2
The Science of Developing Cancer Therapy

A revolution is under way in the development of cancer therapy. Over the past decade, personalized medicine has leveraged scientific advancements in fields such as genomics,1 proteomics,2 molecular biology,3 and metabolomics4 to improve the extent to which medical care is tailored to the individual patient and his or her cancer. 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). As a result, many patients undergo costly treatments and endure the side effects of those treatments without deriving any benefit. Patients also experience an opportunity cost, as an alternative treatment that might be more effective for a patient’s particular disease is delayed or forgone. Better tools are therefore needed to reduce the time and costs wasted by delivering ineffective and toxic treatments. Future treatment decisions will depend on the use of tissue biomarkers5 that can predict outcomes of therapy. By using these

1

Genomics is the study of the complete genetic material, including genes and their functions, of an organism.

2

Proteomics is the study of the structure and function of proteins, including the way they work and interact with each other inside cells.

3

Molecular biology is the branch of biology that deals with the formation, structure, and function of macromolecules essential to life, such as nucleic acids and proteins.

4

Metabolomics is the systematic study of the unique chemical fingerprints that specific cellular processes leave behind; that is, small-molecule metabolites.

5

A biomarker is defined as any biological characteristic that can be objectively measured and evaluated as an indicator of a normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention.



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2 The Science of Developing Cancer Therapy A revolution is under way in the development of cancer therapy. Over the past decade, personalized medicine has leveraged scientific advance- ments in fields such as genomics,1 proteomics,2 molecular biology,3 and metabolomics4 to improve the extent to which medical care is tailored to the individual patient and his or her cancer. 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). As a result, many patients undergo costly treatments and endure the side effects of those treatments without deriving any benefit. Patients also experience an opportunity cost, as an alternative treatment that might be more effec- tive for a patient’s particular disease is delayed or forgone. Better tools are therefore needed to reduce the time and costs wasted by delivering ineffec- tive and toxic treatments. Future treatment decisions will depend on the use of tissue biomarkers5 that can predict outcomes of therapy. By using these 1 Genomics is the study of the complete genetic material, including genes and their functions, of an organism. 2 Proteomics is the study of the structure and function of proteins, including the way they work and interact with each other inside cells. 3 Molecular biology is the branch of biology that deals with the formation, structure, and function of macromolecules essential to life, such as nucleic acids and proteins. 4 Metabolomics is the systematic study of the unique chemical fingerprints that specific cel- lular processes leave behind; that is, small-molecule metabolites. 5 A biomarker is defined as any biological characteristic that can be objectively measured and evaluated as an indicator of a normal biological process, pathogenic process, or pharmacologi- cal response to a therapeutic intervention. 

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM new methods, it will be increasingly possible to group individual cancers into subpopulations with similar characteristics to predict patient outcomes for cancer therapies. That will help to ensure that the treatments prescribed for patients will be more effective. Rising health care costs, the increasing availability of new therapies, and the promise of delivering more effective care make it more important than ever to advance the science underlying personalized medicine (PCAST, 2008). Identifying those subpopulations that are likely to respond to thera- pies can improve and hasten the success rate for the development of new treatments (PCAST, 2008). Being able to predict the therapeutic response and, therefore, being able to deliver safer and more effective treatments to patients will reduce the number of adverse drug events and thus provide cost savings to the entire health care system. Advances in personalized medicine are rooted in the discovery, vali- dation, and qualification of biomarkers that can be measured by in vitro diagnostic tests on samples from patients or through in vivo biomedical imaging. For example, cancer biomarkers can be used to develop and deliver improved patient care by predicting the likelihood of the response to treatment or the likelihood that an adverse reaction to the treatment will develop (IOM, 2007). Examples of biomarkers routinely used in the treat- ment of cancer are shown in Table 2-1. Most diagnostics that are in use today assess a single target; however, it is widely believed that as technologies in genomics, proteomics, metabo- lomics, and molecular profiling mature, diagnostic platforms capable of simultaneously examining a large number of potential markers will improve the predictive powers of these tests (IOM, 2007). For example, the cost of DNA sequencing is continually decreasing with advances in sequencing technologies, making it more feasible to identify the gene defects underlying a particular type of cancer. These technological advancements could dra- matically change how cancer is diagnosed and treated (Niederhuber, 2009). 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) Estrogen receptor Breast Trastuzumab HER-2 Breast Imatinib mesylate BCR-ALB Leukemia Cetuximab and panitumumab KRAS Colorectal Irinotecan UGT1A1 Colorectal

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 THE SCIENCE OF DEVELOPING CANCER THERAPy including large-scale genome sequencing, the Cancer Genome Atlas Project6 aims to catalog the pertinent genetic changes that occur in many types of cancer and identify new potential therapeutic targets. The technologies used to conduct molecular analyses of tissue embed- ded in paraffin have also improved dramatically, enabling the large-scale genomic profiling of messenger RNA, the DNA copy number, and focused analysis of mutations on small tissue samples. For example, a recent study demonstrated the feasibility of profiling the expression of all the genes in the entire genome using formalin-fixed, paraffin-embedded tissues. Expres- sion of more than 6,000 genes was assessed in tissues from patients with hepatocellular carcinoma, and 90 percent of the samples tested (including some that had been archived for many years) yielded data of high quality (Hoshida et al., 2008). 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 differ- ent 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. These are generally located in group-affiliated academic medical or cancer cen- ters. All the Cooperative Groups’ biorepositories use standard operating procedures, but because these repositories were developed to fit the needs of the individual Cooperative Groups, the structure, methods, governance, and access policies differ among the Groups. The Group Banking Steering Committee, which includes representatives from each of the 10 Cooperative Groups and NCI, aims to address many of these issues by improving and harmonizing operations of the Cooperative Group biobanks and by coor- dinating banking activities among Groups conducting phase III and large phase II clinical trials. Five subcommittees are set up to focus on specific issues (Best Practices and Operations, Informatics, Access and Marketing, Regulatory, and Technology Development). Most of the biological speci- mens collected from Cooperative Group trials are formalin-fixed, paraffin- 6 The Cancer Genome Atlas Project is jointly sponsored by the National Cancer Institute and the National Human Genome Research Institute. 7 Samples of material, such as tissue, cells, urine, blood, DNA, RNA, and protein that are associated with clinical information, such as type of therapy and patient outcome. 8 Correlative science is a general term referring to research done on biospecimens that are collected during clinical trials.

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0 A NATIONAL CANCER CLINICAL TRIALS SySTEM embedded tumor tissue, but some frozen tissue and body fluid specimens are also collected (Hamilton, 2009). Because the Cooperative Groups collect specimens under the auspices of a clinical trial, one of their major strengths is that the pathological data and the clinical data for the specimens are linked, making it feasible to conduct retrospective analyses of the clinical and nonclinical factors that influence prognosis and survival. In addition, information on long-term clinical outcomes is often available (Schilsky et al., 2002). Historically, much of the correlative science performed by the Coop- erative Groups focused on the development of prognostic markers (i.e., biomarkers that can predict the progression of disease in the absence of treatment considerations). In recent years, greater emphasis has been placed on identifying predictive markers (i.e., markers that can identify popula- tions that are likely to be sensitive or resistant to specific treatments). Some Cooperative Groups have conducted clinical trials designed to validate the clinical utility of a biomarker, although one (the Marker Validation for Erlotinib in Lung Cancer [MARVEL] trial of lung cancer) was recently dis- continued because of a lack of accrual.9 Lastly, some groups have ongoing efforts in pharmacogenetics to correlate variations in germline DNA with treatment-related toxicity.10 From 2000 to 2008, that work has resulted in 1,350 publications and 36 patents (Hamilton, 2009). The work of the Cooperative Groups has also been instrumental in developing some of the cancer biomarker tests in common use in the clinic (see also Chapter 1). For example, the Cancer and Leukemia Group B (CALGB) Leukemia Correlative Science Committee has a long history (25 years) of conducting key correlative studies of adult leukemia. That group initially focused on the use of immunophenotyping for the diagnosis and prognosis of acute leukemia but has more recently focused on the clinical use of cytogenetic and molecular genetic markers in acute and chronic forms of leukemia. The work of that group has had a major impact on the way clinicians currently diagnose leukemia in adults, predict the outcome, select the appropriate treatment, document complete remission, and moni- tor residual disease (Bloomfield et al., 2006). Another example of a widely used biomarker test resulting from the efforts of a Cooperative Group is the Oncotype DX breast cancer assay. 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. 10 Personal communication, Richard Schilsky, University of Chicago, July 28, 2009.

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1 THE SCIENCE OF DEVELOPING CANCER THERAPy or without radiation. Although additional chemotherapy benefits less than 5 percent of patients with ER positive lymph node negative breast cancers, chemotherapy adds significant toxicity, so a predictive biomarker test to guide the treatment decision has long been sought. The development of the Oncotype DX breast cancer assay, which measures the expression of 21 genes to predict the likelihood of disease recurrence for women with ER- positive and lymph node-negative breast cancer, would not have been pos- sible without the work of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Cooperative Group. NSABP collected and preserved tissue samples collected in the 1990s to test the benefits of treating breast cancer with chemotherapy. Subsequently, those samples were used for the retro- spective clinical validation of the Oncotype DX assay (Wickerham et al., 2008). The results of those retrospective studies showed that the Oncotype DX assay could predict the likelihood of breast cancer recurrence (Paik et al., 2004, 2006). As a result, in the United States today, many ER-positive breast cancer tumors are being tested by use of the Oncotype DX assay (or another multi-gene assay known as Mammaprint11), and use of such tests can reduce the rate of chemotherapy use by at least 20 percent (Hayes, 2009). By sparing many women from needless exposure to chemotherapy, the cost savings attained through the use of this test are also substantial (Lyman et al., 2007). Cooperative Group studies were also instrumental in achieving Food and Drug Administration (FDA) approval for the PathVysion test, which detects amplification of the gene for human epidermal growth factor recep- tor 2 (HER-2) and is used to select therapies for patients with breast cancer (Mauer et al., 2007). At present, the Cooperative Groups are actively participating in more than 25 studies of biomarkers (Hamilton, 2009) in five different cate- gories: (1) correlative studies that use clinically annotated biospecimens and research assays; (2) retrospective-prospective studies that use clini- cally annotated biospecimens, known clinical outcomes, and analytically validated assays; (3) prospective biomarker-drug codevelopment studies; (4) prospective biomarker development studies; and (5) prospective bio- marker validation studies (Schilsky, 2009; see also the section on trial design). 11 The Mammaprint test is another assay that assesses a breast tumor’s genetic signature and is used to predict the likelihood of the recurrence of ER-positive lymph node-negative breast cancer. The test, which has FDA approval, uses a dichotomous algorithm based on the expression of 70 genes in freshly prepared tissues.

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM CHALLENGES IN bIOMARkER DEvELOPMENT The process for the discovery and validation of predictive biomarkers is complex. Only about 20 cancer biomarkers have been approved by FDA, and many of these are not routinely used in clinical practice (IOM, 2008). Taking discoveries of potential biomarkers from the laboratory to routine use in clinical care entails multiple steps that require substantial resources and include a multitude of complex scientific and regulatory challenges. Although hypotheses about putative biomarkers are often generated pre- clinically, true biomarker assessment and validation occur during clinical development and require large numbers of patients who have been treated uniformly in randomized trials. Investigators must show that the biomarker is correlated with a specific biological function, outcome, or characteristic, and they must validate its clinical utility by demonstrating that it provides useful information that can effectively inform clinical decisions by study- ing large numbers of patients who have been treated uniformly. They must also develop an assay that measures the biomarker and demonstrate that it can reliably be used to guide treatment. An increasing number of candidate markers are being identified and are in various stages of development, yet validation and clinical qualification of these markers is not progressing nearly as rapidly. Advances in information technology and molecular research have enabled large retrospective correlative studies linking clinical data to molec- ular data, but a number of obstacles stand in the way of effectively lever- aging 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 correla- tive 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. Poor-quality biospecimens can generate data that are of poor quality or nonreproducible (Compton, 2009). Selection of a therapy on the basis of the results of a diagnostic test performed with a poor- quality biological specimen could result in patients receiving therapies that are unlikely to be beneficial or not receiving therapies that are likely to be beneficial. The lack of consistent standards for biospecimen collection and storage is an impediment to improving the quality of those specimens. Maintaining the biological integrity of biospecimens outside of their natural environment is complex, specimens can easily be damaged, and there are many variables

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 THE SCIENCE OF DEVELOPING CANCER THERAPy in the collection and storage of specimens (Compton, 2009). In addition, a lack of complete annotation of the biospecimens can create challenges for researchers. The information that a scientist has regarding the characteris- tics of a biospecimen and the patient from whom it was collected can affect the groupings, the analysis, or the conclusions drawn from the data. Within a collaborative group, there may be well-established standards for its biorepositories, and some programs funded by NCI, such as the Cancer Genome Atlas, have stringent standards for biorepositories. How- ever, the cancer community and NCI currently lack uniform standards for the collection, processing, and storage of biospecimens; the collection and annotation of the associated data; and consents that govern their use. These obstacles compromise the molecular research that is dependent on biospecimens and impedes the progress of personalized cancer treatment (Compton, 2009). NCI has launched some initiatives to improve the quality and consis- tency of biorepositories. In 2007, NCI released the final version of NCI Best Practices for Biospecimen Resources. That document defines state- of-the-science practices, promotes biospecimen and data quality, empha- sizes access, recognizes the interest of research participants, and supports adherence to legal and ethical rules and guidelines. However, the current NCI Best Practices do not comprise detailed laboratory procedures; rather, they consist of principles by which such procedures should be developed by biospecimen custodians. The document also does not tackle the cost of recovery or transfer of the samples and does not address custodial rights or sample access policies (NCI, 2007a). The ability to conduct good correlative science is affected by policies regarding access, governance, and documentation; contractual agreements with commercial partners; extensive review systems for sample use; and complex administrative interactions and oversight (Hamilton, 2009). Hun- dreds of organizations throughout the United States store tissue samples, and among those organizations, the policies on these issues vary widely (Eiseman and Haga, 1999). One challenge entails patient consent and authorization for the dis- closure of protected health information. 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 Coop- erative Groups to re-contact the patients who provided them to obtain consent and authorization12 (Hamilton, 2009), or to seek permission from 12 Currently, the Privacy Rule, promulgated under the Health Insurance Portability and Accountability Act, does not allow patients to authorize the use of protected health informa- tion for future research. All authorizations must include a “description of each purpose of the requested use or disclosure” (45 C.F.R. § 164.508(b)(4)).

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM an institutional review board (IRB) to use the samples without consent and authorization. The stewards of biological specimens have competing interests regard- ing who owns them, how they are used, and who will benefit from them. Policies regarding ownership and access vary by institution, and this impedes progress. As a result, the means of access to biospecimens for research is inconsistent and can entail complex negotiations with the vari - ous custodians of the samples. Pharmaceutical companies, in particular, may be reluctant to share patient samples with academic collaborators and may require agreements regarding intellectual property rights that are unacceptable to collaborators. Many hospitals also discard clinical samples after a period of time, so valuable resources are lost to research. According to NCI, a custodianship plan should consider how the integrity of the biospecimens and their associated data are maintained and moni- tored; how the rules of access and distribution of biospecimen are defined; what values and responsibilities the biospecimen resource has in place; what legacy or contingency plan, if any, the biospecimen resource has in place; and what circumstances, if any, allow the withdrawal or transfer of biospecimens (NCI, 2008). 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. Thus, the committee recommends that NCI mandate the submission of annotated biospeci- mens to high-quality, standardized central biorepositories when samples are collected from patients in the course of Cooperative Group trials. The accompanying clinical data should be reported on standardized forms, and NCI should establish a national inventory of biological samples held in the central repositories. NCI should also have a defined process for access to biospecimens for research that includes a single scientific peer review linked to funding. All data, including biomarker data from sera, tissues, and biological imaging analyses, should be considered precompetitive and unencumbered by intellectual property restrictions and should be made widely available. This approach would be similar to current practice in the cancer genomics field.13 13 See http://ocg.cancer.gov/.

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 THE SCIENCE OF DEVELOPING CANCER THERAPy Lack of Funding for biomarker Development Within the Cooperative Group Program There is a growing need for correlative and translational studies that use biospecimen banks, but the funding stream for these studies is inad- equate and complex. Funding to support the Cooperative Groups’ biore- positories and correlative science studies is cobbled together from a variety of sources, including the Group’s core U10 grant,14 a U24 grant,15 users’ fees; and other grants, contracts, and institutional commitments. Investiga- tors need a better mechanism to cover the considerable cost of maintaining these important resources. Furthermore, current NCI policies require that research studies that propose to use specimens collected from intergroup protocols undergo scientific review by a scientific steering committee before the specimens are made available. However, such a review is not linked to funding, and thus, investigators often must seek funding through other mechanisms or from other sources. This process creates many review loops, time delays, and significant double jeopardy, in that each proposal requires at least two scientific reviews (each of which involves many people), one to receive specimens and one to receive funding, that are conducted at different times by different review groups. A consistent and adequate funding source, with appropriate peer review, devoted to biomarker studies that use stored samples is imperative. Broader use of high-quality samples from standard- ized repositories would speed the pace of scientific and clinical advances, at a much lower expense than would be required if new samples must be col- lected for the study of each new concept. Thus, the committee recommends that NCI implement new funding mechanisms and policies to support the management and use of Cooperative Group biorepositories for retrospec- tive correlative science. The Cancer Genome Atlas Project provides a model and precedent for the development and adoption of such policies. The increased cost of including biomarker tests within trials is also sub- stantial and is not well funded. As discussed in Chapter 3, NCI has taken some initial steps to address this need. Nevertheless, the committee recom- mends 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. Although the cost of studying and validating biomarkers is high, the funds are well spent if the effectiveness of therapy is improved and futile therapy can be avoided. Despite the relatively high cost of performing the Mammaprint or Oncotype DX assay (~$4,000), 14 A cooperative agreement from NCI to support the operations and infrastructure of the cooperative group. 15 A resource-related research project cooperative agreement, used to support improvements in resources that serve biomedical research.

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM for example, the cost of chemotherapy is far greater (~$50,000); if only 5 percent of patients assessed by the test would benefit from chemotherapy, then many patients will be spared significant toxicity unaccompanied by any benefit (Hayes, 2009). 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. How- ever, unlike the strategy used for drug development, which has clearly defined preclinical, nonclinical, and clinical milestones accompanied by guidance on how each phase should be conducted, the strategy for bio- marker development is significantly less well defined (IOM, 2007; Simon, 2008a). FDA has issued extensive regulatory guidance and procedures to guide drug development, whereas regulatory guidance and procedures for biomarker development are generally lacking. To date, in fact, there are no clear standards for biomarker validation, use, performance, or interpreta- tion (IOM, 2007). In an effort to improve the efficiency of biomarker development, mul- tiple organizations have developed guidelines and proposed standards for various steps in biomarker development (IOM, 2007). For example, in 2007, NCI released a document titled Performance Standards Reporting Requirements for Essential Assays in Clinical Trials for biomarker assays used in Phase II and III clinical trials (NCI, 2007b). Concept proposals and clinical protocols for Phase II and III trials that use such assays must also include standard operating procedures for the proper collection, prepara- tion, handling, and shipping of clinical biospecimens (NCI, 2007b). In addition, several of the Cooperative Groups, such as CALGB, have taken initiatives to standardize methodologies, interpretation of the results, and reporting of the results to ensure accuracy, uniformity, and the completeness of the data set (Compton, 2006). This ad hoc and piecemeal approach, however, is not ideal, because the processes and rules used for such things as determining the composition of a standard-setting committee and the voting rules for the members of the committee are being reinvented on a case-by-case basis. This can lead to heterogeneous results and delays. A systematic, multidisciplinary, and dynamic approach fostered by the National Institutes of Health (NIH) and NCI would ensure that unified national standards are rapidly and consis- tently set as the need arises. Thus, the committee recommends that NCI, in cooperation with other agencies, establish a consistent, dynamic process to oversee the development of national unified standards, as needed, for oncology research. This process should use the input of experts in both subject matter and standards design in the development of standards, and

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 THE SCIENCE OF DEVELOPING CANCER THERAPy it should replicate successful aspects of standards development by other standard-setting bodies, both governmental and nongovernmental (e.g., the American Society for Testing and Materials, the National Standards Foun- dation, National Institute for Standards and Technology, the International Organization for Standardization, and professional societies). NCI could further assist by facilitating the creation of systems and software to aid the process of standards dissemination and implementation. This proposal builds on a past IOM recommendation that “government agencies (e.g., NIH, FDA, CMS, and the National Institute for Standards and Technology) and nongovernment stakeholders (e.g., academia, the pharmaceutical and diagnostics industry, and health care payors) should work together to develop a transparent process for creating well-defined consensus standards and guidelines for biomarker development, validation, qualification, and use to reduce the uncertainty in the process of develop- ment and adoption” (IOM, 2007). uncertain Relevance of Primary Tissue for Patients with Metastatic Disease Tissue samples from tumor biopsies are generally collected and archived at the time of an initial diagnosis and most often consist of primary tumor specimens. Metastatic or recurrent lesions are biopsied much less frequently. With the move toward targeted and personalized therapy, however, ques- tions about whether the primary tumor is representative of the patient’s metastatic disease have arisen, especially in the context of intervening therapy. It is unclear whether primary archived tissue provides biomarker data relevant to predicting the therapeutic response for metastatic cancer or whether another biopsy is required to obtain an accurate and relevant biomarker assessment. It may not be feasible or desirable to ask patients with cancer to undergo multiple invasive procedures to assess recurrent or metastatic disease. 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. Most cancers are not fatal unless they become metastatic, so these questions need to be answered to maximize the effectiveness of cancer therapies. The development of new trial concepts and the provision of funding to compare the molecular pathologies of primary and metastatic tumor tissues and to determine whether it is valid to use archived primary tissue for the selection of therapy for metastatic disease would be helpful. This could be the topic of a Grand Challenge competition, as recommended in Chapter 3.

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110 A NATIONAL CANCER CLINICAL TRIALS SySTEM policies to support the management and use of those resources for retro- spective correlative science. For example, all data, including biomarker data from serum, tissue, and imaging analyses should be considered precom- petitive, unencumbered by intellectual property restrictions, and be made widely available. NCI should also establish a national inventory of samples held in the central repositories and have a defined process for access by researchers that includes a single scientific peer review linked to funding. In addition, clinical data accompanying biospecimens should be reported using standardized forms. High levels of evidence are needed to validate and qualify biomarkers for specific uses, and current funding is inadequate to support the research needed to generate that evidence. The availability of a consistent and adequate funding source devoted to correlative studies with stored samples and with appropriate peer review that includes direct input from the group that collected the samples is imperative. The broader use of high-quality, standardized repositories would speed the pace of scientific and clinical advances at a much lower expense than would be required if new clinical samples had to be collected to study each new concept. The creation of a national inventory of samples held by the Cooperative Groups would also greatly facilitate important research in correlative science. 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. The committee recommends that the Cooperative Groups lead the development and assessment of innovative designs for clinical trials that evaluate cancer therapeutics and biomarkers (including combinations of therapies). The development and use of innovative trial designs could speed prog- ress in clinical trials in numerous ways. For example, prospective clinical trial designs that randomize patients on the basis of biomarkers or treat- ments, or both, should be explored and evaluated. For targeted therapies, a predictive hypothesis for a biomarker should be put forward in the pre- clinical phase and tested in early-phase clinical trials (Phase I and II trials). Better Phase II trial designs are needed to more accurately assess which patients benefit from a particular therapy, and thus guide the decisions about whether to move into Phase III trials. Improved designs for Phase III trials, which are the most costly and lengthy trials and entail the majority of Cooperative Group trials, could lead to faster, more accurate conclu- sions about new therapeutics and in the process reduce costs and conserve resources. For example, recent innovations, such as the use of adaptive

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111 THE SCIENCE OF DEVELOPING CANCER THERAPy designs for Phase II trials that assess response endpoints during trial accrual in real time, suggest that relevant clinical questions might be addressed more efficiently, with fewer patients required, with less time needed to show differences between groups, and with enhanced confidence in the clinically (and statistically) meaningful differences that are observed between groups. These or related designs may be particularly amenable for the comparison of treatment effects in patients with different biomarker profiles and could hasten the identification of the most promising predictive biomarkers that could be validated in a Phase III trial setting. As new scientific methods and technologies develop and mature, stan- dards are needed to ensure appropriate and consistent use. However, when new methods or technologies are incorporated into clinical trials, standards to ensure that the results collected at the various trial sites are consistent enough to attain accurate and meaningful conclusions from a study are often lacking. The current approach to standards development is often ad hoc, with the processes and rules for such things as committee composition and voting rules being reinvented on a case-by-case basis. This can lead to heterogeneous and delayed results. Thus, NCI, in cooperation with other agencies, should establish a consistent, dynamic process to oversee the development of national unified standards as needed for oncology research. This process should be used by NCI when standards are required for any important new technology, tool, or breakthrough method (e.g., biomedical imaging and other biomarkers and biospecimens) and should replicate successful aspects of standards development by other standard-setting bodies, both governmental and non- governmental (e.g., the American Society for Testing and Materials, the National Standards Foundation, the National Institute for Standards and Technology, the International Organization for Standardization, and pro- fessional societies). This process should utilize the input of experts in both subject matter and standards design in developing standards and include consistent operating procedures for developing standards (e.g., representa- tion of stakeholders in committee composition, decision making, and voting rules). The resulting standards should be published and updated in a timely manner so that they are useful for the conduct of clinical trials. A more systematic, multidisciplinary, and dynamic approach to standards develop- ment fostered by NIH and NCI would be advantageous for the rapid and consistent setting of unified national standards as the need arises. NCI could further assist by facilitating the creation of systems and software to aid the process of standards implementation. This need for standards will become increasingly important as the sci- ence 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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112 A NATIONAL CANCER CLINICAL TRIALS SySTEM both those in current use and those under development, have the potential to provide information that can aid drug development and clinical deci- sion making by providing improved means of diagnosis and monitoring. However, the lack of standards for image acquisition and quantification of results compromises the validity of the results and the interpretation of those results. In addition, the lack of harmonization of methods among the different vendors of imaging equipment compromises the quality and consistency of results. The consistent development of standard method- ologies for established tumor-imaging modalities (e.g., computed tomogra- phy, fluorodeoxyglucose positron emission tomography, and conventional magnetic resonance imaging) by expert panels, along with a requirement that manufacturers meet those standards, could significantly improve the accuracy and value of those tests. Validation standards are also needed to continuously evaluate novel imaging methods and modalities to determine their merit and appropriate use. Similarly, expert panels are needed to establish validation and qualifica- tion standards for the development and use of in vitro biomarker tests, to ensure that the results of those tests are consistent and accurate, and for the appropriate interpretation and use of those results. Such standards could also inform FDA guidance for the codevelopment of diagnostic-therapeutic combinations or for the inclusion of a biomarker test on the label for a drug or biologic that is already FDA approved. Continued progress in the development and incorporation of innova- tive 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. Effective collaboration among stakeholders will be particularly important for combination therapies, which may hold the key to successful personalized medicine because most cancers have multiple abnormalities. Companies may be reluctant to work with competitors to test promising combinations at an early and risky stage of development. To date, most combinations tested in Phase III trials have involved at least one agent currently approved by FDA. In addition, the steps needed and the data required to bring target therapies and combinations of products are not well defined. Issues relevant to effective collaboration are addressed in more detail in chapter 3. REFERENCES Adjei, A. A., M. Christian, and P. Ivy. 2009. Novel designs and end point for phase II clinical trials. Clinical Cancer Research 15(6):1866–1872. Akins, E. J., and P. Dubey. 2008. Noninvasive imaging of cell-mediated therapy for treatment of cancer. Journal of Nuclear Medicine 49(Suppl. 2):180S–195S.

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