10

Wrapping Up

Given the complexity of cancer and the mounting evidence that targeted cancer treatments and cancer immunotherapies are likely to have stronger and more long-lasting effects when combined makes it imperative to develop greater collaborations among industry, academia, and government in the development of combination investigational cancer therapies. During the course of the workshop, participants offered numerous suggestions for how to facilitate such collaboration.

In the preclinical arena, participants suggested more effort and funding to develop animal models in which to test investigational drug combinations and their mechanisms of action and pharmacokinetics, as well as resistance mechanisms. These animal models could entail tumor explants or be genetically engineered to develop tumors with the molecular defects commonly seen in human tumors. Surrogate efficacy models can be used to assess the effects of combinations of immunotherapies, which cannot be tested in standard explant models. Alternatively, researchers could create animal versions of the immunotherapies that have been developed, and test them in animals with intact immune systems. Tumor cell lines could also be grown in different microenvironments to see how they affect agents and their targets, and more effort should be made to grow tumor cell lines in three-dimensional culture situations. “There are multiple models, and we still don’t know what is the best model to use to determine which combinations to go forward with,” summarized Dr. Hohneker.

There could be more interplay between the bench and the bedside,



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10 Wrapping Up Given the complexity of cancer and the mounting evidence that tar- geted cancer treatments and cancer immunotherapies are likely to have stronger and more long-lasting effects when combined makes it impera - tive to develop greater collaborations among industry, academia, and government in the development of combination investigational cancer therapies. During the course of the workshop, participants offered numer- ous suggestions for how to facilitate such collaboration. In the preclinical arena, participants suggested more effort and fund- ing to develop animal models in which to test investigational drug combi- nations and their mechanisms of action and pharmacokinetics, as well as resistance mechanisms. These animal models could entail tumor explants or be genetically engineered to develop tumors with the molecular defects commonly seen in human tumors. Surrogate efficacy models can be used to assess the effects of combinations of immunotherapies, which cannot be tested in standard explant models. Alternatively, researchers could create animal versions of the immunotherapies that have been devel- oped, and test them in animals with intact immune systems. Tumor cell lines could also be grown in different microenvironments to see how they affect agents and their targets, and more effort should be made to grow tumor cell lines in three-dimensional culture situations. “There are multiple models, and we still don’t know what is the best model to use to determine which combinations to go forward with,” summarized Dr. Hohneker. There could be more interplay between the bench and the bedside, 73

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74 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES participants suggested. Researchers could use animal models to suggest which combinations of agents would be most effective at countering the specific molecular defects in patients’ tumors. If clinical testing of such combinations cause toxicity or resistance, the same combinations could be retested in animal models to assess better dosing, scheduling, or the molecular resistance mechanisms and what other agents might counter them. Studies of biopsies collected from patients with tumor progression could also point toward more effective combinations of agents. Several participants pointed out the need for higher standards for both preclinical and clinical effectiveness. Tumor shrinkage is likely to be a better endpoint in laboratory studies than blocking tumors from forming or from growing, whereas overall survival is likely to be a better endpoint than time to progression in clinical studies, they argued. Given the numerous possible combinations and limited number of patients and other resources, there has to be some prioritization of what combinations should be tested clinically. Suggestions for prioritizing included testing only those combinations that: • erform well and consistently in several xenograft models; P • Have a biological mechanism for which there is an assay; • ave demonstrated adequate pharmacokinetics and some evi- H dence of activity or target engagement at clinically relevant doses and exposures; • re composed of the best in each class of agents that are pharma- A cologically compatible; and • ave validated biomarkers for patient selection and pharmacodynamics. H Some participants cautioned that effective combinations should not be judged on the basis of the single-agent activity of their components, as many combinations have been found to be effective even though stud- ies of the single agents did not show significant effects. There also was concern about the additive, synergistic, or unexpected toxicities that can result from combinations, particularly those that target the same pathways. Researchers need to explore more creative innovations in the approach to dosing and scheduling to avoid toxicity and improve efficacy, several participants suggested. Agents could be used intermittently or sequenced in a manner that makes sense from a biological, mechanistic perspective. To aid both preclinical and clinical investigations, more basic informa- tion could be gathered on genetic expression, and feedback and network responses to signaling perturbations and DNA damage. Some participants stressed that information is also needed on the non-genetic effects that influence treatment, including the microenvironment of the tumor, the

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75 WRAPPING UP host immune response, and proteins made by the tumor and surround - ing cells. In the clinical arena, there was enthusiasm for using adaptive trial designs to determine the best combinations and dosing strategies, and to assess patient selection biomarkers as the trial progresses. “Adaptive trial designs may really facilitate the ability to screen for drugs,” Dr. Hohneker summed up. Several participants suggested repeat biopsies of patient tumors to assess effectiveness and confirm mechanism of action of inves - tigational agents. Assessing the maximum tolerated doses of all the drugs used in combination may not be meaningful or appropriate, especially for combinations that employ immunotherapies. But researchers should have enough sampling points so they can model the dose–response curve. Several participants suggested that different cancer patient advocate groups join together to encourage the same specific goals, particularly because such advocacy proved highly valuable in fostering rapid devel- opment of effective treatments for HIV infection. Patient advocates could be helpful in putting pressure on companies and institutions to work more collaboratively, have quicker IRB reviews, and share patient speci- mens. Advocates can also work with investigators to assess and promote the clinical testing of priority combinations. Mutual education between advocates and scientists can be helpful in furthering progress. Companies could communicate more about their compounds in pre - clinical development and join forces when they do not individually have all the agents needed for an effective combination in their portfolios, and other companies can supply the missing agents. Compelling those col- laborations will be the “good science” underlying them, Dr. Hohneker said. “If the data are there, people will work together. I don’t think you’ll find much resistance to good science.” More efforts should be made to collect patient specimens during clini- cal trials, and store and make these tissues available for future research on biomarkers, several participants noted. The development, validation, and use of biomarkers for patient selection and treatment effectiveness will be key to the success of cancer combination therapies. Easier access to study drugs would also be helpful. Safe harbors for companies and institutions, such as FNIH and the CEO Roundtable on Cancer Life Sciences Consor- tium, have proven helpful in negotiating collaborations and managing the patents and other intellectual property rights that result from such collaborations. A safe harbor to distribute study drugs to investigators, or to do preliminary clinical testing of combinations, might substantially further development of combination cancer therapies, many participants stressed. Within the regulatory arena, FDA recognizes the importance of com- bination therapies for cancers and is currently revising its guidelines on the combination of investigational therapies and codevelopment of

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76 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES a diagnostic with a therapeutic. The agency has indicated that it wants to be flexible in what is required of sponsors, and will sometimes accept preclinical data instead of extensive clinical testing of drug combinations. FDA welcomes pre-IND consultations, especially for innovative study designs. “We still will have to show the contribution of the agents, but the encouraging part is that how we do that is something that can be discussed,” as Dr. Hohneker pointed out. More effort should be made to make FDA regulations compatible with EMA regulations so as to foster global drug development, some participants suggested. To help tackle some of the other complex legal issues linked to devel - oping combination therapies, such as IP and indemnification, there could be more reliance on NERFs and the development of standard clauses and core principles to make legal negotiations more expedient. Identifying key decision makers, who are knowledgeable about the legal issues, can also be helpful in legal negotiations. Antitrust issues are not likely to pose barriers to collaborations among companies, particularly if they will not limit competition; if the collaborators do not already have entrenched products; if the collaboration is limited to core research efforts; and if it is possible to show benefits that the collaboration will achieve that could not be achieved as easily on an independent basis. It is possible to obtain prior guidance with the FTC or the DOJ about antitrust issues. Antitrust lawyers can also advise research and development efforts. There are several examples of collaborations in the early development as well as the clinical testing of combination cancer therapies. These col - laborations show that barriers are not insurmountable and provide exam- ples for others to follow. Particularly notable innovative clinical testing examples are the I-SPY 2 TRIAL and the BATTLE 2 trial. Several scientific tools to aid cancer combination therapy development are available in the public domain, including GSK’s epigenetic toolbox and preclinical data, NCI’s mechanism-of-action assays and preclinical models for combina- tions, as well as the investigational agents that NCI makes available for preclinical testing. Several participants stressed the importance of doing whatever it takes to facilitate collaboration in the development of combination investi - gational cancer therapies. “There is really an urgency to identify solutions for the barriers because we have patients at stake,” said Dr. Hohneker. Dr. Mendelsohn agreed with the urgency to speed up combination drug development, given that “one-third of our patients will not live 5 years— that’s a half-million people a year.” Dr. Hohneker concluded the confer- ence by stating, “The takeaway is that for success and learning, it takes a team of people who are very committed and passionate, and willing to work together to come up with the solutions, as well as strong collabora - tions, persistence, good science, and the willingness to learn.”