Neuro-Oncology 2008 10(4):631-642; doi:10.1215/15228517-2008-021
Society for Neuro-Oncology
Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium
Susan M. Chang,
Kathleen R. Lamborn,
John G. Kuhn,
W.K. Alfred Yung,
Mark R. Gilbert,
Patrick Y. Wen,
Howard A. Fine,
Minesh P. Mehta,
Lisa M. DeAngelis,
Frank S. Lieberman,
Timothy F. Cloughesy,
H. Ian Robins,
Lauren E. Abrey,
Michael D. Prados North American Brain Tumor Consortium
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA (S.M.C., K.R.L., M.D.P.); Pharmacotherapy Education and Research Center, University of Texas Health Science Center San Antonio, San Antonio, TX (J.G.K.); Department of Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (W.K.A.Y., M.R.G.); Dana-Farber Cancer Institute, Boston, MA (P.Y.W.); Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (H.A.F.); University of Wisconsin Hospital, Madison, WI (M.P.M., H.I.R.); Memorial Sloan-Kettering Cancer Center, New York, NY (L.M.D., L.E.A.); University of Pittsburgh Medical Center Cancer Pavilion, Division of Neuro-Oncology, Pittsburgh, PA (F.S.L.); Neuro-Oncology Program, David Geffen School of Medicine at UCLA, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA (T.F.C.); USA
Address correspondence to Susan M. Chang, Department of Neurological Surgery, University of California San Francisco, 400 Parnassus Ave., A-808, San Francisco, CA 94143-0350, USA (changs{at}neurosurg.ucsf.edu).
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Abstract
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The North American Brain Tumor Consortium (NABTC) is a multi-institutional
consortium with the primary objective of evaluating novel therapeutic
strategies through early phase clinical trials. The NABTC has
made substantial changes to the design and methodology of its
trials since its inception in 1994. These changes reflect developments
in technology, new types of therapies, and advances in our understanding
of tumor biology and biological markers. We identify the challenges
of early clinical assessment of therapeutic agents by reviewing
the clinical trial effort of the NABTC and the evolution of
the protocol template used to design trials. To better prioritize
effort and allocation of patient resources and funding, we propose
an integrated clinical trial design for the early assessment
of efficacy of targeted therapies in neurooncology. This design
would mandate tissue acquisition prior to therapeutic intervention
with the drug, allowing prospective evaluation of its effects.
It would also include a combined phase 0/I pharmacokinetic study
to determine the safety and biologically optimal dose of the
agent and to verify successful modulation of the target prior
to initiating a larger, phase II efficacy study.
Keywords: brain tumor, clinical trials, North American Brain Tumor Consortium, targeted therapies
Received November 19, 2007; Accepted January 4, 2008
Over the last decade, increasing knowledge of the pathogenesis
of glioma formation and progression has led to exploration of
novel therapeutic strategies to improve patient outcome. Early
phase I and II clinical trials are designed and conducted to
assess the safety, toxicity, and efficacy of these strategies.
To date, however, minimal antitumor activity has been demonstrated
using the single-targeted-agent approach in neurooncology.
1-3 Challenges in the evaluation of targeted agents have been
previously identified,
4-9 and in this review we focus on the
North American Brain Tumor Consortium (NABTC) experience testing
these agents to learn from this effort and to highlight areas
for potential improvement in clinical trial design.
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History of the NABTC: Goals, Institutions, and Infrastructure
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The NABTC is a National Cancer Institute (NCI)-funded group
effort with the primary objective of evaluating novel therapeutic
strategies through early phase trials. The consortium was initially
funded in 1994 and comprises 10 member institutions and one
data management center (
Table 1). Michael Prados, M.D., of the
University of California, San Francisco, is the principal investigator
for the grant supporting the consortium. A major initial challenge
for the group was to establish a central operations office to
oversee the regulatory process of activation and conduct of
the clinical trials. Proposals to study novel agents are based
on the availability of novel therapeutics provided by the Cancer
Therapy Evaluation Program (CTEP) of the NCI. Chemotherapeutic
agents are also provided by pharmaceutical companies if they
are approved by CTEP.
Following a review of potential therapeutic strategies, consortium
members prioritize study concepts. Individual institutional
investigators are responsible for generating the protocol documents
for activation. The NABTC performs phase I pharmacokinetic trials
and pilot phase II studies in CNS tumors. A rotational system
allocating sites for participation as phase I study slots become
available facilitates accrual at all sites. Differences in patient
eligibility criteria also allow for accrual to noncompeting
studies. The pharmacology group at the University of Texas Health
Science Center, San Antonio, under the leadership of John Kuhn,
Pharm.D., has been critical for implementing the pharmacokinetic
component of these studies. Over the last 12 years of funding,
21 trials have been completed and 11 are ongoing (
Table 2).
More than 1,000 patients, primarily with recurrent malignant
glioma, have been accrued.
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Protocol Template Development
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There were clear advantages to developing a protocol template
for the consortium. The main objectives were to facilitate efficient
design and development of studies and to standardize important
elements such as eligibility criteria and assessment of outcome
to create a historical database for the next generation of studies.
Sections specific to the nature of the agent, the scientific
background and rationale of the therapeutic approach, and expected
toxicities were provided by the principal investigator responsible
for the protocol. Biostatistical and pharmacology input is provided
by the consortium's core directors. Templates for phase I/II
studies in newly diagnosed glioblastoma multiforme (GBM), recurrent
malignant glioma, and recurrent meningioma were developed.
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End Point Assessment
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In 1999, Wong et al. described outcomes and progression for
patients with recurrent glioma, which suggested that 6-month
progression-free survival (6moPFS) was a more appropriate end
point for these patients than clinical response.
10 Following
this development, the NABTC changed the end point for assessment
of efficacy from response rate to 6moPFS on the protocol template
in 2000. End points such as radiographic response and symptom
assessment are often imprecise measures of tumor burden and
drug efficacy.
11,12 Progression status at 6 months can more
directly define clinical benefit and is an important determinant
of overall survival.
13 While evaluation of efficacy might also
take into consideration imaging and symptoms, progression-free
survival (PFS) is strongly correlated to overall survival, and
therefore an appropriate end point for determining the value
of an experimental treatment. The biostatistical considerations
associated with establishing 6moPFS as our primary efficacy
end point were standardized in the protocol template. In the
future, an end point that takes into consideration quality of
life may also be appropriate when evaluating new therapies,
but such an end point has yet to be validated.
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Cytotoxic Therapies
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The standard approach for the early clinical evaluation of therapeutic
agents for cancer involves the completion of a phase I study
to assess dose-limiting toxicities and determine the maximal
tolerated dose for phase II studies (
Fig. 1). Pharmacokinetic
studies are linked to these early studies to provide information
on drug clearance and steady state characteristics. Between
1994 and 1998, phase II NABTC studies in brain tumor patients
were performed using dosing schedules derived from previous
phase I studies of cytotoxic agents in patients with other systemic
solid tumors. However, the results of a phase II study of paclitaxel
revealed that the toxicity profile seen in a population of patients
with brain tumors was unexpectedly different from previous clinical
experience in patients without brain tumors.
14 Specifically,
although a 30% rate of myelosuppression was expected, our patients
rarely experienced this in the phase II study. This highlighted
the potentially unique factors in this patient population with
respect to the use of hepatic enzyme-inducing antiepileptic
drugs (EIAEDs) such as phenytoin, carbamazepine, and phenobarbital.
These agents alter the pharmacokinetics of therapeutic agents
metabolized through the P450 cytochrome system. Based on this
finding, a phase I/pharmacokinetic study of paclitaxel was performed
in patients who were taking EIAEDs (designated group B), and
the maximal tolerated dose was found to be 1.5 times the dose
administered to patients who were not being treated with these
agents (group A). Correlative pharmacokinetic studies demonstrated
similar pharmacokinetic results at the respective maximum tolerated
doses (MTDs) in the two groups.
15 In addition, the toxicity
profile was very different in the group B patients, for whom
central neurotoxicity rather than standard myelosuppression
was the dose-limiting toxicity.
As a result of this finding and the known common metabolism of agents through the P450 cytochrome system, the first standardized template was developed allowing phase I/pharmacokinetic trials with concurrent dose escalations within the two groups (those patients taking EIAEDs and those not). This also afforded a comparison of the pharmacokinetic parameters between the two groups, which was critical for proceeding to the phase II studies. The availability of newer, non-P450-substrate antiepileptic agents such as levetiracetam allowed the NABTC to further modify its clinical trial design by first assessing efficacy in group A patients using established phase II doses prior to embarking on phase I/II evaluation in group B patients (Fig. 2). This protocol ensured that only if sufficient antitumor activity was seen in group A patients would the resources be committed to further study the appropriate dose in group B patients.
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Fig. 2. Phase I/II clinical trial design that takes into account use of P450 hepatic enzyme inducing antiepileptic drugs (EIAEDs). Only if sufficient antitumor activity is seen in patients not taking EIAEDs (group A) would resources be committed to further study of the appropriate dose in patients taking EIAEDs (group B). Abbreviations: PK, pharmacokinetic; MTD, maximum tolerated dose.
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Molecularly Targeted Agents
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Perhaps the most important factor that has necessitated review
of the methodology and process of early evaluation of novel
agents has been the availability of targeted therapies relevant
to glioma and the rapid translation of these agents to the clinical
arena. These therapies have been developed based on the knowledge
of specific pathways known to affect glioma growth and invasion.
Biological pathways dysregulated in tumors, but not in normal
tissue, allow for rational selection of targets for modulation.
There are many challenges in the evaluation of these agents
in clinical research; key questions that should be addressed
prior to initiating targeted studies are listed in
Table 3.
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Fig. 3. Phase I/II design for recurrent malignant glioma taking into account use of hepatic enzyme-inducing antiepileptic agents, with pilot tissue correlate study for targeted agents. Abbreviations: PK, pharmacokinetic; MTD, maximum tolerated dose.
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One of the primary questions is whether the drug reaches the
tumor. To address this, the NABTC protocol template was changed
to incorporate a small pilot arm of 10 patients with recurrent
malignant glioma who required reoperation as part of their standard
management. This served as an exploratory arm to determine the
practicality of collecting data of this type, and the accrual
of 10 patients was thought to be both feasible and sufficient
to average out some patient variability. For this very select
group of patients, the agent was administered preoperatively
and at the time of surgery; tissue correlative studies assessing
target inhibition and tissue pharmacokinetic studies were included
(
Fig. 3). This procedure provided preliminary data on tissue
distribution and signaling pathway status pertinent to the agent
administered.
To fully address the utility of targeted therapies, particularly in trying to assess the biological effects of treatment and to identify the population of patients who may benefit most from the treatment, a more prospective approach is needed. This has been outlined by Lang et al.,16 and in ideal circumstances includes the acquisition of tissue to characterize baseline status of key signaling pathways before drug administration, followed by a short period of exposure to the agent, followed by another surgical procedure to evaluate the effects of the agent on the pathway of interest (Fig. 4). The advantages of this approach are the delineation of the pathway before and after treatment and the prospective acquisition of tissue that can be analyzed subsequently. However, there are many practical and ethical barriers to the conduct of these complex studies, including the requirement of two surgical procedures in a short time interval, one of which has no therapeutic intent, and the accompanying risks, as well as the high cost. In the past, biological and clinical correlations were made from retrospective analyses17,18 (Fig. 5). This approach has the disadvantages of providing incomplete data for some patients treated and inability to assess whether the target was modulated. The latter is of particular concern when the end point is PFS or overall survival rather than response, because it may be unclear whether improved outcome indicates that the therapy was more successful in a particular patient group or that tumors with a particular marker are inherently less aggressive. Also, selection of patients is not based on the pretreatment characteristics specific to the drug and additional time is necessary to conduct the retrospective analyses.
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Lessons Learned
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Several lessons have been learned from the completion of studies
evaluating targeted agents. Minimal efficacy has been demonstrated
for single agents tested in the brain tumor population to date.
Knowledge of potential targets existing in glioma and the ease
and tolerability of administration of the agents provided the
rationale for evaluation in phase II studies without first addressing
key aspects regarding the use of specific targeted therapies.
Insufficient early studies have been performed to assess drug
distribution (especially to the CNS), mechanism of action, and
biological activity before proceeding with phase II studies.
Furthermore, there has been a lack of prospective studies to
ensure tissue analyses to select the population who may benefit
and, instead, inefficient and usually incomplete analyses of
most correlative studies have been performed as retrospective
studies.
For newer NABTC trials implemented in 2006, prospective acquisition of tissue samples following drug administration is then followed by a standard phase II component. When possible, tissue for original diagnosis is also acquired. This approach improves our ability to link key aspects of the biological effects of the agent to clinical outcome in all patients. This approach has limitations, however, because relatively large numbers of patients are subjected to a therapeutic agent before its biological activity has been validated and because analyses of tissue correlates are performed retrospectively. Therefore, potentially important information regarding the agent's mechanism of activity is not incorporated into the planning of the study.
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The Challenge
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Before committing patients and clinical trial resources to further
studies of targeted therapies, the challenge is to improve our
methods of investigating targeted agents. This has been the
rationale in proposing an integrated phase 0/I/II correlative
study protocol template for the NABTC (
Fig. 6). Phase 0 trials
generally evaluate pharmacokinetic and pharmacodynamic profiles
of new drugs in a small group of patients prior to initiating
classic phase I tolerability studies.
19 These early studies
can also examine the biological effects of targeted agents
20 but cannot replace phase I dose-escalating or toxicity studies.
Our new proposal consists of three distinct protocols, each
with its own objective. The goal of this study design is to
acquire the important translational information linked to clinical
end points that would justify allocating resources to continued
evaluation of a targeted agent. One of the major priorities
of this approach is the acquisition of tissue for all patients
at the time of initial diagnosis and at the time of recurrence
when applicable. This is consistent with the glioma molecular
diagnostic initiative led by Howard Fine, M.D., director of
the Neuro-Oncology Branch of the National Institutes of Health.
21 Tissue acquired at the time of initial surgery could be studied
in laboratory models such as orthotopic xenograft models or
stem cell cultures. These studies would include genomic characterization
of individual tumors, to provide a tissue reference for future
clinical trials and an ongoing resource for additional translational
research. This approach is especially critical as more knowledge
is gained about specific pathways and interrelationships of
pathways. As basic science research has demonstrated, the interdependence
of signaling pathways is extremely complex.
As it is well recognized that the MTD may not be the optimal
biological dose for targeted agents, our design proposes the
integration of an early phase study (phase 0) with the primary
objective of determining the optimal biological dose as defined
by "successful" targeting. This would require tissue acquisition
from a limited number of patients who have had preoperative
exposure to the agent. Only if the target is successfully modulated
in the phase 0/I setting would a phase II study in a general
patient population be performed. Otherwise, more preclinical
studies would have to be performed before allocating further
resources to study the agent. This early, small, tissue-based
study has been a missing link in the prior evaluation of targeted
therapies. However, it would not replace the standard phase
I dose-escalation or toxicity assessment.
For phase II studies, mandating the availability of tissue for analysis of the presence of the target and other relevant biological markers would ensure that once the phase II efficacy study in the general brain tumor population has been completed, analyses of the biological markers in conjunction with clinical outcome would be performed to identify the population of patients most likely to benefit. Once this population is characterized, a phase II study of the preselected patient population enriched for the desired target would be planned to estimate the degree of activity of the agent. If the assays of biological activity and target modulation are robust enough to justify an enriched population for initial phase II study, the agent may not need to be tested in the general brain tumor population. In this case, following the phase 0/I protocol, the agent would proceed directly to a phase II study in the enriched population. To date this has not been possible, but it is where future trials should focus in order to avoid enrolling patients who are not expected to benefit.
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Fig. 6. Integrated phase 0/I/II tissue correlate protocol designs for targeted therapies. The phase 0 protocol is used to determine the biologically optimal dose. The phase I protocol is a standard toxicity study. The phase II protocol is performed in a general population of patients with brain tumors to determine efficacy, and ultimately in an enriched population selected for their molecular characteristics. Abbreviation: PK, pharmacokinetic.
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Identifying and validating therapeutic targets require novel
biomarkers and analytical tools, the development and application
of which are not without their own challenges and have been
thoroughly discussed elsewhere.
22,23 It is likely that multiple
oncogenes and pathways are activated or dysregulated before
malignancies develop in the brain, and therefore the presumed
target may not necessarily be responsible for efficacy of the
drug. Development of clinically relevant animal models is needed
to better understand the specific biological pathways and more
precisely identify targets. It is also important to be able
to measure whether the target was affected by the drug, the
effect of target modulation on the pathway and relevant downstream
components, and the clinical outcome.
24 Methods of measuring
the abnormal target and pathway modulation also need to be standardized
in order to avoid potentially conflicting results, as has been
seen in a number of retrospective genomic analyses.
16,17 In
addition, the statistical components should take into account
the frequency of the target in the general population to avoid
rejecting a drug that would require a large sample size to demonstrate
efficacy. It is also important to note that identifying targets
in tissue may require sophisticated or expensive molecular techniques,
which would be unsuitable for screening large groups of patients
prior to initiating clinical trials. Assays must be accessible
and practical in order to be applicable to the clinical setting.
The rapid development of targeted agents has made it necessary to reevaluate clinical trial design in all fields of oncology, and other teams of researchers have reached similar conclusions with regard to more stringent studies of therapeutic agents in smaller populations of patients prior to initiating standard phase I studies.20,24-26 Kummar et al.20 outlined a proposal for incorporating "phase 0" trials that would utilize strong preclinical data, pharmacodynamic assays, and multiple biopsies to determine if a target has been modulated.
Many of these issues are relevant to clinical trials of gliomas; however, studies in brain tumor patients have unique limitations imposed by the challenges in tumor acquisition and the potential for brain injury from tumor sampling or treatment. Evidence of drug safety, from phase I pharmacokinetic studies of MTD or studies of the drug in solid tumors, is necessary prior to initiating a trial for brain tumors that requires tissue acquisition. For example, it must be determined that the drug will not inhibit wound healing or cause hemorrhage following surgical procedure. In addition, because of the increased risk of morbidity associated with serial biopsies, the development of surrogate markers of activity is much more critical in the design of future trials and resources must be allocated to developing such surrogates. Validated imaging markers would be particularly beneficial. MR spectroscopy imaging, diffusion- and perfusion-weighted imaging, and PET with novel imaging probes are promising tools that may be incorporated into future trials.
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Challenges Specific to Antiangiogenic Agents in Neurooncology
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Malignant gliomas rely on blood vessels for survival and growth,
providing a strong rationale for antiangiogenic treatment strategies.
27 There are specific challenges in assessing the efficacy of
these agents in clinical trials. First, the integrated paradigm
that includes tissue acquisition following administration of
the agent to assess biological activity would not be feasible
for studies of these agents. Inhibition of wound healing would
be a major contraindication to the administration of antiangiogenic
agents in the immediate preoperative period. Therefore, other
methods of measuring of biological activity must be evaluated.
Batchelor et al. have reported on elegant physiological imaging
techniques, visualizing vascular perfusion and permeability
characteristics, which were used to evaluate the activity of
AZD2171.
28 These techniques need to be validated, standardized,
and assessed prospectively. The NABTC currently has two ongoing
studies of vascular endothelial growth factor (VEGF)-trap and
pazopanib, both of which target the VEGF-related pathway. Perfusion-weighted
MRI scans of patients in these trials are being evaluated prospectively
to assess the effects of treatment. However, until this technique
has been validated as a surrogate of drug activity, the results
of the imaging component of the study cannot be used to influence
the design of the study in either determining eligibility criteria
or assessing efficacy.
Second, appropriate end points to assess clinical benefit should be selected for these agents, including those related to response, survival, and quality of life. Clinical evaluation of bevacizumab and irinotecan demonstrated a high response rate and improvement in 6moPFS compared to prior strategies.29,30 Improvement in the volume of contrast enhancement, which in previous studies of cytotoxic agents has been assumed to indicate antitumor effect, may, in the case of antiangiogenic agents, represent restoration of the blood-brain barrier, which is a transient phenomenon for the patient. Although 6moPFS and response rate may be generally improved for patients treated with antiangiogenic therapies, overall survival may not differ from that for other treatments. Therefore, criteria for assessment of efficacy need to be revised for these agents, and 6moPFS must be revalidated as a clinically relevant surrogate of overall survival. Serial serum biomarkers, such as circulating endothelial cells and plasma basic fibroblast growth factor, may be surrogates of an agent's activity and should also be validated in future studies. Transient improvement of edema, mass effect, and brain shift with concomitant improvement of clinical symptoms and reduction of the need for corticosteroids have been reported following treatment with antiangiogenic agents.28,29 Incorporation of standardized quality-of-life assessments are important for these studies and should be considered as secondary end points of clinical benefit.
Third, these agents can be associated with significant adverse effects, including hypertension, proteinuria, thromboembolic disease, and intracranial hemorrhage. It is therefore critical to try to identify the patient population that would benefit most from these treatments, thereby sparing ineffective, potentially toxic treatment for those unlikely to benefit. Although preoperative sampling as part of the clinical trial design of antiangiogenic agents may not be feasible, retrospective evaluation of tissue characteristics evaluating angiogenic markers may be important to assess benefit. Validated imaging surrogates, as explored by Chen et al.31 using fluorothymidine PET in patients treated with bevacizumab and irinotecan, or serum biomarkers may help in identifying the optimal patient population.
Finally, despite initial improvement in the imaging and clinical status of patients treated with antiangiogenic agents, tumors almost always recur. Strategies to circumvent the resistance mechanisms that result in progression of disease need to be evaluated, especially those that pertain to tumor invasion and cooption of normal brain vasculature. Early markers of progressive disease or lack of efficacy, when available, should be incorporated into the trial design. This is applicable for any new therapeutic agent and not limited to antiangiogenic therapies.
Fig. 7 outlines a potential trial design in which an imaging or serum biological surrogate of an agent's activity is used, rather than direct measures of pathway modulation measured from tissue samples following exposure. The surrogate marker must have been validated as a measure of drug effect. The phase 0 trial evaluates a limited number of patients with pretreatment and serial posttreatment acquisitions of the surrogate marker to assess the success of the agent in having an effect on the marker. If this is demonstrated, then a phase II study is conducted that mandates the availability of tissue markers from a previous surgery as well as the planned pretreatment and serial acquisition of the surrogate markers. Standard assessment of efficacy is made and analyzed with the surrogate marker and tissue results to identify patients who may benefit and enable the selection of an enriched population for further study.
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Key Elements to Ensure Success of the Integrated Approach
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To ensure the success of this approach, some key elements would
need to be in place. There must be a close interaction with
basic scientists to understand and define pathways, targets,
and the mechanism of action of the agent. Basic scientists need
to be involved on an ongoing basis in the design and conduct
of the clinical trial. This is critical for the definition of
reliable, reproducible assays to identify targets and in the
selection of biological end points that indicate successful
effect of targeted therapy. Such assays are indispensable if
information about the effect of the agent is to be accurately
evaluated before studying the effects in the general brain tumor
population. Involvement of a biostatistician to assist with
determining the size of the phase 0/I study population will
be critical. In addition, real-time assessment of the biological
end points will need to be mandated to move the trial design
forward efficiently. A multidisciplinary approach and infrastructure
to ensure tissue acquisition and processing in all patients
will need to be established, along with central tissue and animal
cores to support continued research while clinical studies are
ongoing. Noninvasive markers of activity (e.g., imaging, serum
markers) need to be explored in addition to the known biological
tissue markers.
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Conclusions
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Significant effort has been expended on the part of patients
and clinical trial personnel to design and conduct early clinical
trials in neurooncology through the NABTC. What we have learned
has been critical in rethinking the design of trials involving
targeted therapies. To gain the most information about these
agents in an efficient manner, we propose an integrated clinical
trial design for the early assessment of efficacy of targeted
strategies. There will need to be close and ongoing interaction
of basic scientists and clinicians to translate information
learned both in the laboratory and at the bedside to effectively
identify the patient population most likely to benefit and to
assess efficacy. Further development of noninvasive biomarkers
will be a key component of this effort. Identifying enriched
populations will ensure that patients have quick access to the
most effective strategy for their individual tumors, without
being exposed to unnecessary treatments. With the budgetary
constraints present in the current era, it is imperative that
the prioritization of effort and allocation of resources allow
for expeditious evaluation of these exciting agents.
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Appendix. Individual NABTC and General Clinical Research Center grants providing financial support for the research reported in this article
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Acknowledgements
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We thank Ilona Garner, Department of Neurological Surgery, University
of California San Francisco, for editorial support. Financial
support was received through prime award CA 62399 from the National
Institutes of Health to the North American Brain Tumor Consortium
(NABTC) investigators and through the individual NABTC and General
Clinical Research Center grants listed in the appendix.
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Abstract
History of the NABTC:...
