that will develop consensus-based recommendations for moving the field of cancer clinical trials forward. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus views of workshop participants or members of the National Cancer Policy Forum.

NEW CLINICAL TRIAL DESIGNS

Phase 0 Trials

The first session of the workshop was on new clinical trial designs. Dr. David Jacobson-Kram of the FDA began this session by giving his overview of the exploratory investigational new drug study and how it differs from the traditional IND study. The main purpose of the exploratory IND is to assess the likely therapeutic effectiveness of a compound, based on whether it affects its target in people and how long it is active in the body. An exploratory IND study tests a new experimental drug on human subjects prior to a Phase I clinical trial, which is the first traditional test of a compound in humans to assess safety and the dosing of subsequent trials. For that reason, the exploratory IND study is also called a Phase 0 trial.2 Dr. Jacobson-Kram discussed the current problems in drug development and testing and how various types of exploratory IND studies might help assuage some of those problems.

As Dr. Jacobson-Kram noted, we currently face a crisis in drug development with the number of drugs in the pipeline declining, the number of drug failures increasing, and the costs of developing drugs rising. The FDA finds that less than 20 percent of new molecular entities progress through clinical trials to the point where approval for them is sought so they can enter the market as drugs. Currently about half of drugs in Phase III clinical trials fail because of toxicity or a lack of efficacy, Dr. Jacobson-Kram reported using FDA data. “That is really a disaster, because by the time you are in a Phase III trial you have invested an enormous amount of money, resources, and time,” he said. The cost of developing a new molecular entity that makes it to the market is estimated to be nearly a billion dollars.

2

To receive FDA approval for market, most drugs have to undergo three phases of clinical testing. Phase I testing determines safety and dose on a small number of individuals. Phase II testing is done on a larger group of volunteers to assess safety and effectiveness. If those tests are promising, a large-scale Phase III is usually done to confirm safety and effectiveness.



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 WORKSHOP SUMMARY that will develop consensus-based recommendations for moving the field of cancer clinical trials forward. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus views of workshop participants or members of the National Cancer Policy Forum. NEW CLINICAL TRIAL DESIGNS Phase 0 Trials The first session of the workshop was on new clinical trial designs. Dr. David Jacobson-Kram of the FDA began this session by giving his overview of the exploratory investigational new drug study and how it dif- fers from the traditional IND study. The main purpose of the exploratory IND is to assess the likely therapeutic effectiveness of a compound, based on whether it affects its target in people and how long it is active in the body. An exploratory IND study tests a new experimental drug on human subjects prior to a Phase I clinical trial, which is the first traditional test of a compound in humans to assess safety and the dosing of subsequent trials. For that reason, the exploratory IND study is also called a Phase 0 trial.2 Dr. Jacobson-Kram discussed the current problems in drug development and testing and how various types of exploratory IND studies might help assuage some of those problems. As Dr. Jacobson-Kram noted, we currently face a crisis in drug develop- ment with the number of drugs in the pipeline declining, the number of drug failures increasing, and the costs of developing drugs rising. The FDA finds that less than 20 percent of new molecular entities progress through clinical trials to the point where approval for them is sought so they can enter the market as drugs. Currently about half of drugs in Phase III clini- cal trials fail because of toxicity or a lack of efficacy, Dr. Jacobson-Kram reported using FDA data. “That is really a disaster, because by the time you are in a Phase III trial you have invested an enormous amount of money, resources, and time,” he said. The cost of developing a new molecular entity that makes it to the market is estimated to be nearly a billion dollars. 2To receive FDA approval for market, most drugs have to undergo three phases of clini- cal testing. Phase I testing determines safety and dose on a small number of individuals. Phase II testing is done on a larger group of volunteers to assess safety and effectiveness. If those tests are promising, a large-scale Phase III is usually done to confirm safety and effectiveness.

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS To help abate this crisis in drug development, the FDA published its guidance on exploratory INDs in January 2006. According to this guidance, the goals of an exploratory IND are to • gain an understanding of the drug’s mechanism of action and whether it affects a target relevant to a disease process (pharmacodynamics), • provide information on how the drug is broken down by the body and how long it remains active (pharmacokinetics), • indicate the most promising lead product from a group of candi- date drugs designed to interact with a particular therapeutic target, and/or • reveal where the drug is distributed in the body using various imag- ing technologies. An exploratory IND study is done in a very small number of human subjects, with dosing up to 7 days, and is not designed to be therapeutic or assess the effectiveness of the experimental drug. “This is really important to keep in mind,” said Dr. Jacobson-Kram. “These trials are not designed to treat patients. These are simply experiments that are being done in human beings.” The FDA’s existing regulations are flexible in the amount of preclinical data it requires investigators to submit before conducting an exploratory IND. That data depends on the goals of the investigation, the testing being proposed, and the expected risks. For example, an exploratory IND that tests a single subpharmacologic drug dose would require a minimal data- set from a single animal species. More extensive data would be needed to conduct a repeated-dose clinical study designed to induce pharmacologic effects, but this expanded dataset would still be less than that required to initiate a traditional IND. Exploratory INDs allow sponsors to evaluate up to five experimental drugs simultaneously in the clinic so as to better choose the most promis- ing drug candidate to undergo traditional drug development and test- ing. Exploratory INDs can help to reduce the resources involved in drug development, including the amount of time and drug product needed to select promising drugs, and help to eliminate those that lack promise. The FDA guidance gives examples of several types of exploratory IND studies, including the microdose study, a study design developed by Pharmaceuti- cal Research and Manufacturers of America (PhRMA), and a study design

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 WORKSHOP SUMMARY proposed by the National Cancer Institute (NCI) to specifically study experimental cancer drugs. The sole aim of a microdose study is to use imaging or other means to assess where in the body a compound is distributed and for how long it remains in these sites. A microdose is defined as less than 1/100th of the dose calculated to yield pharmacological effects, and less than 100 micro- grams. A microdose study is designed not to induce pharmacologic effects; rather, it can indicate whether an experimental drug reaches its target. The FDA assumes the risks of a microdose study are small and thus only requires a single study in a mammalian species, usually a rat, to assess safety prior to granting approval for a microdose exploratory IND study. The animals in this preclinical study would only have to be dosed a single time via the same route of administration that investigators would use in the exploratory IND study. The animal study must show a minimally toxic dose or show that the doses used in the microdose study would be well outside a toxic range. Genetic toxicology testing on the animals is not routinely needed. (The European Medicines Agency, in contrast, asks for additional safety data, including general toxicity studies using two ways of administering the compound, orally and intravenously, as well as in vitro genotoxicity studies.) Another example of an exploratory IND study is the paradigm pro- posed to the FDA in 2004 by PhRMA. This study tests, in healthy sub- jects or minimally ill patients, up to five compounds that have a common biological target, but might not be structurally related. These compounds are given in up to seven repeated doses to assess pharmacological response, but not a maximum tolerated dose, as is determined in traditional Phase I studies. The risks in the PhRMA paradigm are greater than in the microdose study, so it requires genetic toxicity studies, as well as a repeated-dose toxic- ity study in rodents and another mammal, usually a dog. If the dog shows toxicity at a dose level that does not cause toxicity in the rat, the compound is not included in the exploratory IND, under the assumption that its toxic- ity had not been adequately evaluated to be tested in humans. PhRMA used a database of 106 drugs tested in two species and in Phase I clinical trials to support the safety of its proposed exploratory IND using an analysis that assumed certain starting and stopping doses. That analysis revealed the trials would have been safe under the exploratory IND paradigm. In a presentation to the FDA, PhRMA discussed the advantages of its proposed exploratory IND versus a traditional IND (Table 1). The exploratory IND would accelerate discovery and development of new drugs,

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS TABLE 1 Comparison of the PhRMA Exploratory IND and the Conventional IND Conventional IND PhRMA Exploratory IND Active Pharmaceutical • 1–3 kg • 10–300 g Ingredient (API) Preclinical Resources • 9–12 studies • 5–6 studies • 220 rodent and 38 • 170 rodent and 6 non-rodent non-rodent • 9–18 months • 3–6 months Benefits • Full toxicology • Predictable API profile requirement • Escalation to • Faster progression to maximum tolerated clinical trials dose (MTD) in • Capability to evaluate clinical trials candidates based on • Progression directly target activity to Phase II • Better development decisions made more quickly • Early and less costly attrition Disadvantages • Larger quantity of • MTD not established API • Potential delayed • Slower decisions progression to Phase II • Late and costly attrition SOURCE: Jacobson-Kram presentation (October 4, 2007). PhRMA claimed, because it would require a smaller number of animal studies that would take about one-third less time to perform using much less of the tested active ingredient of the drug. There would be a significant savings in non-rodent experimental animals, Dr. Jacobson-Kram pointed out. In addition, the exploratory IND would enable better development decisions to be made more quickly so there is early and less costly attrition of drugs that lack promise. This innovative IND would also give sponsors the ability to evaluate drug candidates based on target activity, and should enable faster progression to clinical trials. The only disadvantages cited for the exploratory IND were that it did not determine the maximum toler-

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 WORKSHOP SUMMARY ated dose and thus could potentially delay the progression to Phase II trials, which entails closing the exploratory IND and opening a new, traditional IND, with the standard requirements for toxicology. The FDA used its own data to analyze clinical studies that were pre- ceded by 2-week or 4-week toxicology studies in two animal species and found that the PhRMA paradigm succeeded in identifying safe starting and stopping doses, but in many cases, the dogs or monkeys had lower no- observed-adverse-effect levels. In addition, an analysis of NCI data found that the toxicology data from the nonrodent species more closely resembled what is seen in humans than the data from rodents (Tomaszewski, 2004). “What this is saying is, at least for some cases, the dog better predicts the maximum tolerated dose in the clinical trial, so the exploratory IND might not be then as viable an option,” said Dr. Jacobson-Kram. He noted that the NCI developed its own version of an exploratory IND for oncology drugs. For what the agency termed “first-in-man” stud- ies, researchers should aim to assess the blood levels of the drug needed to induce the desired effect, instead of focusing on toxicity and basing doses for future studies on such toxicology findings. The NCI exploratory IND is used to select promising drugs for life-threatening diseases, primarily cancers, with up to 3 days of dosing in the clinic. Participants for these tests are terminally ill patients without therapeutic options; but because there is no therapeutic intent in the studies, the safety bar is the same as it would be for healthy volunteers. “The thinking is if you are just doing an experiment, why would you make sick people sicker?” said Dr. Jacobson-Kram. In a later presentation, Dr. James Doroshow of NCI added that researchers need to address the ethical issues linked to an exploratory IND by consulting with their research oversight committees, Institutional Review Boards, to develop a process to obtain the appropriate informed consent from patient volun- teers in these studies. According to Dr. Doroshow, because the exploratory IND is not considered therapy, participation in a Phase 0 trial should not preclude patient volunteers from then proceeding immediately to another clinical trial; the usual 3- to 4-week period between studies is not required in these cases. Despite these various Phase 0 study options, the FDA has received only a handful of exploratory INDs, Dr. Jacobson-Kram reported (although it was added later during the discussion that the agency’s recordkeeping of this may not be complete). “Although PhRMA was very excited about this pos- sibility, in the 2 years that this tool has been available it has been used very sparingly,” he said. He offered several reasons for why exploratory INDs are

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS not being done more often by drug sponsors, including the slowness of the established drug industry to adopt a new paradigm and the potential that microdose studies do not accurately predict what is likely to be seen with doses in the therapeutic range. But perhaps the biggest stumbling block to more widespread use of an exploratory IND, according to Dr. Jacobson- Kram, is excessive optimism on the part of a drug development team. “No development team thinks that their drug is a loser. So they don’t want to use a tool that is going to kill their drug early, because they are convinced it is going to be a winner,” he said. In the discussion that followed Dr. Jacobson-Kram’s presentation, participants voiced more reasons for hesitancy to adopt exploratory INDs. Oncology researcher Dr. Giulio Draetta of Merck noted that although the exploratory IND is an excellent concept that he and his colleagues welcome, “no established clinical oncologist inside or outside the company would think of these Phase 0 trials as being important for reaching a go or no-go decision about a drug,” he said, implying that more knowledge is needed for such a decision. Dr. Jacobson-Kram countered that exploratory INDs offer more than decisions on whether to move a drug forward in the clinical testing hierar- chy. “With the current paradigm, from the tens of thousands of different structures you synthesize every day, you only take one into the clinic, and that is a big decision. But if you could take a handful of them in people and find the one that looks the most promising, based on clinical data, I think you have a much better chance of succeeding than just choosing that single one based on preclinical data,” he said. Another participant from Merck, Dr. John Wagner, concurred with Dr. Draetta that all of Merck’s exploratory INDs have been in oncology, and asked what can be done to improve the usefulness of an exploratory IND for oncology purposes. Dr. George Mills, who, when he was at the FDA, helped develop the agency’s guidance on exploratory INDs, responded by stressing the usefulness of an exploratory IND that uses imaging to determine which drug in a pool of candidates is the most promising. “All drugs will be promis- ing at some level,” he said. Further, Dr. Mills commented that clarification of which drug to focus on and thus accelerate the decision-making process for the group of drug candidates comes when rates and routes of clearances and target and non-target organ distribution are analyzed. Dr. Jerry Collins of NCI added that another advantage of the exploratory IND is that “it is an open invitation to a dialogue with the FDA.” He added that an exploratory IND reduces the number of toxicology studies needed, which is a distinct

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 WORKSHOP SUMMARY advantage for academic researchers, many of whom lack the expertise or resources to conduct such testing. Dr. Jacobson-Kram summed up his talk by stressing the FDA’s commitment to improving the “critical path” to new medical products and sees the implementation of exploratory INDs as an important means for carrying out that commitment. Dr. Mills, Vice President of Perceptive Informatics, Inc., expanded on some of the points Dr. Jacobson-Kram made, but narrowed the focus of his talk to the use of molecular imaging and linked nanotechnology techniques in exploratory INDs. He noted that small pharmaceutical companies and biotechnology companies developing biologic drugs are particularly keen on using exploratory INDs that employ imaging because this approach literally enables investors to visualize the likely effectiveness of a potential drug com- pound by showing if it hits targets such as tumors, abscesses, or the amyloid plaques in Alzheimer disease patients, and whether it is relatively absent in the liver, kidney, or other organs where it could pose toxicity problems (Figure 1). “These companies have limited amounts of funds and need rapid proof-of-concept for the investment community,” Dr. Mills said. “You can take an image and show it to the investment banking industry person, who doesn’t understand our world, but understands from the image that this drug does go to colorectal cancer and the other ones don’t.” But particularly for oncology applications, it is not sufficient for a drug to just reach its target and be concentrated there. Its effectiveness or toxicity also depends on its duration in the target tissues as well as other parts or the body. An exploratory IND that uses imaging can show this effectively, he said. Radiation dosimetry studies can reveal rates and routes of clearance much more quickly and simply than the standard techniques used to determine these endpoints in Phase I studies, he claimed. After his presentation, audience participant Dr. Tim McCarthy from Pfizer pointed out that although an exploratory IND that uses imaging can reveal distribu- tion data to compare compounds, it does not provide information about specificity of the target. Dr. Mills responded that he expected new software and perhaps combination products that might provide that specificity information in the future. Dr. Mills added that the reduction in pharmacology and toxicology studies that an exploratory IND offers, especially one with an imaging component, is another incentive to drug companies. Many companies, he said, have several preclinically developed drug candidates, but are unwill- ing or unable to devote the financial resources to do the pharmacology and toxicology studies needed to take them to the next step. “The exploratory

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0 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS FIGURE 1 Whole-body biodistribution imaging. Time points 1, 2, and 3 show a radio- labeled bio-distribution study of a therapeutic agent as it targets an abdominal tumor. Time point 1 shows no tumor localization in the mid-abdomen; time point 2 shows localization in the abdomen; and time point 3 demonstrates routine clearance of the labeled agent from the body. Brightness of signal corresponds to density of therapeutic agent. SOURCE: Mills presentation (October 4, 2007).

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 WORKSHOP SUMMARY IND allows those products to come off the shelf and come into human experience to be able to determine if they are going to be promising,” he said. A pre-IND development teleconference with the FDA can determine the exploratory IND’s minimum pharmacology, toxicology, chemistry, and manufacturing and control information needed for all products evaluated, Dr. Mills said. Dr. Mills also stressed the advantages of being able to make simultane- ous comparative assessments of competitive drug compounds in a single study. Drug developers can also do imaging studies to see how new drug compounds compare to standard therapies. Those that do not perform bet- ter than the standard treatment, in terms of distribution and persistence in various regions of the body, are not developed further. He pointed out that sequential assessments of competitive drug compounds can also be done with a series of exploratory INDs so that the first to perform adequately moves on to Phase I trials, and no further testing is done on other similar compounds. Smaller drug companies tend to pursue this vertical approach to Phase 0 testing because it is more cost- and time-effective than the hori- zontal approach where compounds are compared simultaneously, Dr. Mills said (Figure 2). Exploratory INDs can also address the concern recently raised by those pursuing nanotechnology that, when particle size is changed, the potential safety profile is changed as well. “With an exploratory IND, you can do comparative imaging to determine if particle size change will alter the distribution. It is very straightforward and immediate,” he said. Some companies are developing nanoparticles to carry both a therapeutic and an imaging marker, he added. Dr. Mills summarized his talk by concluding, “Exploratory INDs that use imaging can, in 5, 10, or 15 subjects, effectively let you make those business decisions that are so necessary and cost-effective in drug development.” Dr. Mills’ talk was followed by a presentation on how best to use Phase 0 clinical trials in cancer drug development, given by Dr. James Doroshow of the NCI. Dr. Doroshow discussed the recent shift in cancer drug devel- opment from traditional cytotoxic chemotherapies for cancers to drugs that act on specific molecular signaling targets. This shift has created a need early on in drug development for reliable and sensitive tests that reveal if the drug is affecting its target, as well as confirmation of this in people before initiating large clinical trials to assess the drug’s effectiveness. Phase 0 studies can address that need and establish standard operating procedures

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS 1 2 3 4 Horizontal Portfolio Analysis 1 2 3 4 Vertical Portfolio Analysis FIGURE 2 Exploratory IND assessment schemes of competitive drug compounds. The horizontal portfolio analysis assesses biodistribution of drug compounds simultaneously, regardless of performance and cost. The vertical portfolio analysis is a sequential, “top- down” assessment. In other words, “the first to perform, wins”; this is a cost-effective and time-effective approach. In the figure, 1–4 represent exploratory INDs dependent on chemistry, manufacturing, and controls (CMC) and pharmacology/toxicology. SOURCE: Mills presentation (October 4,Figure 22007). needed to appropriately gather data in subsequent clinical studies, according to Dr. Doroshow. Researchers can also use findings from Phase 0 studies to closer approximate a safe, but potentially effective starting dose and limit the patient tissue sampling required in subsequent trials. “These are experiments that need to be performed to allow you to adequately inform the clinical trial, and even though they are not hypothesis driven, they are critical to the process,” he said. Dr. Doroshow pointed out that, for tests of a drug’s effectiveness on tumor cells (or surrogate markers in the blood), clinical researchers often

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 WORKSHOP SUMMARY do not concern themselves with accurately duplicating in people how those samples were acquired and processed in animals for the same tests. But vari- ability in these standard operating procedures (SOPs) can affect the accuracy of the tests in clinical trials. Dr. Doroshow advocated using an exploratory IND to fine-tune SOPs for human subjects and create the appropriate bridge between what is done preclinically to what is done clinically. Dr. Doroshow gave an example of an exploratory IND he and his col- leagues conducted on the ability of a drug to inhibit the activity of the DNA repair enzyme poly(ADP-ribose) polymerase, known as PARP, in tumors, and how long that inhibition lasted. Before conducting this study, the researchers developed a sensitive test for PARP inhibition in tumor tissues and determined the SOPs for tissue removal, processing, and testing that were followed in the animal studies. “We tried to model the entire clini- cal experiment in a mouse—we had a veterinarian pretend that she was a radiologist and handle all the tissues the same way they would be handled in people,” Dr. Doroshow said later in response to a question posed by an audience participant. The exploratory IND study was done on only 13 patients, yet it gave the investigators the information needed to consider how best to combine the experimental drug with other cancer drugs in future clinical trials. Dr. Doroshow said this information was acquired much more quickly than in a traditional IND study that determines the maximum tolerated dose, yet lacks information on how long the drug affects its target. Dr. Doroshow pointed out that Phase 0 studies, such as the example he gave, are best done on targeted drugs with a fairly wide therapeutic index, as opposed to traditional toxic chemotherapy drugs that have a much narrower range of doses in which they can be safely used. He also noted that his enthusiasm for conducting such studies would be dampened for experimental drugs that lack an accurate and reliable test for the drugs’ effects on targets. “If you are going to go to the trouble of trying to do a proof-of-principle study, there has to be a principle to prove.” He also reiterated the importance of researchers using Phase 0 studies to fine-tune their methods in people prior to progressing to large clinical trials. “It makes sense to take a small number of patients, ask them to volunteer, and to evaluate and develop your methodology prior to using them on a broader scale,” he said. Much of the discussion that followed the Phase 0 presentations focused on how to fund exploratory IND studies. Dr. Richard Schilsky of the University of Chicago pointed out that the Phase 0 study example that

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 WORKSHOP SUMMARY RAB25 Aberration frequency ZNF217 14-3-3σ CCND1 FGFR1 MDM2 ERBB2 S6K MYC FIGURE 6 Recurrent copy number aberrations in breast cancer. Ten to fifteen percent of the transcriptome/proteome is deregulated by recurrent aberrations. Functional studies support the concept that many of these contribute to cancer pathophysiology. A: Frequencies of genome copy number gain and loss plotted as a function of genome location. Vertical lines indicate chromosome boundaries, and vertical dashed lines indi- cate centromere locations. Positive and negative values indicate frequencies of tumors showing copy number increases and decreases, respectively. B: Frequencies of tumors Figure 6 showing high-level amplification. Data are displayed as described in A. ACRONYMS: 14-3-3σ (SFN, stratifin), CCND1 (cyclin D1), ERBB2 (v-erb-b2 eryth- roblastic leukemia viral oncogene homolog), FGFR1 (fibroblast growth factor receptor 1), MDM2 (transformed 3T3 cell double minute 2), MYC (v-myc myelocytomatosis viral oncogene homolog), RAB25 (member RAS oncogene family), S6K (ribosomal protein S6 kinase), ZNF217 (zinc finger protein 217). SOURCE: Gray presentation (October 4, 2007), reprinted from Cancer Cell, Volume 10, Chin, K., S. DeVries, J. Fridlyand, P.T. Spellman, R. Roydasgupta, W.-L. Kuo, A. Lapuk, R.M. Neve, Z. Qian, T. Ryder, F. Chen, H. Feiler, T. Tokuyasu, C. Kingsley, S. Dairkee, Z. Meng, K. Chew, D. Pinkel, A. Jain, B.M. Ljung, L. Esserman, D.G. Albertson, F.M. Waldman, and J.W. Gray, Genomic and transcriptional aberrations linked to breast cancer pathophysiologies, pp. 529-541, Copyright 2006, with permission from Elsevier. receptor, which the drug Herceptin targets, is activated farther upstream. But even when ErbB2 is overexpressed, downstream genes are activated to different degrees in different tumors, according to Dr. Gray’s slide of gene expression in three different breast cancers (Figure 7). “We have to under- stand how these ancillary aberrations, co-acting with the target, condition response,” Dr. Gray said. Fortunately, recent large-scale “omics” technologies that enable simulta- neous assessment of all expressed genes or proteins with automated devices

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0 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS FIGURE 7 Aberration combinations in the same pathway vary considerably among tumors—even in subsets having the same therapeutic target. ACRONYMS: 14-3-3σ (SFN, stratifin), CCND1 (cyclin D1), ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog), MDM2 (transformed 3T3 cell double minute 2), MYC (v-myc myelocytomatosis viral oncogene homolog), RAB25 (member RAS oncogene family), S6K (ribosomal protein S6 kinase), ZNF217 (zinc finger protein 217). SOURCE: Gray presentation (October 4, 2007). can reveal telltale molecular patterns relevant to specific cancers and how they are likely to respond to various targeted treatments. This information can be used to identify markers that indicate which drug combinations are most likely to be effective for individual cancer patients. But these markers are not usually available until late in the drug development process, so they are not often used to guide early trials or to prioritize which drug combina- tions should be tested preclinically based on the likelihood that they will have synergistic effects. Adding to the complexity is the fact that there are about 100 FDA- approved cancer drugs and more than 400 experimental cancer drugs in Phase II or III trials. The target specificities for most of these drugs are not well known, Dr. Gray pointed out, and clinical tests of these agents are not coordinated or guided by biomarkers. Unfortunately, the cost of molecularly characterizing all available cancer drugs and their effects on genes known to play a role in cancers would be enormous.

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31 WORKSHOP SUMMARY Another approach that Dr. Gray’s consortium and others are taking is to develop preclinical models for the molecular heterogeneity found in tumors that can be used to determine which drug combinations are the best to test clinically and which patients are likely to respond to these treat- ments. He and his colleagues have collected and characterized about 50 breast cancer cell lines that have enough molecular diversity to enable the detection of molecular abnormalities linked to response. These cell lines also seem to adequately mirror clinical findings. For example, the cell lines have the same patterns of gene expression (genetic signatures) that are seen in primary tumors (Figure 8). Even when the cell lines are broken down by type of breast cancer (e.g., luminal versus basal), they closely mimic the gene expression of the primary tumors for each type. Consortium investigators are using these cell lines to test large numbers of drug combinations in an automated fashion. Researchers can currently 1 3 5 7 9 11 13 15 17 19 21 x 1.0 Cell lines Frequency 0.0 -1.0 1.0 Primary tumors Frequency 0.0 -1.0 1 3 5 7 9 11 13 15 17 19 21 x Distance Along Genome FIGURE 8 Cell lines retain the recurrent genomic characteristics of primary tumors. A and B: Frequencies of significant increases or decreases in genome copy number are plotted as a function of genome location for 51 cell lines (A) and 145 primary tumors (B). Positive values indicate frequencies of samples showing copy number increases [Log2(copy number) > 0.3], and negative values indicate frequencies of samples showing fig 8 copy number decreases [Log2(copy number) < −0.3]. SouRCE: Gray presentation (october 4, 2007), reprinted from Cancer Cell, Volume 10, Neve, R.M., K. Chin, J. Fridlyand, J. Yeh, F.L. Baehner, T. Fevr, L. Clark, N. Bayani, J.-P. Coppe, F. Tong, T. Speed, P.T. Spellman, S. DeVries, A. Lapuk, N.J. Wang, W.-L. Kuo, J.L. Stilwell, D. Pinkel, D.G. Albertson, F.M. Waldman, F. McCormick, R.B. Dickson, M.D. Johnson, M. Lippman, S. Ethier, A. Gazdar, and J.W. Gray, A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes, pp. 515-527, Copyright 2006, with permission from Elsevier.

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS test hundreds of drugs and drug combinations simultaneously, and expect to use improved automation techniques to eventually boost such simultane- ous testing to as many as 10,000 drugs or drug combinations. This testing has already revealed various cancer drugs’ target specificities. For example, an AKT inhibitor appears to affect genes abnormally activated in luminal tumors, but not basal tumors. Some of these findings have been confirmed in clinical studies. For example, tests of lapatinib indicated it would only be effective in tumors that overexpress or phosphorylate ErbB2, and this was shown to be true when the drug was tested clinically (Di Leo et al., 2007). Dr. Gray’s studies have also revealed basic information about cancer pathways that will help to optimize targeted cancer treatments. There are two parallel molecular pathways relevant to breast cancer that are activated when ErbB2 is activated—the AKT pathway and the Raf-MAP kinase path- way (Figure 9). Research on the breast cancer cell lines reveals that luminal cancers have an activated Raf-MAP kinase pathway, whereas basal tumors have an activated AKT pathway. This suggests that using drug combina- tions that block the primary pathway activated by a mutation as well as the alternate “bypass” pathway could be effective. Dr. Gray summarized the strength of this modeling approach by point- ing out that cell lines can be characterized in exhaustive molecular detail, unlike patients or their tumor samples, and automated testing techniques can quickly indicate the most effective drug combinations to test clinically. In addition, the mechanism of action of an experimental drug can be easily assessed. For example, if it appears that the AKT pathway is important to a drug’s effects, it can be tested by altering the activity of that pathway in a cell line and seeing if it correspondingly affects the drug’s activity. The in vitro studies can also reveal promising new targets. Researchers have identified only about 20 percent of the genes in the abnormally duplicated regions of the breast cancer cell lines, Dr. Gray said in the discussion following his presentation. The main weakness of his cell line model is that more cell lines, including resistant cell lines, are needed to more completely represent the molecular heterogeneity of breast cancer. In addition, better modeling of the in vivo microenvironment is needed, and some culture-specific aberra- tions may accumulate over time such that the cell lines eventually may not adequately mimic what is seen clinically. Despite that potential problem, Dr. Gray is “fairly confident that this is at least a way forward of helping us

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 WORKSHOP SUMMARY GFR RAS IRS1 Luminal RAF PI3Kp85 PI3Kp110 Basal PTEN Torc1 Mek Rictor PDK1 PDK2/mTOR erk AKT PKA LKB1 TSC2 AMPK ATP AMP TSC1 Glucose Rheb Amino Acids Torc1 mTOR Autophagy Raptor p27 Cell cycle S6K 4-EBP Motility Apoptosis S6 eI4FE FIGURE 9 Basal and luminal tumors may use different parts of the growth factor sig- naling network. Drug combinations can be selected to block activating mutations and alternate bypass pathways. The signaling pathways shown impact cell motility, growth, and survival. ACRONYMS: 4-EBP (translational repressor eukaryotic initiation factor 4E-binding Figure 9 protein), AKT (v-akt murine thymoma viral oncogene homolog), AMP (Adenosine Monophosphate), AMPK (AMP-Activated Protein Kinase), ATP (adenosine triphosphate), eI4FE (messenger RNA 5-cap binding protein), erk (extracellular-signal-regulated kinase), GFR (Rap guanine nucleotide exchange factor 5), IRS1 (insulin receptor substrate 1), LKB1 (serine/threonine kinase), Mek (mitogen-activated protein kinase), mTor (Mammalian target of rapamycin), p27 (SSSCA1, Sjögren syndrome/scleroderma autoantigen 1), PDK1 (pyruvate dehydrogenase kinase, isozyme 1), PDK2/mTOR (pyruvate dehydrogenase kinase, isozyme 2), pI3kp110 (phosphatidylinositol 3-Kinase p110 subunit), pI3kp85 (Phosphatidylinositol 3-Kinase p85 subunit), PKA (Protein Kinase A), PTEN (phosphatase and tensin homolog), RAF (a protein kinase), raptor (regulatory associated protein of mTOR), RAS (GTP-activated protein involved in cell growth regulation), Rheb (Ras homolog enriched in brain), rictor (rapamycin-insensitive companion of mTOR), s6 (ribosomal protein involved in translation), Torc1 (Target of rapamycin complex 1), TSC1 (tuberous sclerosis 1), TSC2 (tuberous sclerosis 2). SOURCE: Gray presentation (October 4, 2007); pathways courtesy of Gordon Mills.

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS to prioritize these drugs and drug combinations for introduction into the clinic,” he said. In addition to using cell line models to indicate the most optimal drug combinations to test clinically, researchers can use them to select in vitro response biomarkers that are likely to work in a clinical setting. According to Dr. Gray, ideally, a clinically useful in vitro biomarker would be a genome aberration whose detection does not vary with culture condi- tion. The marker should also be the same in both the cell cultures and the primary tumors. Dr. Gray gives higher priority to transcriptional markers than to protein markers because the former are currently easier to measure, although he acknowledged that genomic markers won’t necessarily inform the biology as well as protein markers. Thus both approaches are ultimately needed. Dr. Gray and his colleagues are currently pursuing an innovative marker-intensive clinical trial of breast cancer treatment that uses a series of core breast biopsies and magnetic resonance imaging (MRI) to determine before-and-during-treatment responses, and the effectiveness of markers in predicting such responses. “We think this is a reasonable way of taking the drugs and markers that come out of our in vitro system and quickly evalu- ating them just for general efficacy in the neoadjuvant environment. Then for those things that seem to be behaving the way that we expect them to, we will introduce them into a later phase clinical trial to assess long-term outcome,” Dr. Gray said. This approach should lead to more efficient clinical trials, he noted, because the early trials would target patient subpopulations most likely to respond, and would be less likely to miss drugs effective against small subpopulations. The model system would also provide a rationale for use of drug combinations that may not show independent efficacy. In addition, patients would be more likely to participate in such trials because they would be given treatments tailored to be effective against their specific type of cancer. The end results would be lower costs due to testing in patients more likely to respond first, and increased patient participation. Trials that have a primary focus on biomarker development would also provide mate- rial to assess not just target response, but the presence of other molecular aberrations that affect treatment effectiveness, including those that contrib- ute to the development of resistance. In a discussion following Dr. Gray’s presentation, Dr. Roy Herbst from MD Anderson Cancer Center asked Dr. Gray about the role that animal models might play in modeling molecular heterogeneity to enhance multi-

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 WORKSHOP SUMMARY drug clinical trial designs. Dr. Gray responded that the cell line model is just the first stage in the process, but that animal models can provide informa- tion that cell lines lack. “What our studies do is identify interacting aber- rations that look like they condition response to drugs. But we will never get to the point in vitro where we model all of the nuances of the micro- environment, so the next logical step is to go into the mouse models and complement it there,” he said. He added that the NCI’s Mouse Models of Human Cancers Consortium6 is developing a robust set of models that are genetically engineered to have many of the same molecular abnormalities linked to cancer progression or response to treatment that are seen in cell lines. (Dr. Anderson also discussed how to model the microenvironment in his presentation, which is summarized below.) Another discussant, patient advocate Kathy Needham, raised the ques- tion of whether cancers should be grouped according to their underlying genetic abnormalities rather than by the type of organ in which they occur when assessing drug effectiveness. Dr. Gray noted that the genetic abnor- malities in ovarian, prostate, and breast cancer are remarkably similar. But he added that the molecular conditioning abnormalities that affect response to treatment differ by organ site and tumor subtype. “So you have to pay attention to both. Clearly people are already pursuing targets, not organ types. But it is by organ site that the drugs get introduced into the clinic,” he said. Dr. Dancey added that although there hasn’t been a test case yet, the NCI has developed new clinical trial designs that enroll patients according to the molecular abnormalities in their tumors and not necessarily by where the tumors appear. Discussant Dr. Steven Shak from Genomic Health then raised the issue that solid tumors often have tens of thousands of mutations, prob- ably many of which are silent or biologically insignificant. But the large number of mutations makes it difficult to discern those mutations that do play a major role in the tumor. “Yes, there are a lot of mutations out there,” Dr. Gray responded, “but they tend not to be recurrent. What we need to do is identify the ones that are recurrently present.” He noted a recent journal article from researchers at Johns Hopkins University in which they catalogued mutations in 13,000 genes in breast and colorectal cancer. The researchers narrowed this list down to a few hundred genes that might be candidates for mutations that play an important role in the progression of these cancers (Sjöblom et al., 2006). 6See http://emice.nci.nih.gov/emice/MMHCC/mmhcc_organization.

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS Preclinical Model Systems The discussion was followed by a presentation on translation from preclinical model systems to the bedside (and back) in multiple myeloma by Dr. Kenneth Anderson of the Dana-Farber Cancer Institute at the Harvard Medical School. Dr. Anderson developed laboratory models for myeloma that researchers used to predict the effectiveness of several new cancer therapies, most of which are now FDA-approved and widely used in the treatment of myeloma. The thrust of his talk was that researchers can use preclinical modeling to collect the information needed to choose which drugs should be developed and to design clinical trials for those drugs. Although this concept was explored by previous speakers, Dr. Anderson went a step further by showing how best to model the tissue microenviron- ment in which myeloma tumors form so as to gather more clinically relevant information from preclinical studies. This microenvironment determines the expression of the genes that foster myeloma tumors or enable their resistance to treatment. “If one is going to make a preclinical model of cancer that is valid, one needs very strongly to reflect the microenviron- ment,” he said. Because of the recent extraordinary explosion of genetic findings, Dr. Anderson said, myeloma is now classified into seven groups based on the genes expressed in the tumors. Although researchers have detected hundreds of genes that are abnormally expressed in such tumors, studies to systemati- cally assess the effects of overexpression or deletion of these genes reveal a much smaller number of genes believed to play a major role in myeloma. But additional genes that strongly affect survival or metastasis of the tumor, or its resistance to treatment, are only expressed when myeloma cancer cells attach to particular bone marrow cells called stromal cells. Such attachment requires specific adhesion molecules. Some of the genes activated by attach- ment to the bone marrow stromal cells trigger the activity of a complex of proteins in the cells called proteasomes. By breaking down key proteins, proteasomes block normal cell death and enable cancer cells to live for a long time and actively divide. This understanding of the microenvironment of myeloma tumors explains why a proteasome inhibitor drug such as bortezomib is more effec- tive against myeloma cells with the preserved microenvironment of bone marrow stromal cells and adhesion molecules than in cell lines that lack this crucial microenvironment, Dr. Anderson pointed out. The microenviron- ment also explains why conventional myeloma therapies are not effective:

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 WORKSHOP SUMMARY they are susceptible to cell adhesion-mediated drug resistance. “So testing the drug in the microenvironment is critical,” Dr. Anderson said. Dr. Anderson and his colleagues have developed both in vitro and ani- mal models that mimic the microenvironment of myeloma tumors. In their in vitro models, myeloma cell lines or patient tumor cells are bound to bone marrow stromal cells grown in the laboratory. They also have in vivo mouse models, including a mouse with a transplanted human bone chip in which fluorescent human myeloma cells have been injected. Researchers use this model to test drugs and assess the genes that confer resistance or sensitiv- ity to them, and how well that correlates with what is found from in vitro studies. “It is critical to look and see whether what you have proposed and observed qualitatively in vitro is reflected in vivo,” Dr. Anderson said. He also noted that the interplay between laboratory and clinical stud- ies can be bidirectional. For example, his genomic studies in patients with myeloma revealed a gene, XBP-1, which is overexpressed in all the patients. He used this finding to develop a mouse model in which the mice are genetically engineered to overexpress XBP-1 and have bone destruction and other features similar to that seen in patients with myeloma. “This is a genetic model of multiple myeloma which came from an observation made in patients by the new genomics,” he said. “We always think of bench-to- bedside research, but we can do it the other way around.” Dr. Anderson and his colleagues have used their preclinical models to screen many classes of drugs. They found that some drugs target the tumor and the microenvironment, while others target just one or the other. But whatever the mechanism, a drug must cause tumor cell death, even when the tumor is bound to the bone marrow stromal cells, in order to proceed further in the drug development and testing pathway. These studies led to four highly effective drugs receiving FDA approval in the past 3 years for the treatment of multiple myeloma, as well as several promising experimental drugs currently in clinical trials (Figure 10). Two of the approved drugs, bortezomib7 and lenalidomide,8 when used along with a steroid drug or, in the case of bortezomib, a steroid drug and various chemotherapy agents, 7Bortezomib (Velcade) received accelerated FDA approval as a single agent for relapsed, refractory multiple myeloma in 2003 (see http://www.fda.gov/bbs/topics/NEWS/2003/ NEW00905.html). 8FDA granted approval in 2006 to lenalidomide (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma who have received one prior therapy (see http://www.fda.gov/cder/Offices/OODP/whatsnew/lenalidomide.htm).

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 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS Targeting Multiple Targeting Multiple Myloma Cell and Myloma Cell Bone Marrow Milieu IGF-1 inhibitors, CD40 Ab, Bortezomib, NPI0052, 17-AAG, PK11195, Smac Thalidomide, Revlimid, mimetics, Telomestatin, SAHA,Tubacin, CHIR 258, Rad 001 PTK787, Perifosine Bone Marrow stromal cells Targeting Bone Marrow Milieu IKK inhibitors, defibrotide p38MAPK inhibitors FIGURE 10 Novel agents targeting multiple myeloma (MM) cells and/or the bone marrow microenvironment. ACRONYMS: 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin), CD40 ab (antibody to the CD40 integral membrane protein), CHIR258 (Tyrosine Kinase Inhibitor), IGF-1 (Insulin-like growth factor 1), IKK (conserved helix-loop-helix ubiquitous kinase), NPI0052 (proteasome inhibitor), p38 MAPK (mitogen activated protein kinase 14), PK11195 (peripheral benzodiazepine receptor (PBR) ligand), figure 10 PTK787 (multi-VEGF receptor inhibitor), Rad001 (serine-threonine kinase inhibitor of mTOR), SAHA (Suberoylanilide hydroxamic acid), Smac (Second mitochondria- derived activator of caspase). SOURCE: Anderson presentation (October 4, 2007). each produce remarkable and unprecedented response rates of 80 to 90 percent in newly diagnosed myeloma patients and about a 50 percent complete or near-complete response rate in some studies. Both bortezomib and lenalidomide take advantage of and overcome the growth, survival, and drug resistance potential that is conferred by the microenvironment,

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 WORKSHOP SUMMARY Dr. Anderson noted. His preclinical models led to the bench-to-bedside development of lenalidomide in just 6 years—about half the typical amount of time needed for such development. Researchers also used Dr. Anderson’s preclinical models to determine the appropriate design of subsequent generations of myeloma drugs. Find- ings on the main proteasome activities that affect tumor cell growth and spread in the microenvironment led to the creation of a new type of pro- teasome inhibitor, NP10052, which inhibits a wider range of proteasome activities than bortezomib. Animal studies showed that about two-thirds of mice treated with NP10052 survived bortezomib-resistant myeloma, whereas all untreated mice died within 100 days. The drug is currently being tested in the clinic. “This drug came from preclinical lab and animal models that showed it was more effective to use broader inhibition of pro- teasome activities,” Dr. Anderson said. Dr. Anderson ended his talk by showing how his preclinical models help researchers discern which drugs to combine and how to test their combinations clinically. For example, these models revealed that proteasome inhibitors interfered with the ability of cultured myeloma cells to repair their DNA. This led the FDA to approve the use of the DNA-damaging agent doxorubicin combined with the proteasome inhibitor bortezomib for the treatment of multiple myeloma.9 Doxorubicin is not FDA approved as a single agent for myeloma, Dr. Anderson noted, but its combination with bortezomib extended time to progression by about 3 months, and increased the response rate and overall survival, one clinical study found. “This com- bination would not have gone forward if it were not for preclinical model- ing, which showed that this inhibitor of the proteasome has another feature inhibiting DNA repair,” he said. “The explosion in genetics and the ability to study the biology better than we have ever had before allows us to target the tumor directly, but as I hope we have illustrated for you, indirectly as well,” Dr. Anderson concluded. The kinds of genetic studies that have been mentioned and the modeling that I have stressed not only define targets, but also define and inform the design of clinical trials.” This new paradigm targeting the tumor cell in its microenvironment has great promise not only to change the natural history of multiple myeloma, but also to serve as a model for 9 Approved in May 2007. See http://www.cancer.gov/cancertopics/druginfo/ fda-doxorubicin-HCL-liposome.