Facilitating Collaborations to Develop Combination Investigational Cancer Therapies Workshop Summary (2012) / Chapter Skim
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3 Scientific Challenges in Developing Investigational Combination Therapies
3 Scientific Challenges in Developing Investigational Combination Therapies
Pages 11-36
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From page 11... ...
Such preclinical development presents numerous challenges that may be exacerbated in the development of combination therapies, including cell lines or animal models that do not adequately mimic the tumor, tumor microenvironment, or the propensity to develop 11
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From page 12... ...
as surrogate efficacy mod els for anticancer immunotherapies • S trategies to ensure target engagement and inhibition • I nnovative approaches to maximize dose and schedule of combinations • B etter ways to distinguish on-target versus off-target toxicities • G reater use of animal models to identify resistance mechanisms • G reater use of statistical modeling Inadequate Models of Human Tumors and Tumor Microenvironment Dr. Lewis Cantley, professor of medicine at Harvard Medical School and director of the Beth Israel Deaconess Hospital Cancer Center, noted that cell lines do not adequately model the diversity of tumor types, but rather those tumor cells that can grow in a petri dish or under other com mon laboratory conditions.
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It is also more expensive to test therapies in explant animal models than in numerous cell lines, Dr. Stern added.
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James Allison at Memorial Sloan Kettering Cancer Center, have tested combination immunotherapies preclinically by creating animal versions of the human antibodies or other immunotherapies that have been developed, and testing those in animals with intact immune systems. But even these animal models may not fully mimic how the human immune system interacts with the tumor, according to Dr.
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From page 15... ...
So any advantages or disadvantages a combination immunotherapy might have in that regard cannot be predicted in preclinical testing in such animal models, he said. One participant stressed that it is critical that the therapeutic mecha nism targeted by a treatment is present in the animal model in which it is tested, and is relevant to human disease.
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Lutzker gave an example of the extensive preclinical testing of combination targeted cancer therapies done by Genentech. This preclinical testing of an MEK inhibitor combined with a PI3K inhibitor, which took about a year, not only assessed additivity versus synergy in various genetically diverse cancer cell lines, but also tested a wide range of daily dosing versus intermittent dosing in animal models that aided subsequent clinical trial design.
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Dr. Donald Berry, professor of biostatistics at the MD Anderson Cancer Center, suggested going from bench to bedside and back to the bench by doing Bayesian statistical modeling of mouse preclinical test results the same way one would do for a clinical trial.
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Dr. Saber suggested basing dose selection on data, when available, from Phase I clinical trials with the single agents that researchers plan to use in combination.
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Engelman added, "We are going to have more combinations than we have patients." Dr. Engelman suggested using stricter preclinical benchmarks for effectiveness when deciding which combinations to test in the clinic.
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William Pao and Mia Levy at Vanderbilt University have built to disseminate information on patients' tumor mutations and responses to various therapies to enable a genetically-informed approach to cancer medicine. The My Cancer Genome website is an international collaboration of contributing physicians and physician scientists that compiles information on the mutations influencing cancer progression and growth, potential therapies that may be effective against specific mutations, and available clinical trials that target specific mutations.
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Stern is collaborating with Dr. Marcus Bosenberg to conduct high-throughput screening of 40 compounds at 3 concentrations on 30 tumor cell lines that model common human combinations of mutations.
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"We can do the cell line work and the xenograft work, but still you get to the clinic and you find that your efficacy is not as good as you had hoped based on those preclinical tests. So we really need to go one step further to understand: What are the predictive biomarkers for these monotherapies and combination therapies?
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Stern, and this is slowing the progress in developing molecu larly targeted therapies. He added that on a detailed level, "there is a fundamental lack of knowledge on how even the most effective targeted therapies work.
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IMPROVING CLINICAL TRIALS FOR COMBINATION THERAPIES Suggestions from Various Workshop Participants on How to Improve Clinical Trials for Combination Therapies • H aving assays to select likely patient responders • U sing adaptive trial designs to determine the best combi nations, dosing, and patient selection biomarkers as the trial progresses • U sing appropriate endpoints and setting a higher bar for effectiveness • E stablishing a single Institutional Review Board of record for multi-institutional trials • R epeat biopsies of patient's tumors to assess therapeutic effectiveness • D eveloping a precompetitive venue for testing drug com binations in a limited number of patients
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From page 25... ...
Dr. Chen added that patient selection will be important not only to improve clinical trial efficiency, but to find those patients who can fit into a narrow window of therapeutic effectiveness because they are so sensitive to a drug's effect to a target that a low enough dose can be effective without causing toxicity.
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Dr. LoRusso gave a positive example of patient selection in a Phase II clinical trial of a MEK inhibitor tested in combination with a BRAF inhibitor by Jeff Infante of the Sarah Cannon Research Institute in Nashville, Tennessee.
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Adaptive Trial Designs According to Dr. Berry, adaptive clinical trial designs are especially suited for answering the numerous questions that combination therapy raises, such as which of several possible drug combinations, patient selection biomarkers, doses, and dosing schedules are the safest and most effective.
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"We have to figure out ways that we can update that information and use additional markers to understand who benefits from treatment. The only way to do it is to build it into our clinical trial structure and learn as we go," he said.
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Berry presented were well suited to trials of investigational drug combinations because they avoid the problem of setting the maximum tolerated dose prematurely, which often occurs with standard Phase I trial designs that have a small
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Dr. Steven Piantadosi, director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, stressed that some sort of factorial clinical trial design must be used to investigate the interactions of agents when they are used in combination, and that there be enough sampling points in the "two-dimensional dose space" from which researchers can reap adequate information about how the response changes over that two-dimensional surface.
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Dr. Cantley added that the combination of clinicians and patient advocates stressing the importance of the biopsies required in the clinical trials he has been involved with has led to patient willingness to have these biopsies performed and to enroll in protocols in which such biopsies are mandatory.
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Dr. Chen added that hundreds of clinical trials testing combinations of these targeted agents reveal they can be quite toxic.
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Because of this, a clinical trial design quite different from a standard Phase I approach is needed. For example, in a Phase I clinical trial of a cell-based immunotherapy, his research group tries to identify an optimal biologic dose rather than the more standard maximum tolerated dose.
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Speeding Up the Collaborative Clinical Trial Process Dr. Vassiliki Papadimitrakopoulou, professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, pointed out that multiple steps need to be satis fied to have several pharmaceutical companies and academic institutions collaborate in combination therapy trials of investigational anticancer agents, including coordinating Institutional Review Board (IRB)
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From page 35... ...
He suggested that presenting a strong trial concept initially to the IRBs can help speed things up, as can having regular face-to-face meetings and teleconferences, and having investigators with clinical trial experience on a research team, in addition to the Principal Investigators, to provide valuable advice and help oth ers to benefit from their experience.
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