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Precision medicine-based
clinical trials
Clara Natoli
Drug discovery and
development timeline
3-5 years
5-7 years
2-3 years
http://www.yourgenome.org/facts/how-are-drugs-designed-and-developed
CLINICAL TRIALS PITTFALLS
 Only 5% of cancer patients actually
join clinical trials
 37% of clinical trials fail to reach their
recruitment goals
 11% of sites fail to recruit a single
patient
New trends of drug development
EMPIRICAL ONCOLOGY
1980
MOLECULAR ONCOLOGY
1990
Phase I
Phase I -II
Phase II
2010
Phase III
Phase III
About 90% of topselling medicines only
work for 30% to 50%
of patients.
Side effects and
adverse reactions
caused by
medications, account
for 30% of acute
hospital admissions
every year.
Nature 520, 609–611; 2015
Genomic Landscape of 5,000 Human Cancers
Source: MacConaill, L, et. al., J Mol Diagn 2014, 16: 660-672
Precision
medicine
should ensure delivery
of the right intervention
to the right patient at
the right time
Precision Oncology Treatment
genomically selected trials
Development of reliable endpoints to allow
an early recognition of clinical benefit
ENDPOINTS
Effect on molecular target
Circulating tumor cells
Circulating tumor DNA
Functional imaging
Wilson et al. Lancet Oncol 2015
so, what do we need?
‘select the trial for the patient, not
the patient for the trial’
The precision medicine trials aim to indicate
a treatment individually
A few studies have been published,
and a few more are ongoing…
Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.
NSCLC
… but only few of these
targets have agents with FDAEMA approval
The NCI has put forth a national strategy for
precision medicine with two broad components
The first is the exceptional responder initiative (ERI),
which seeks to evaluate the genomics of tumor from
patients who had an exceptional response to a drug that
were not effective for most other patients. In order to be
eligible, patients must have received a treatment in which
<10% of patients had a complete or durable partial
response.
The malignant (and normal if available) tissue from these
exceptional responders will undergo whole exome
sequencing and/or mRNA sequencing.
.[NCT02243592]. https://clinicaltrials.gov/ct2/show/NCT00243592?term=NCT02243592&rank=1
The NCI has put forth a national strategy for
precision medicine with two broad components
The second is the NCI Molecular Analysis for Therapy
Choice (MATCH) trial which screens for molecular
features that may predict response to a drug with a given
mechanism of action.
This trial design is in response to the observation that
certain driver mutations which may be common in a
particular tumor type are mutated in other diseases at low
frequency (<10%).
In low frequency mutations, testing the utility of certain
targeted therapy requires screening large numbers of
patients.
New Precision Medicine Trials Design
Umbrella trials
Basket trials
Adaptive Design
Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.
December 8, 2016. doi:10.1001/jamaoncol.2016.5299
 One type of cancer
 Different genetic mutation
https://www.bhdsyndrome.org/forum/bhd-research-blog/genetic-sequencing-approaches-to-cancer-clinical-trials/
 Multiple types of cancer
 1 common genetic mutation
https://www.bhdsyndrome.org/forum/bhd-research-blog/genetic-sequencing-approaches-to-cancer-clinical-trials/
BASKET TRIAL
across tumor types, selected by single
marker or for a single candidate drug
L.A. Renfro et al. / Cancer Treatment Reviews 43 (2016) 74–82
NCI MATCH study design will target molecule abnormalities directed
by next generation sequencing and will “match” patients with
appropriate targeted agents
http://meetinglibrary.asco.org/content/114000071-144
NCI-MATCH TRIAL
However, no control arms are included, which could dramatically
affect the interpretation of the final results …
Relying on efficacy results from uncontrolled clinical trials can
result in expedited drug approval, but the disadvantages of this
practice must be taken into account.
For example, the apparent improvements in outcomes observed
in an early single-arm trial of a new therapy might reflect the
prognostic nature of the target, rather than a true treatment
effect.
Moreover, the predictive role of biomarkers can be definitively
ascertained only randomly assigning patients to a control arm.
NCI M-PACT: Molecular Profiling Based
Assignment of Cancer Therapy
R
NCI M-PACT: Molecular Profiling Based
Assignment of Cancer Therapy
actionable mutations of interest (aMOIs)
New Precision Medicine Trials Design
Basket trials
Umbrella trials
Adaptive Design
New trials design
Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.
Umbrella Studies
Within 1 tumor type, selected by different
markers for single or multiple candidate drugs
• Efficiency in drug evaluation compared with traditional histology driven
sequential studies • Evaluate large effects of targeted agents on relatively
rare targets • Different types with shared molecular aberrations may be
more similar than tumors from same type lacking molecular features
Sleijfer, S et al. Designing Transformative Clinical Trials in the Cancer Genome Era. J Clin Oncol 31: 1834-184
ONCOGENIC PATHWAYS CURRENTLY BEING TARGETED IN
NON-SMALL CELL LUNG CANCER
Front. Med., 10 April 2017 https://doi.org/10.3389/fmed.2017.00039
National Lung Matrix Trial
The UK trial recruits patients with stage IV disease, or stage III disease not amenable to
surgery or radical radiotherapy, and allocates them to a treatment arm according to their
molecular phenotype as determined by the Stratified
Medicine pre-screening
Programme 2.
NLMT is a multi-arm multi-stage trial currently recruiting to 21 clinical arms.
Lung-MAP protocol (NCT02154490)
Sub-studies currently open in the
Lung-MAP protocol (NCT02154490)
Multiple sub-studies that
independently evaluate
investigational therapies
Lung-MAP design principles
 New sub-studies can enter the trial at any time when relevant
drug-biomarker pairs with sufficient proof-of concept become
available.
 According to the results of the futility analysis in the phase II
portion, the sub-studies can be quickly closed or move to a phase
III registration trial.
 This strategy significantly reduces time, number of patients, and
cost needed to bring promising agents to the clinical setting. The
use of a common and detailed genotype platform facilitates broad
screening and efficient allocation of patients to biomarker-specific
sub-studies.
 The presence of a “non-match” arm, allow for all eligible patients
to be accrued.
 The master protocol is flexible and adaptable, allowing for
incorporation of “new standards” in an evolving field.
AURORA – Aiming to Understand the Molecular
Aberrations in Metastatic Breast Cancer
Patients will be treated according to physician’s
choice or will be given the opportunity to enter
clinical trials based on the genotype of their disease.
In both cases, patients enrolled in AURORA will be
followed with collection of clinical data and plasma
and serum samples every 6 months to determine
response and clinical outcome end points for a
period of 10 years.
© 2014 Cancer Research UK.
British Journal of Cancer (2014) 111, 1881-1887; doi:10.1038/bjc.2014.341
New Precision Medicine Trials Design
basket trials
umbrella trials
Adaptive Design
Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.
Adaptive Trial Designs
Chow, SC and Chang, M. Adaptive design methods in clinical trials – a review. Orphanet Journal of Rare Diseases 2008, 3:11
Biomarker design with
response-adaptive
(D) adaptive enrichment design
randomization
L.A. Renfro et al. / Cancer Treatment Reviews 43 (2016) 74–82
Adaptive Trial Designs
 Allows researchers to analyze accumulating study data at
prospective interim time points and to alter the course
of a single patient’s study plan or trial itself, without
undermining the validity and integrity of the trial
 Stopping early/extending accrual with a conclusion of either
superiority or futility
Adaptively assigning doses to more efficiently assess the
dose outcome relationship
 Dropping/adding arms or doses
 Seamless phases of drug development within a single trial
 Changing proportion of patients randomized to each arm
and accrual rate
Adaptive Trial Designs
 Potential to speed up the process of drug development
Potential to receive marketing approval for multiple
indications from a single successfull trial
 Shorter clinical time lines than conventional approaches
 A feasible way to conduct clinical trials in rare cancers
BUT …..
Often less statistically efficient than fixed plans
Statistical methods for the design and analysis are more
complex than those associated with conventional
designs
PRECISION MEDICINE OPEN ISSUES
Bruce Chabner:
‘Underlying this new effort is my conviction that
genomic medicine is neither totally precise nor
completely rational at this point in its
development.’
The Oncologist 2016
The scope of publications will include all types of clinical
research (basket trials, exceptional response results,
informatics, mechanism- and evidence-based case reports,
and small series of educational value), provide a forum for
novel multi-institutional databases to advance outcomes
measurements, and include extensive expert driven
commentary, editorials, and reviews considering the
challenges and value of targeted therapies based on genomic
analyses.
Oncologists await historic first: a pan-tumor predictive
marker, for immunotherapy
•Ken Garber Nature Biotechnology 35, 297–298 (2017) doi:10.1038/nbt0417-297a
FDA Approves First Cancer Treatment for
Any Solid Tumor With a Specific Genetic
Feature
FDA News Release May 23, 2017
The U.S. Food and Drug Administration today granted accelerated approval to a treatment
for patients whose cancers have a specific genetic feature, biomarker. This is the first time
the agency has approved a cancer treatment based on a common biomarker rather than the
location in the body where the tumor originated.
Pembrolizumab is indicated for the treatment of adult and pediatric patients with
unresectable or metastatic solid tumors that have been identified as having microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers
patients with solid tumors that have progressed following prior treatment and who have no
satisfactory alternative treatment options and patients with colorectal cancer that has
progressed following treatment with chemotherapy drugs.
n engl j med 372;26 nejm.org june 25, 2015
A phase 2 study
recruiting patients with
hereditary nonpolyposis
colo-rectal cancer (i.e.
Lynch-syndrome) and
with sporadic mismatch
repair–deficient tumors,
a condition that causes
MSI.
CONCLUSIONS