A National Cancer Clinical Trials System for the 21st Century Reinvigorating the NCI Cooperative Group Program (2010) / Chapter Skim
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2 The Science of Developing Cancer Therapy
2 The Science of Developing Cancer Therapy
Pages 77-120
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From page 77... ...
This is because most cancer treatments available today are effective in only a minority of patients, in part due to the tremendous variability in the molecular abnormalities that drive tumor formation (IOM, 2007; PCAST, 2008; Spear et al., 2001)
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. For instance, by applying new sequencing technologies to genome analysis, TAbLE 2-1 Examples of Validated Biomarkers Routinely Used to Predict Response to Cancer Therapy Therapeutic Agent Biomarker Cancer Type Endocrine therapies (e.g., tamoxifen)
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. THE ROLE OF COOPERATIvE GROuPS IN bIOMARkER DEvELOPMENT The NCI Clinical Trials Cooperative Groups have a long history of collecting highly annotated specimens7 from patients with many different forms of cancer in clinical trials, including all the major pediatric and adult cancers, and have in place effective systems for collecting, storing, and tracking specimens to conduct correlative science.8 Each of the 10 Cooperative Groups has its own repository for biological specimens.
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About half of newly diagnosed cases of breast cancer are estrogen receptor (ER) positive and lymph node negative, and approximately 75 percent of those cases are adequately treated with surgery and hormonal therapy with 9 The objective of the MARVEL trial was to definitively establish whether the presence or absence of epidermal growth factor receptor activation can help to guide the treatment of lung cancer.
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prospective biomarker development studies; and (5) prospective biomarker validation studies (Schilsky, 2009; see also the section on trial design)
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Advances in information technology and molecular research have enabled large retrospective correlative studies linking clinical data to molecular data, but a number of obstacles stand in the way of effectively leveraging these advances, including inconsistent access to quality, annotated biospecimens; a lack of standards for assays or analysis of samples in a clinical setting; a lack of standards and templates for the design of correlative and other biomarker studies; a lack of clear and consistent policies that define tissue ownership and access to biospecimens; and a lack of adequate funding or funding that is piecemeal and requires multiple reviews. biospecimen Collection, Storage, Annotation, and Access The quality of biospecimens can significantly influence clinical and research outcomes.
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The informed-consent documents obtained from patients for their participation in a clinical trial may not adequately specify the use of patient samples for additional, future research studies. Therefore, to test the samples, it may be necessary for the Cooperative Groups to re-contact the patients who provided them to obtain consent and authorization12 (Hamilton, 2009)
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. Because the Cooperative Groups have a long history of responsible stewardship of biorepositories and well-established networks throughout the country with access to large, diverse patient populations, they are a logical choice for playing a central role in the ongoing efforts of NCI to establish consistent policies regarding ownership and access and could be instrumental in conducting future correlative studies.
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From page 85... ...
As discussed in Chapter 3, NCI has taken some initial steps to address this need. Nevertheless, the committee recommends that NCI adequately fund highly ranked trials to cover the costs of the trial, including biomedical imaging and other biomarker tests that are integral to the trial design.
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. Lack of Standards for biomarker Development and use Analytical validation and clinical validation are important for using predictive imaging and other biomarker tests during clinical trials.
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However, a second analysis of biological material can also include assessment of samples obtained by noninvasive or less invasive means, such as blood for analysis by blood-based assays (for example, for analysis of serum DNA, the serum protein profile, or circulating tumor cells) or molecular imaging for a relevant target.
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Tumors that overexpress HER-2 are often sensitive to treatment with Herceptin, a monoclonal antibody that blocks the function of this receptor -- one of the most well-known applications of personalized medicine. Genentech used a biomarker assay throughout the drug development process to test the efficacy of trastuzumab, but the company was not able to obtain FDA approval for that test at the time that FDA approved the drug.
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From page 89... ...
For example, the I-SPY 2 TRIAL,16 which builds on the I-SPY 1 TRIAL,17 is a Phase II adaptive trial that uses Bayesian statistics to predict how the drugs will perform in Phase III studies (see also the section on trial design below)
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For example, investigators will need to determine whether this research design is portable to other diseases besides breast cancer. Because breast cancer has more established biomarkers than most other types of cancer, identifying suitable markers for similar studies of other cancers may prove more difficult.
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. GlaxoSmithKline and Novartis have also initiated a similar early-stage collaboration to evaluate the combination of two investigational kinase inhibitors.18 While these types of collaborations are just emerging, it is thought that combining targeted agents early in development may accelerate the delivery of promising cancer therapies and ultimately change the drug development paradigm.
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From page 92... ...
can define an effective mechanism for the development of targeted cancer therapies, with particular emphasis on combination products. TRIAL DESIGN The increasing complexity of cancer clinical trials, along with the great expense and high failure rate of late-stage clinical trials, has spurred innovations in trial design, with the aim of conducting clinical trials more efficiently and with greater likelihood of success.
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Although many enhancements have been made to trial design and analysis over the ensuing decades, the current explosion of biological knowledge demands increased attention to developing trial designs that can take advantage of this knowledge more fully, with a goal of improving the efficiency of trials without reducing the reliability of results. Many clinical trialists are developing approaches to clinical trials that involve multiple stages or otherwise permit increased flexibility by allowing for changes to be made during the trial, based on emerging results.
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. Most clinical trials are designed to employ classical "frequentist" statistical methods.20 Another approach to clinical trial design and analysis is the Bayesian approach, which considers the treatment effect as a random variable with a probability distribution rather than as an unknown constant that the investigator wishes to estimate.
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. Another aspect of cancer clinical trials that investigators are reconsidering is the reliance on the tumor response rate as an endpoint in Phase II trials.
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To improve the efficiency of Phase II randomized trials, statisticians have proposed a number of innovative trial designs, including randomization of a small portion of patients to a reference arm, the incorporation of a randomized Phase II trial into the first stage of a Phase III protocol, or the use of a Phase II trial that directly compares two experimental regimens to prioritize candidacy for Phase III studies (Rubinstein et al., 2009)
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2009. Clinical trial designs for predictive biomarker validation: One size does not fit all.
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23 Seehttp://www.breastinternationalgroup.org/Research/TRANSBIG/MINDACT.aspx. 24 BIG is a nonprofit organization for academic breast cancer research groups that facilitates breast cancer research at international level.
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If a predictive marker is not known or is not validated before the start of a clinical trial, an "adaptive signature" trial design could be used. In a trial with such a design, different subsets of data within the Phase III trial are used to develop a predictive marker and to evaluate the effects of the treatment in populations identified by the marker (Simon, 2008b)
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clinical trial, in which the hypothesis and study design are developed specifically to answer questions faced by decision makers. A pragmatic clinical trial selects clinically relevant alternative interventions to compare; includes a large, diverse population of study participants; recruits participants from heterogeneous practice settings; and collects data on a broad range of health outcomes (although data collection is still greatly minimized compared to standard FDA-style registration trials)
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bIOMEDICAL IMAGING AS A CANCER bIOMARkER The quest to incorporate innovative science into clinical trial design and to evolve toward personalized medicine demands a reassessment of the role of biomedical imaging. The use of anatomic imaging to assess changes in tumor size has long constituted the main application of imaging in clinical trials.
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Role of Anatomic Imaging in Clinical Trials Anatomic imaging is and will remain essential for staging primary cancer, determining the extent of recurrence and metastasis, and assessing the response to treatment in clinical trials. However, enhanced quantification methods could further improve the assessment of treatment response.
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biological basis for Improved Cancer Imaging in Oncology Emerging knowledge about cancer has improved the understanding of the optimal goals for imaging in clinical oncology and clinical trials. First, in vivo, tumors are masses that consist of cancer cells and their supporting nonmalignant cells and blood vessels that are organized into a community of interacting cells.
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Molecular imaging allows in vivo detection, characterization, and quantitative analysis of the key molecules, molecular events, and cellular components that are fundamental to the development and progression of cancer. Molecular Imaging and Its Potential Applications in Clinical Trials Recent revolutionary advances in molecular and cell biology, imaging probe development, and imaging technology have rapidly expanded the actual and potential applications of molecular imaging.
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From page 105... ...
provides data reflective of tumor vascularity and angiogenesis and is one of the phenotypic imaging techniques most often used in clinical trials and clinical practice. Because changes in tumor vascularity tend to occur earlier than changes in tumor size, DCE-MRI is useful for monitoring the effects of or predicting responses to cancer treatments, including chemotherapy for breast and bladder cancers, radiotherapy for rectal and cervical cancers, and androgen deprivation for prostate cancer (Padhani and Leach, 2005)
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However, unlike in vitro diagnostic tests, most emerging molecular imaging methods rely on probes that must be injected, posing concerns similar to those faced in drug development. In some cases, a single entity serves as both a diagnostic imaging probe and a therapeutic agent, or a theranostic (Kassis et al., 2008)
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During the IOM workshop on Improving the Quality of Cancer Clinical Trials, the participants suggested that imaging and image analysis laboratories for clinical trials be established at NCI-designated Comprehensive Cancer Centers. Such laboratories could ensure the proper execution of experimental imaging protocols and use image response assessment teams to interpret the imaging data from clinical trials and assist with the design of clinical trials (IOM, 2008)
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Standards should be published and updated in a timely manner so that they are useful in clinical trials. SuMMARy The recommendations in this chapter support the committee's goal to incorporate innovative science and trial design into cancer clinical trials.
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For example, to achieve the goals of targeted cancer therapy, the use of validated biomarkers will be essential. High-quality annotated biorepositories are needed to gain useful knowledge about the biology of cancer and biomarkers from the analysis of patient samples archived from past trials.
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The committee also concluded that the Cooperative Groups are in a unique position to develop innovative designs for clinical trials and to demonstrate the feasibility and utility of using innovative, efficient designs in their clinical trials. The increasing complexity of cancer clinical trials, along with the great expense and high failure rate of late-stage clinical trials, has spurred innovation in trial design, with the aim of conducting clinical trials more efficiently and with a greater likelihood of success.
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This need for standards will become increasingly important as the science of cancer research becomes more complex and more dependent on technologies such as imaging and on molecular tools such as biomarkers. In the case of biomedical imaging, many technologies and imaging reagents,
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Continued progress in the development and incorporation of innovative science into clinical trials will require the efforts of many stakeholders. For example, NCI, NIH, FDA, industry, investigators, and patients all have a role to play in defining an effective mechanism for the development of targeted cancer therapies.
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Presen tation to the Institute of Medicine Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, July 22, 2009, Washington, DC. Arbab, A
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Presentation to the Institute of Medicine Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, April 23, 2009, Washington, DC. Conti, P
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Presentation to the Institute of Medicine Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, July 22, 2009, Washington, DC. Evelhoch, J., M
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Presentation to the Institute of Medicine Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, April 23, 2009, Washington, DC. Hanahan, D., and R.A.
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2007. The role of cooperative groups in cancer clinical trials.
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Presentation to the Institute of Medicine Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, July 22, 2009, Washington, DC. Sargent, D
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2008b. The use of genomics in clinical trial design.
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Presentation at the Conference on Clinical Cancer Research, Engelberg Center for Health Care Reform of the Brookings Institution and Friends of Cancer Research, September 14, 2009. Zakian, K
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