NcXHF

ZARDAVAS AND PICCART-GEBHART
triple-negative breast cancer. In particular, patients with this
breast cancer phenotype whose disease develop early systematic
relapse will be eligible. Once metastatic tumor tissue has
been analyzed by NGS and upon availability of these results,
the patients will be entered into one of multiple parallel,
molecularly-driven arms, randomly assigned between the
standard of care or the respective targeted agent(s), dictated
by the genotype of their disease.
Basket Trials
This is an innovative, histology-independent trial design, in
which patients with cancer diagnoses of different histologies
can be enrolled in the study protocol based on the presence of
a specifıc molecular aberration. There is an ongoing clinical
trial that aims to develop a small molecule HER2 blocking
agent for patients with ERBB2-mutated cancers that exemplifıes
this approach. 42 The main disadvantage in this innovative
design is a biology-driven one; in particular this is the
issue of the potentially different functional outputs that a specifıc
molecular aberration could have among different types of
cancer. This has been reported in studies documenting lack of
antitumor effıcacy of vemurafenib, a BRAF small molecule inhibitor,
in the setting of BRAF-mutated metastatic colorectal
cancer; these fındings are in direct contradiction with the dramatic
antitumor activity seen among patients with metastatic
melanoma bearing the V600E BRAF mutation. 43 A major advantage
of this study design is that it is very informative about
which are the tumor types where single-agent therapy is worth
pursuing in phase III trials versus other types where combination
treatment strategies should be prioritized. Interestingly,
there is an ongoing study by the NCI, called MATCH (Molecular
Analysis for Therapy Choice) that combines elements from
both master and basket trial design. In particular, this trial will
assess molecularly targeted agents within specifıc molecular
niches of cancer types such as erlotinib for EGFR-mutated
NSCLC and crizotinib for cases with EML4-ALK translocations
(master-trial component), as well as across different tumor
types sharing a molecular aberration, e.g., vemurafenib in
BRAF-mutated melanoma, thyroid cancer, and NSCLC
(basket-trial component).
Adaptive Trials
Adaptive trials represent another transformative study design,
recently exemplifıed by the BATTLE (Biomarker-
Integrated Approaches of Targeted Therapy for Lung Cancer
Elimination)-1 and -2 clinical trials, focusing on patients
with metastatic NSCLC, 44 or the I-SPY (The Investigation of
Serial Studies to Predict Your Therapeutic Response with
Imaging and Biomarker Analysis) 1 and 2 trials conducted in
the neoadjuvant setting of breast cancer. 45-47 These are dynamically
evolving trials, with the particular aspect of during
the initial phase of the adaptive study patients are recruited in
the different arms at an equal ratio; however, as more patients
are enrolled and effıcacy data are being generated and pooled
from the different treatment arms, the adaptive phase follows.
During this second, adaptive phase, randomization ratios
can be changed and treatment arms can be dropped
and/or added, in cases where either predefıned thresholds of
effıcacy are not reached or new promising data for new compounds
emerge, respectively. 48 Additionally, in trials having
an adaptive design, the biomarker selection strategy can be
changed, even when the treatment assignment remains the
same, depending on emerging evidence associating new biomarkers
not previously identifıed with (lack of) sensitivity to
one or more of the treatments under assessment.
N-of-1 Trials
This is a study design that has been more frequently employed
in fıelds of clinical research other than oncology, such
as trials conducted for patients with musculoskeletal or pulmonary
conditions. 49,50 The defıning characteristic is the recruitment
of patients exposed to different experimental
agents or placebo in different sequencing, with washout periods
in between. 51 This type of design practically renders
each involved patient to serve as his or her own comparator,
through the comparison of the effıcacy seen for the different
experimental agents that the patient receives. In oncology, a
modifıed N-of-1 study design has been performed, which assessed
the antitumor activity of different anticancer compounds
matched to the genotype of the patients. 52 This trial
recruited 86 patients with different types of advanced tumor
who had been heavily pretreated, that had molecular profıling.
Sixty-six of these patients were treated according to these
results. Concerning the effıcacy, 18 patients had a PFS ratio of
1.3 or higher (95% CI, 17% to 38%; one-sided, one-sample
p 0.007). The study met its primary endpoint, which was
the comparison of PFS obtained by the targeted treatment
with the PFS achieved by the previous systemic treatment
within each individual patient. This is an approach that could
be of help for molecular aberrations of really low prevalence,
where randomized studies are extremely challenging.
Window-of-Opportunity Trials
Window-of-opportunity trials incorporate a design assessing
the administration of an investigational agent over a short
period of time, most often in the presurgical setting allowing
serial tumor biopsies, though such studies can be conducted
in the metastatic setting as well. 53,54 These trials do not have
an effıcacy endpoint, since it is the in vivo biologic effects of
an experimental agent and not the antitumor activity with
offıcially predefıned measures of outcome that they aim to
assess. An ongoing study utilizing this innovative design is
the D-beyond trial, a preoperative window study evaluating
denosumab, a RANK ligand inhibitor, and its biologic effects
for premenopausal women with early breast cancer. 55 Patients
entering this trial receive preoperatively two doses
of 120 mg of denosumab subcutaneously 1 week apart that
will be followed by surgery. Ten to 21 days after the fırst
administration, surgical excision of the primary tumor
will take place; the primary objective is the antiproliferative
effect exerted by denosumab, as indicated by Ki67
immunohistochemistry-based assessment. Another example
of a window-of-opportunity trial that will soon be initiated is
the RHEA (Biomarker Research Study for PF-03084014 in
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