or rule out
 α or type 1 error is the probability that a difference ≥ δ is a
false positive result (usually α = 0.05)
 β or type 2 error is the probability of failing to detect a real
difference ≥ δ, i.e. of a false negative result (usually β = 0.1
or 0.2)
The “power of the study” is then 1- β or
0.9 or 0.8
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 3 Trials: How to Determine
Sample Size
Sample size for trials can be estimated from on-line calculators. e.g.
http://www.openepi.com/v37/SampleSize/SSCohort.htm
Roughly 300 patients will be needed to detect or rule out a 15%
absolute difference in survival & about 1,000 patients for a 10%
difference!
Thus phase 3 trials require a large sample size to detect or rule out
differences in outcome that might reasonably be expected
They require collaboration between multiple sites and are usually
organized either by cooperative groups or companies
For company-organized trials it is essential that there be safeguards
to ensure the validity of the data
ICTW, Cordoba, Argentina
Dr. Tannock
Phase 3 Trial: An Example
A phase 1 trial indicates that a new drug, miraculin at 50mg/m2
IV every three weeks, can be added safely to standard
gemcitabine/cisplatin
A phase 2 trial suggests that miraculin is active as second-line
therapy for people with metastatic urothelial cancer (TCC)
MiraPharma agree to sponsor the following randomized phase
3 trial to determine if miraculin will become part of first-line
treatment for this disease:
450 patients with
metastatic TCC
and no prior
chemotherapy
Gemcitabine + cisplatin +
miraculin
Gemcitabine + cisplatin +
matched placebo
ICTW, Cordoba, Argentina
Primary
endpoint is
overall
survival
Dr. Tannock
Survival Curves and Hazard Ratios
Patients are recruited to clinical trials at different times and have
different length of follow up.
In actuarial survival curves patients alive at last follow-up are
“censored”. The tail of the curve may depend on few patients
(given as numbers under curves) and is subject to error.
Proportional hazards applies when the ratio of ‘events’ (e.g.
deaths) in the experimental and control arms remains roughly the
same over the time of observation.
ICTW, Cordoba, Argentina
Dr. Tannock
Survival Curves and Hazard Ratios
The Hazard Ratio (HR) is ratio of events in experimental to control
arm in any given time interval.
HR < 1 with 95% confidence interval excluding 1.0 implies statistical
benefit of experimental treatment.
Note that statistical significance is not the same as clinical
significance
ICTW, Cordoba, Argentina
Dr. Tannock
Survival Curves and Hazard Ratios –
An Example
Baselga J, et al. N Engl J Med 2012; 366:109-119
ICTW, Cordoba, Argentina
Dr. Tannock
Common Errors in Design, Analysis and
Interpretation of Phase 3 Trials
 Control arm is not an accepted standard treatment
 The primary endpoint has not been shown to convey
benefit to patients (i.e. not a surrogate for survival or
its quality)
 Sample size too small to detect or rule out a
reasonable difference in outcome (failing to find a
difference is not the same as proving no difference)
 Sample size so large that difference in clinical
outcome is statistically significant but not clinically
meaningful
 Making conclusions on the basis of secondary
endpoints
 Failure to provideICTW,
detailed
report
of toxicity
Cordoba,
Argentina
Dr. Tannock
Post-marketing (Phase 4) Studies…
...evaluate a wider population of patients treated with a
new therapy.
They can help to better define its tolerance and side
effects in a wider population.
Often the unstated purpose of such studies is to
encourage oncologists to become familiar with the new
treatment (sometimes with financial reward) so that they
will continue to use it when it is marketed.
ICTW, Cordoba, Argentina
Dr. Tannock
Meta-Analyses
Similar (but not necessarily identical) trials are combined (e.g. any
adjuvant chemotherapy vs. none for women with primary breast cancer).
In a patient-based meta-analysis (preferred) the data are analyzed like
one large trial to produce survival curves.
Date of randomization and death (or last follow-up alive) are known for
all patients on multiple trials.
Data are displayed as a Forest plot: individual trials are represented by a
square proportional to sample size, with whiskers showing confidence
interval for Hazard or Odds Ratio.
Literature based meta-analysis combines published survival curves from
reports of individual trials but is subject to error.
ICTW, Cordoba, Argentina
Dr. Tannock
Meta-Analyses: Example of a Forest Plot
Meta-Analysis of Aromatase Inhibitors vs. Tamoxifen
Dowsett M, et al. J Clin Oncol 2009; 28:509-518
ICTW, Cordoba, Argentina
Dr. Tannock