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I-spy 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy
nature publishing group
I-SPY 2: An Adaptive Breast Cancer Trial Design
in the Setting of Neoadjuvant ChemotherapyAD Barker1, CC Sigman2, GJ Kelloff1, NM Hylton3, DA Berry4 and LJ Esserman3
I-SPY 2 (investigation of serial studies to predict your
treatment options remain limited. These patients continue
therapeutic response with imaging and molecular analysis 2)
to represent a disproportionately large fraction of those who
is a process targeting the rapid, focused clinical development
die of their disease. Given that the standard of care for these
of paired oncologic therapies and biomarkers. The framework
women increasingly includes neoadjuvant therapy prior to sur-
is an adaptive phase II clinical trial design in the neoadjuvant
gical resection, this combination of group and setting represents
setting for women with locally advanced breast cancer.
a unique opportunity to learn how to tailor the treatment to
I-SPY 2 is a collaborative effort among academic investigators,
patients with high-risk breast cancers.
the National Cancer Institute, the US Food and Drug
Cancer research from the past decade has shown that breast
Administration, and the pharmaceutical and biotechnology
cancer is a number of heterogeneous diseases; this finding sug-
industries under the auspices of the Foundation for the
gests that directing drugs to molecular pathways that charac-
National Institutes of Health Biomarkers Consortium.
terize the disease in subsets of patients will improve treatment
efficacy. Currently, however, most phase II and III trials of new
I-Spy 2 RatIonale and BackgRound
breast cancer drugs are in the metastatic setting, followed by
The daunting statistics that currently define cancer incidence randomized phase III registration trials in the adjuvant setting.
and mortality require innovative strategies that will address These trials do not reflect the fact that there is a wide range
the prohibitive expenditures of time and cost associated with of molecular characteristics of the patient’s disease. Adjuvant
the development of new oncology drugs. Although there are trials require long-term follow-up and the enrollment of many
many promising new oncology drugs in the pipeline, the cur-
thousands of patients,2 and it may take 10−20 years3 to gain
rent process for development and regulatory review is ineffi-
marketing approval for successful drugs. Moreover, substantial
cient and expensive, requiring a decade or more to complete. investments of time and other resources are required for the
While biomarkers show promise for informing all aspects of development of drugs that ultimately fail. Although the use
oncology drug development, diagnosis, and treatment, clinical of biomarkers (molecular profiles, protein pathways, imaging,
validation (qualification) has proved extremely difficult. The etc.) in the selection of patient populations for tailored studies
Cancer Steering Committee of the Foundation for the National of new drugs is promising, developing translational approaches
Institutes of Health Biomarkers Consortium is taking several in clinical trials for prediction of drug response presents a
innovative approaches to remove this “biomarker barrier” in major challenge. The development and use of biomarkers for
order to qualify both biomarkers and drugs for evidence-based early measures of therapeutic response would facilitate the
efficient evaluation of new agents in focused early clinical
Over the past 20 years, significant progress has occurred in the trials4 and enable the development of more informed, smaller
detection and treatment of breast cancer. In fact, many women phase III trials.
who present with stage I and II mammographically detected
I-SPY 2 represents a unique approach toward addressing the
disease have excellent outcomes because of improved adjuvant “biomarker barrier.” It will be performed as a neoadjuvant trial
therapy and lower risk of recurrence. Despite this progress, in women with large primary cancers of the breast (>3.0 cm),
10–15% of newly diagnosed breast cancers present as locally and the end point for response to treatment will be the measure-
advanced cancers, with the likelihood of favorable long-term ment of pathologic complete response. I-SPY 2 will also test,
outcomes being significantly lower.1 The absolute numbers analytically validate, and qualify biomarkers as new drugs are
of these cancers have not decreased over time, and successful tested; employ an adaptive trial design to enable efficient learning
1National Cancer Institute, Bethesda, Maryland, USA; 2CCS Associates, Mountain View, California, USA; 3University of California, San Francisco, California, USA;
4MD Anderson Cancer Center, University of Texas, Houston, Texas, USA. Correspondence: AD Bar
Received 10 February 2009; accepted 30 March 2009; advance online publication 13 May 2009.
CliniCal pharmaCology & TherapeuTiCs
| VOLUME 86 NUMBER 1 | JULY 2009
about each drug’s biomarker signature; and utilize organizational New drugs will enter as those that have undergone testing are
manage ment principles and sophisticated bioinformatics in order graduated or dropped.
to eliminate the current inefficiencies in clinical trials.
I-SPY 2 evolved from a previous program, I-SPY 1. I-SPY 1 Biomarkers
was a collaboration of the National Cancer Institute Specialized Biomarkers for I-SPY 2 will consist of three distinct classes.
Programs of Research Excellence, the American College of Standard biomarkers
, accepted and approved by the Food and
Radiology Imaging Network; the Cancer and Leukemia Group B; Drug Administration, will be used to determine patient eligi-
and the National Cancer Institute Center for Biomedical bility and randomization for the trial. Qualifying biomarkers
Informatics and Information Technology. This first trial was will be those that are not yet approved by the Food and Drug
designed to connect clinical, laboratory, and bioinformatics Administration but show promise for determining patient
investigators with a new model for the evaluation of neoadjuvant eligibility or measuring treatment response; those with suf-
chemotherapy in the setting of locally advanced breast cancer: ficient existing data will be evaluated under Investigational
bringing together data from multiple molecular biomarker stud-
Device Exemptions, whereas those with less robust data will
ies with imaging. In I-SPY 1, chemotherapy was administered be tested in Clinical Laboratory Improvement Amendments–
prior to surgery, and test biomarkers were compared with tumor certified laboratories to further develop evidence needed for
response on the basis of magnetic resonance imaging (MRI), FDA approval. Exploratory biomarkers
will be those that are of
pathologic residual disease at the time of surgical excision, interest on the basis of promising preliminary data suggesting
and 3-year disease-free survival. I-SPY 1 demonstrated that a predictive or prognostic value for breast cancer treatment. Well-
collaborating group of investigators could effectively integrate annotated tissue and blood samples collected prospectively in
biomarkers and imaging into the course of care by agreeing on I-SPY 2 will contribute to the analytical validation and quali-
standards for data collection, biomarker assessment, and MRI. fication of exploratory biomarkers, both during the trial and
The group also developed and shared methods to optimize retrospectively.
assays, small amounts of frozen core biopsy material, tools for
tissue tracking, and common information management plat-
forms and repositories.5–9 This robust infrastructure will be Standard biomarkers will be used to define the initial signatures
against which treatment will be assigned: hormone receptor sta-
tus (+/−), human epidermal growth factor receptor 2 (HER2)
I-Spy 2 tRIal deSIgn
status (+/−), and MammaPrint11,12 status (highest MP2, other
I-SPY 2 will compare the efficacy of novel drugs in combina-
shows that estrogen receptor, progesterone
tion with standard chemotherapy with the efficacy of standard receptor, and HER2 status as assessed by community immu-
therapy alone. The goal is to identify improved treatment regi-
nohistochemistry or fluorescence in situ
hybridization will be
mens for patient subsets on the basis of molecular characteristics part of the routine diagnostic workup for determining patient
(biomarker signatures) of their disease. As described for previ-
eligibility. Two additional assays of HER2 (qualifying biomark-
ous adaptive trials,10 regimens that show a high Bayesian predic-
ers) will be performed during I-SPY 2.
tive probability of being more effective than standard therapy
Data from the qualifying biomarker class will be evaluated
will graduate from the trial with their corresponding biomar-
for their sensitivity and specificity for stratifying patients and/
ker signature(s). Regimens will be dropped if they show a low or for predicting pathologic complete response. Successful
probability of improved efficacy with any biomarker signature. qualifying biomarkers will be used to improve randomization
Eligibility determined by:ER, PRHER2 (IHC/FISH, gene expression, protein microarray)MammaPrint score (from full 44 k microarray)
I-SPY 2 eligibility and treatment assignment. ER, estrogen receptor; FISH, fluorescence in situ
hybridization; HER2, human epidermal growth factor
receptor 2; I-SPY 2, investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2; IHC, immunohistochemistry;
PR, progesterone receptor; Pt, patient. For MammaPrint scoring, see refs. 11,12.
VOLUME 86 NUMBER 1 | JULY 2009 | www.nature.com/cpt
and treatment as the trial progresses. For example, HER2 interest based on the biology they represent and their expected
gene expression will be evaluated using the Agendia 44 k full high prevalence in the study population have been character-
genome microarray,11,12 and phosphorylated HER2 (pHER2) ized for I-SPY 2. Several of these signatures represent disease
will be assayed using reverse phase protein microarray.13 Also, types for which there is a widely recognized need for improved
in view of the fact that I-SPY showed MRI volume to be the treatment—for example, HER2+ tumors; hormone receptor and
best predictor of residual disease after the administration of HER2− tumors (triple-negative disease); and tumors with poor
chemotherapy,14,15 the measurement of MR volume at baseline prognosis on the basis of having the highest MammaPrint score
and during and after treatment will be automated and used to level (Supplementary Table S1
online). In order to obtain infor-
inform the randomization of patients as the trial proceeds.
mation about treatment effects as early as possible, relationships
between pathologic complete response and baseline and longi-
overall clinical trial design
tudinal markers will be modeled, and outcomes will be assessed
The overall trial design for I-SPY 2 will feature two continually during the trial. Randomization probabilities will
arms of a standard neoadjuvant chemotherapy regimen, starting be determined using the accumulating data pertaining to all
with weekly paclitaxel (plus trastuzumab (Herceptin) for HER2+ the drugs in the trial. The trial is designed to “learn” over time
patients) fol owed by doxorubicin (Adriamycin) and cyclophos-
which profiles predict response to each drug.
phamide (Cytoxan). In the other arms, five new drugs will be
For the assignment of drugs to patients, Bayesian methods
tested simultaneously, each being added to standard therapy. On of adaptive randomization10 will be used to achieve a higher
the basis of statistical models, each drug will be tested in a mini-
probability of efficacy. Drugs that do well within a specific
mum of 20 patients and a maximum of 120 patients. Following molecular signature will be preferentially assigned within that
an initial core biopsy, MRI and blood sample draw to determine signature and will progress through the trial more rapidly. Each
biomarker signature and eligibility patients will be drug’s Bayesian predictive probability10 of being successful in a
randomized to the novel drug agents, which will be administered phase III confirmatory trial will be calculated for each possible
weekly during the paclitaxel phase of the trial. After 3 weeks of the signature. Drugs will be dropped from the trial for reasons of
assigned treatment, patients wil undergo a repeat MRI and core futility when this probability drops sufficiently low for all sig-
biopsy and continue treatment for 9 additional weeks. A third natures. Drugs will be graduated at an interim point, should
MRI and core biopsy will be performed prior to initiating stand-
this probability reach a sufficient level for one or more signa-
ard chemotherapy with doxorubicin and cyclophosphamide, and tures. Drugs that have high Bayesian predictive probability of
a blood sample draw as well as a fourth MRI will be performed being more effective than standard therapy will graduate along
prior to surgery. Tumor tissue will be col ected at surgery to assess with their corresponding biomarker signatures, allowing these
whether the patient has pathologic complete response. This is agent–biomarker(s) combinations to be tested in smaller phase
the primary trial end point, but patients will also be fol owed for III trials. When the drug graduates, its predictive probability
disease-free and overall survival for up to 10 years.
will be provided to the company for all the signatures tested.
Depending on the patient accrual rate, new drugs can be added
adaptive statistical design
at any time during the trial as other drugs are either dropped
Drugs will be evaluated against biomarker signatures consisting or graduated.
of combinations of hormone receptor + or −, HER2 + or −, and
two levels of MammaPrint scores. Although this design produces Investigational drugs
256 possible signatures, most are biologically uninteresting or In order to enter I-SPY 2, drugs must meet specific criteria
represent only small markets. Fourteen signatures of possible relating to safety and efficacy A candidate drug is
I-SPY 2 trial design. For HER2+ patients in the study, some new drugs with specific anti-HER2 activity may be administered in lieu of trastuzumab:
anthracycline (AC) (e.g., doxorubicin) and cyclophosphamide (Cytoxan). HER2, human epidermal growth factor receptor 2; I-SPY 2, investigation of serial studies
to predict your therapeutic response with imaging and molecular analysis 2; MRI, magnetic resonance imaging.
CliniCal pharmaCology & TherapeuTiCs
| VOLUME 86 NUMBER 1 | JULY 2009
table 1 Summary of criteria for I-Spy 2 drugs
provides a model for rapid assessment of novel phase II drugs
and identification of effective drugs and drug combinations
Compatible with standard taxane therapy (i.e., no unacceptable additive
so as to determine which breast cancer subtypes will benefit.
toxicity) and for HER2/neu
–directed agents, compatibility with taxane plus
Specifically, learning will occur as the trial proceeds, and use of
information from each patient will inform subsequent treatment
Rationale or known efficacy in breast cancer
assignments. Given the highly competent I-SPY 2 team, exist-
Fits strategic model for optimizing combinations of single/multiple
ing infrastructure from I-SPY 1, adaptive trial design, existing
molecular targeting drugs with or without standard chemotherapy
and developing biomarker candidates and test drugs, and the
Targets key pathways/molecules in breast cancer: HER2 (Hsp90, HER2,
potential to learn what works within months rather than years,
HER3), IGFR, PI3K, macrophage, Akt, Akt + MAPK, PI3K + MEK, death
this initiative promises to be transformational for patients with
is linked to the online version of the paper at
HER2, human epidermal growth factor receptor 2; I-SPY 2, investigation of serial
studies to predict your therapeutic response with imaging and molecular analysis 2; IGFR, insulin-like growth factor receptor; MAPK, mitogen-activated protein kinase;
conFlIct oF InteReSt
MEK, mitogen-activated protein/extracellular signal–regulated kinase kinase; mTOR,
The authors declared no conflict of interest.
mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.
2009 American Society for Clinical Pharmacology and Therapeutics
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VOLUME 86 NUMBER 1 | JULY 2009 | www.nature.com/cpt
Antimicrobial activity of Reboulia hemispherica Comparative evaluation of antimicrobial activity of methanolic extract and phenolic compounds of a liverwort, Reboulia hemispherica Chetna Sharma, Anu Sharma and Meenu Katoch Dept. of Biotechnology, IIIM Jammu. Email: firstname.lastname@example.org Abstract Comparative evaluation of antimicrobial activity of methanolic extract and phenol
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