In response to the precision medicine or an old term ‘personalized
medicine’, the clinical trial designs are also evolving in order. Over the last
several years, two clinical trial designs have been proposed and implemented in
many oncology trials: basket (or bucket) trials and umbrella trials. The basket and umbrella trial designs are
generally falling into the enrichment trial design with the purpose of avoiding
over-treatment and saving valuable resources by matching the right drug to the
right subgroup of patients through genetic biomarkers. While basket and
umbrella trial designs are almost exclusively in oncology trials, we can assume
that such designs can be generalized to therapeutics areas other than the
oncology.
In general,
here are the comparison of basket and umbrella trial designs with some example
trials:
Basket (or Bucket) Trial
|
Umbrella Trial
|
Targeted
Therapy: biomarker analysis to identify patients likely to response
|
|
One
Molecular Abnormality Targeted Across Multiple Tumor Types
Cancer is defined based on the genetic aberrant or biomarker signature (cancer with xxx positive biomarker) |
One
tumor type, multiple molecular targets
Cancer is defined as body location or histology (lung cancer, liver cancer,...) |
Many diseases (or many cancer types),
single subgroup, one drug
|
One disease (or one cancer type),
multiple subgroups (identified by the biomarkers), many drugs
|
Test the effect of one or more drugs
on one or more single mutations in a variety of cancer types
|
Test the impact of different drugs on
different mutations in a single type of cancer
|
Biomarkers is usually measured locally
|
Biomarkers are usually measured
centralized
|
Allows
patients with multiple diseases and one or more target to be enrolled in cohorts
or groups in one trial (the basket). This allows researchers to separately
analyse the responses of patients as each tumour type can be put in one
cohort, and assess the impact of the drug on all of the patients as one
group. If one group shows a good response, we expand this group to
immediately assess whether others could benefit from the new therapy. If
another group does not show evidence of effectiveness, this group may be
closed and the other cohort can continue the recruitment.
|
Designed
to test the impact of different drugs on different mutations in a single type
of cancer, on the basis of a centralised molecular portrait performed after
obtaining informed consent: one disease, several molecular subtypes, several
therapies. This design allows validation of a strategy based on a mixture of
biomarkers and drugs
|
Cancers of
different types are tested to see if they have a particular molecular abnormality.
If they do, the patients with that abnormality are eligible to be treated
with a new drug that targets that particular abnormality. The advantage of
this approach is that it allows us to test new treatments across cancer
types. On the other hand, we often have to test many patients to find that
handful that have the abnormality targeted by the new treatment. If can be
incredibly frustrating for a patient who agrees to be tested, only to be told
he/she is not eligible to be treated on the study because his/her cancer does
not have the appropriate target.
|
Patients
with a given type of cancer are assigned a specific treatment arm based on
the molecular makeup of their cancer. Umbrella trials have many different
arms under the umbrella of a single trial.
Since
the treatment assignment/stratification is based on molecular biomarkers, Umbrella
trial requires the complicated process for centralized screening tests for
multiple biomarkers. The genotyping to identify the molecular biomarkers, if
done locally, could have results less reproducible.
|
NCI
MATCH Targeted Therapy Directed by Genetic Testing in Treating Patients With
Advanced Refractory Solid Tumors or Lymphomas
NCI MPACT Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Solid TumorsJohn Hainsworth, et al (2016) MyPathway trial |
E.S. Kim
(2011) The
BATTLE Trial: Personalizing Therapy for Lung Cancer SAFIR01/UNICANCER trial F André et al (2014) Comparative
genomic hybridisation array and DNA sequencing to direct treatment of
metastatic breast cancer: a multicentre, prospective trial
(SAFIR01/UNICANCER)
Focus4
Trials a molecularly stratified, multi-site
randomised trial programme for patients with colorectal cancer
|
Basket Trials
|
|
Basket and Umbrella Trials
|
I don’t know
when exactly the terms ‘basket trial’ and ‘umbrella trial’ proposed, but the
following articles used these terms and provided very good explanations about ‘basket
trial’ and ‘umbrella trial’.
- Herbst (2015) Lung Master Protocol (Lung-MAP)—A BiomarkerDriven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400
- Abrams (2014) National Cancer Institute’s Precision Medicine Initiatives for the New National Clinical Trials Network
- Mandrekar (2015) Improving Clinical Trial Efficiency: Thinking outside the Box
In
clinicaltrials.gov, we can see many cancer trials are designed as basket or
umbrella trials and the terms basket and umbrella trials may be explicitly
indicated.
- Basket Trials in clinicaltrials.gov: https://clinicaltrials.gov/ct2/results?term=basket+trial
- Umbrella Trials in clinicaltrials.gov: https://clinicaltrials.gov/ct2/results?term=umbrella+trial
Basket and Umbrella trial design will require having a master protocol.
Master protocol refers to one overarching protocol that includes one or more of the
following:
- Multiple diseases
- Multiple therapies
- Multiple biomarkers
Launching a clinical trial typically takes long time to go through the administrative (for example contract negotiation) and regulatory approvals (health authority and IRB/EC approvals). The master protocol can create an experimental plan to test several candidate drugs or conduct the trials in multiple diseases under a one protocol so that we don’t need to have a fresh protocol approval each time and minimize the delay caused by the clinical trial launching. It’s like a Plug and Play. Here is a slide presentation and a youtube video by Friends of Cancer Research for Lung Cancer Master Protocol Trial and a video by Dr Fred Hirsch who talked about the development of a master protocol.
To see what the master protocol
looks like, the FOCUS4 clinical trial programme provides an excellent
opportunity. All protocols including the master protocol and each of the
umbrella protocols. The master protocol describes the overall study design and
all common procedures across all umbrella protocols. The umbrella protocol provides information about
procedures for entering patients into FOCUS4-A after a patient has been registered through
the procedures described in the FOCUS4 Master Protocol.
- Appendices for FOCUS4 Master Protocol v4.0, 25.02.2015
- FOCUS4-A Protocol
- FOCUS4-B Protocol v3.0 18.11.2015
- Appendices for FOCUS4-B Protocol v1.0, 18.08.2015
- FOCUS4-C Protocol
- FOCUS4-D Protocol v3.0, 25.02.2015
- Appendices for FOCUS4-D Protocol v4.0, 25.02.2015
- FOCUS4-N Protocol v3.0, 25.02.2015
- Appendices for FOCUS4-N Protocol v4.0, 25.02.2015
There are statistical
considerations when we come to the master protocol, the basket trial, and
umbrella trial. The operation of these trials will be more challenging than the
usual single disease single drug trial. Statisticians need to embrace these new
trial designs and adapt to the new paradigm of the clinical trial designs in
the era of precision medicine. To this aspect, it is helpful to read Dr LaVange
discussion on “Statistical
Considerations in Designing Master Protocols”
Further
reading:
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Journal of Clinical Trials & Research is an international peer reviewed scholarly journal whose primary aim is to dissemination and development of knowledge on all aspects of clinical trial design, management.Clinical Trials & Research
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