Adaptive Trials in the Neoadjuvant Setting: A Model to Safely Tailor Care While Accelerating Drug Development

Article (PDF Available)inJournal of Clinical Oncology 30(36) · November 2012with24 Reads
DOI: 10.1200/JCO.2012.44.1022 · Source: PubMed
of the procarbazine in infertility in this population will be difficult to
determine. While the study was randomized and some children did
not receive procarbazine, the majority of these patients, when they
progressed, went on to receive other potentially toxic chemotherapy
regimens, including alkylators and/or cranial irradiation. Unlike the
Hodgkin lymphoma survivors, these children often receive multiple
successive treatments. The young age of the patients also limits the
number who will be over 20 years of age when Children’s Oncology
Group ends the follow-up. Finally, endocrine deficits were only one
aspect of the multiple late effects of brain tumors and treatment that
can lead to childlessness.
The standard consent form included infer
tility as one of the risks of therapy, so parents were informed. However,
it would be misleading for parents to be told that treatment with one
regimen would be more likely to cause inability to have children, since
so many other factors also contribute to this problem in this popula-
tion. For example, the regimen that may be most preserving of fertility
may to be the one that prevents progression and the need for these
subsequent treatments or delays radiation beyond a critical age. It is
clear with all these issues, further study of fertility in brain tumor
survivors is needed.
Joann L. Ater
University of Texas MD Anderson Cancer Center, Houston, TX
The author(s) indicated no potential conflicts of interest.
1. Toledano H, Ben-Arush M, Yaniv I: Procarbazine and infertility in low-grade
gliomas in children. J Clin Oncol 30:4583, 2012
2. Ater JL, Zhou T, Holmes E, et al: Randomized study of two chemotherapy
regimens for treatment of low-grade glioma in young children: A report from the
Children’s Oncology Group. J Clin Oncol 30:2641-2647, 2012
3. Hobbie WL, Ginsberg JP, Ogle SK, et al: Fertility in males treated for
Hodgkins disease with COPP/ABV hybrid. Pediatr Blood Cancer 44:193-196,
4. Dann EJ, Blumenfeld Z, Bar-Shalom R, et al: A 10-year experience with
treatment of high and standard risk Hodgkin disease: Six cycles of tailored
BEACOPP, with interim scintigraphy, are effective and female fertility is pre-
served. Am J Hematol 87:32-36, 2012
5. Armstrong GT, Liu Q, Yasui Y, et al: Long-term outcomes among adult
survivors of childhood central nervous system malignancies in the Childhood
Cancer Survivor Study. J Natl Cancer Inst 101:946-958, 2009
6. Green DM, Nolan VG, Kawashima T, et al: Decreased fertility among female
childhood cancer survivors who received 22-27 Gy hypothalamic/pituitary irradi-
ation: A report from the Childhood Cancer Survivor Study. Fertil Steril 95:1922-
1927, 2011, 1927 e1
DOI: 10.1200/JCO.2012.46.4842; published online ahead of print at on November 13, 2012
Adaptive Trials in the Neoadjuvant
Setting: A Model to Safely Tailor
Care While Accelerating
Drug Development
TO THE EDITOR: It is clear from the Schott and Hayes
critique of
the I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeu-
tic Response With Imaging and Molecular Analysis 2) trial that they
and your readers would benefit from a more-detailed understanding
of the study.
Patients in I-SPY 2 have breast cancers 2.5 cm. A core
biopsy sent for molecular characterization with the US Food
and Drug Administration–approved 70-gene test (Mam-
must be 70-gene high risk, hormone receptor–nega
tive or human epidermal growth factor receptor 2–positive for a
patient to be eligible for random assignment to weekly pacli-
taxel 12 weeks with our without an investigational agent
followed by four cycles of doxorubicin and cyclophosphamide.
Biomarkers are used to identify signatures for experimental
regimens that predict an improved pathologic complete re-
sponse (pCR), which is defined as no invasive tumor present in
breast or axillary lymph nodes.
Adaptive random assignment
hastens this process. Regimens are dropped if they do not
improve pCR rates for any biomarker signature.
The I-SPY 2
design was created to rapidly evaluate the interaction between
the investigational agent and paclitaxel and to drop agents if
problems are observed, whereas drugs that improve pCR can
follow a regulatory pathway for accelerated approval.
and Hayes
raise three important issues that we considered
carefully when designing the I-SPY 2 trial.
First, they are concerned that novel agents when added to
standard therapy for 12 weeks might not enhance the pCR rate.
These are the hypotheses being tested. For an investigational agent
to be eligible for I-SPY 2, there must be preclinical evidence that
shows a lack of interference with taxanes and a strong scientific
rationale for additivity or synergy. As a consequence of the adap-
tive design, if the pCR rate is not increased by paclitaxel plus an
investigational agent versus paclitaxel alone for any biomarker
signature, as few as 20 patients will be exposed to the combination.
Moreover, an agent can be dropped completely or dropped for
specific subsets of patients who have no evidence of an enhanced
response. This compares with many thousands of women exposed
to new agents in the postsurgical adjuvant model favored by the
authors. We agree with the authors that neoadjuvant endocrine
therapy does not induce pCR in 12 weeks, but we are not consid-
ering endocrine therapy in the trial. Moreover, patients with hor-
mone receptor–positive tumors and MammaPrint low-risk scores
are not eligible to proceed to chemotherapy in I-SPY 2 because they
may benefit from endocrine therapy alone. We are not exposing
these patients to chemotherapy plus investigational agents.
The second concern of Schott and Hayes
relates to the potential
toxicity of investigational agents when given in combination with
paclitaxel. Experimental drugs included in I-SPY 2 must demonstrate
safety data for the combination and receive approval by an indepen-
dent advisory committee and the US Food and Drug Administration.
Moreover, weekly patient visits allow close toxicity evaluation. Finally,
an external independent data safety and monitoring board (DSMB)
meets monthly to review toxicity. Patient safety has been at the heart of
the trial design. Real-time monitoring helps ensure patient safety.
The authors’ third concern is the potential interference of
new agents with paclitaxel. They drew an analogy of inferior results
with concurrent versus sequential chemotherapy and tamoxifen.
In this example, the preclinical data that predicted this outcome
© 2012 by American Society of Clinical Oncology
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were published years
before the 1,500-patient adjuvant clinical
trial, which showed inferior results with concurrent tamoxifen.
Meanwhile, before trial completion, thousands of women were
treated inappropriately.
Just as Schott and Hayes
are concerned about the I-SPY 2 design,
we are concerned about the pace and price of testing one drug every 5
to 10 years in thousands of women. Innovation can and should exist
while guaranteeing patient safety. I-SPY 2 has teamed with 50 pa-
tient advocates, 100 academics and community physicians, 22 clin-
ical centers, the Foundation for the National Institutes of Health
Cancer Biomarkers Consortium, the US Food and Drug Administra-
tion, the National Cancer Institute Cancer Therapy Evaluation Pro-
gram, an independent advisory group composed of senior cancer
leaders who are not involved in the trial, an independent DSMB, and
10 pharmaceutical and biomarker companies. To date, we have
randomly assigned more than 200 patients without limitations im-
posed by the DSMB.
The concerns expressed by Schott and Hayes
were prime consider
ations inourtrial design, but we arrived at a different conclusion regarding
the way forward. The conducting of an intensive study of patients receiv-
ing neoadjuvant therapy is a model for the treatment of all cancers. By
testing new agents on a standard-of-care platform, performing molecular
profiling, incorporating imaging, applying strict criteria for drug inclu-
sion, using adaptive random assignment, and providing real-time safety
monitoring, we are fulfilling the demands of our patients to bring the
promise of personalized therapies to the clinic.
Douglas Yee
Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Tufia Haddad
Mayo Clinic Cancer Center, Rochester, MN
Kathy Albain
Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL
Anna Barker
Arizona State University; Quantum Leap Healthcare Collaborative, Tempe, AZ
Christopher Benz
Buck Institute for Age Research, Novato, CA
Judy Boughey
Mayo Clinic Cancer Center, Rochester, MN
Meredith Buxton
University of California, San Francisco, San Francisco, CA
Amy Jo Chien
Carol Franc Buck Breast Care Center, University of California, San Francisco,
San Fransciso, CA
Angela DeMichele
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
David Dilts
Oregon Health & Science University, Quantum Leap Healthcare Collaborative,
Portland, OR
Anthony Elias
University of Colorado, Boulder, CO
Paul Haluska
Mayo Clinic Cancer Center, Rochester, MN
Michael Hogarth
University of California, Davis, Davis, CA
Alan Hu
Quantum Leap Healthcare Collaborative, San Francisco, CA
Nola Hytlon
Magnetic Resonance Science Center, University of California, San Francisco,
San Francisco, CA
Henry G. Kaplan
Swedish Cancer Institute, Seattle, WA
Gary G. Kelloff
National Cancer Institute, Bethesda, MD
Qamar Khan
Cancer Center, University of Kansas Medical Center, Kansas City, KS
Julie Lang
Arizona Cancer Center, University of Arizona, Tucson, AZ
Brian Leyland-Jones
Sanford Health, Fargo, ND
Minetta Liu
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
Rita Nanda
Center for Advanced Medicine, University of Chicago, Chicago, IL
Donald Northfelt
Mayo Clinic Arizona, Scottsdale, AZ
Olufunmilayo I. Olopade
Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL
John Park
Bay Area Breast Cancer SPORE, University of California, San Francisco,
San Francisco, CA
Barbara Parker
Moores Cancer Center, University California, San Diego, San Diego, CA
David Parkinson
Nodality, South San Francisco, CA
Sonia Pearson-White
Foundation for the National Institutes of Health, Bethesda, MD
Jane Perlmutter
Gemini Group, Ann Arbor, MI
Lajos Pusztai and Fraser Symmans
M.D. Anderson Cancer Center, University of Texas, Houston, Houston, TX
Hope Rugo
University of California, San Francisco, San Francisco, CA
Debu Tripathy
Norris Comprehensive Cancer Center, University of Southern California, Los
Angeles, CA
Anne Wallace
University of California at San Diego, San Diego, CA
David Wholley
The Biomarkers Consortium Foundation for the National Institutes of Health,
Bethesda, MD
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
Laura van’t Veer
University of California, San Francisco, San Francisco, CA
Donald A. Berry
M.D. Anderson Cancer Center, University of Texas, Houston, Houston, TX
Laura Esserman
Carol Franc Buck Breast Care Center, University of California, San Francisco,
San Francisco, CA
Although all authors completed the disclosure declaration, the following
author(s) and/or an author’s immediate family member(s) indicated a
financial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U” are
those for which no compensation was received; those relationships marked
with a “C” were compensated. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: David Parkinson, New Enterprise
Associates (C), Threshold Pharmaceuticals Inc (C), Zyngenia (C); Laura
van ’t Veer, Agendia (C); Donald A. Berry, Berry Consultants, LLC (C)
Consultant or Advisory Role: Minetta Liu, Agendia (C), sanofi-aventis
(C), Genentech/Roche (C); John Park, Merrimack Pharmaceuticals (C);
Barbara Parker, Roche (C); David Parkinson, Abbott Pharmaceuticals
(C); Fraser Symmans, Nuvera Biosciences (U); Debu Tripathy,
Genentech (C); Donald A. Berry, Berry Consultants (C) Stock
Ownership: John Park, Merrimack Pharmaceuticals; Fraser Symmans,
Nuvera Biosciences; Laura van ’t Veer, Agendia; Donald A. Berry, Berry
Consultants Honoraria: Kathy Albain, Genomic Health, Genentech,
Novartis, Roche; Julie Lang, Genomic Health, Aptiv Solutions; Minetta
Liu, GlaxoSmithKline; John Park, Genentech, Agendia, Novartis,
Genentech, Bristol Myers Squib, Agendia Research Funding: Minetta
Liu, Genentech/Roche, GlaxoSmithKline, Novartis, sanofi-aventis;
Barbara Parker, sanofi-aventis, Roche, GlaxoSmithKline Expert
Testimony: John Park, Genentech (C) Other Remuneration: Kathy
Albain, Pfizer; John Park, Merrimack Pharmaceuticals
1. Schott AF, Hayes DF: Defining the benefits of neoadjuvant chemotherapy
for breast cancer. J Clin Oncol 30:1747-1749, 2012
2. van de Vijver MJ, He YD, van’t Veer LJ, et al: A gene-expression
signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-
2009, 2002
3. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast
cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol
25:4414-4422, 2007
4. Barker AD, Sigman CC, Kelloff GJ, et al: I-SPY 2: an adaptive breast cancer
trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther
86:97-100, 2009
5. Esserman LJ, Woodcock J: Accelerating identification and regulatory ap-
proval of investigational cancer drugs. JAMA 306:2608-2609, 2011
6. Osborne CK, Kitten L, Arteaga CL: Antagonism of chemotherapy-induced cytotox-
icity for human breast cancer cells by antiestrogens. J Clin Oncol 7:710-717, 1989
7. Albain KS, Barlow WE, Ravdin PM, et al: Adjuvant chemotherapy and timing
of tamoxifen in postmenopausal patients with endocrine-responsive, node-
positive breast cancer: A phase 3, open-label, randomised controlled trial. Lancet
374:2055-2063, 2009
8. Meropol NJ, Kris MG, Winer EP: The American Society of Clinical Oncolo-
gy’s blueprint for transforming clinical and translational cancer research. J Clin
Oncol 30:690-691, 2012
DOI: 10.1200/JCO.2012.44.1022; published online ahead of print at on November 19, 2012
Advocates’ Perspective: Neoadjuvant
Chemotherapy for Breast Cancer
TO THE EDITOR: Although it is clear that Schott and Hayes
motivated to improve treatment for breast cancer, they appear
overly cautious about moving beyond the traditional drug-
development paradigm that focuses on incremental improvements
by adding new drugs to traditional chemotherapy. Because we have
been personally affected by cancer, we are not satisfied by this
approach and believe we must seek innovative strategies to accel-
erate progress. Like Schott and Hayes,
we are committed to
evidence-based medicine, although we often come to different
conclusions about the best path forward. As advocates, many of
whom have been involved in the I-SPY 2 (Investigation of Serial
Studies to Predict Your Therapeutic Response With Imaging and
Molecular Analysis 2), we have written this letter to urge innova-
tion, including the use of neoadjuvant trials and to address the
criticism of I-SPY 2 of Schott and Hayes.
First, we take issue with their claim that there are “limited
clinical advantages of neoadjuvant chemotherapy” because only
a fraction of patients who are not eligible for breast-conserving
surgery become eligible with neoadjuvant therapy. For those
women, the advantage is significant. We recommend that for
women without the initial option of breast-conserving surgery,
the standard of care should include the offer of neoadjuvant
systemic therapy.
Second, neoadjuvant trials provide more rapid indication of the
potential value of investigational agents and the appropriate subgroup
of patients. Such trials lead to the refinement of imaging and bio-
marker assessments of which Schott and Hayes
are concerned.
Third, Schott and Hayes
express concerns about the potential an
tagonism of targeted and cytotoxic therapy in neoadjuvant trials. Preclin-
ical data have suggested that additive or synergistic effects are more likely.
Combinations need to be tested in clinical trials. A potential innovative
trial design might administer a targeted therapy neoadjuvantly and a
cytotoxic therapy postsurgically, perhaps sparing patients who achieve a
pathologic complete response (pCR) the toxicity of chemothera-
py altogether.
Fourth, Schott and Hayes
worry about false negatives. Many
false negatives, particularly for targeted agents, may be a consequence
of testing them in patients with an extensive tumor burden that is
highly mutated. Patients with early-stage breast cancer may be more
likely to benefit from these agents, and thus, our concern about false
negatives decreases for neoadjuvant trials of early-stage breast cancer.
As concerns the three clinical scenarios that Schott and
describe, we again offer alternative reactions. Their first
scenario is a patient who is estrogen receptor–positive, proges-
terone receptor–positive, and human epidermal growth factor
receptor 2–negative who does not achieve a pCR after neoadju-
vant chemotherapy. Although the pCR rate is lower in women
with estrogen receptor–positive disease, it is not insignificant.
The administration of endocrine therapy neoadjuvantly and
deferring a decision about chemotherapy until after surgery
could reduce the number of women subjected to the toxicity of
© 2012 by American Society of Clinical Oncology
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    • "Adaptive designs comprise a spectrum of potential trial design changes (Meurer et al. 2012 ). A simple adaptation involves early trial termination rules based on statistical boundaries (Pocock 1977), while a complex adaptation in a dose-finding trial could identify promising treatments for specific subpopulations and tailor enrollment to maximize information gained (Yee et al. 2012). The overarching objective of ADAPT-IT is " To illustrate and explore how best to use adaptive clinical trial designs to improve the evaluation of drugs and medical devices and to use mixed methods to characterize and understand the beliefs, opinions , and concerns of key stakeholders during and after the development process " (Meurer et al. 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Mixed methods research offers powerful tools for investigating complex processes and systems in health and health care. This article describes integration principles and practices at three levels in mixed methods research and provides illustrative examples. Integration at the study design level occurs through three basic mixed method designs-exploratory sequential, explanatory sequential, and convergent-and through four advanced frameworks-multistage, intervention, case study, and participatory. Integration at the methods level occurs through four approaches. In connecting, one database links to the other through sampling. With building, one database informs the data collection approach of the other. When merging, the two databases are brought together for analysis. With embedding, data collection and analysis link at multiple points. Integration at the interpretation and reporting level occurs through narrative, data transformation, and joint display. The fit of integration describes the extent the qualitative and quantitative findings cohere. Understanding these principles and practices of integration can help health services researchers leverage the strengths of mixed methods.
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