Improving the Quality of Cancer Clinical Trials Workshop Summary (2008) / Chapter Skim
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New Clinical Trial Designs
New Clinical Trial Designs
Pages 3-39
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From page 3... ...
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.
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From page 4... ...
Exploratory INDs allow sponsors to evaluate up to five experimental drugs simultaneously in the clinic so as to better choose the most promising drug candidate to undergo traditional drug development and testing. 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.
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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.
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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.
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. "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.
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Dr. Jacobson-Kram countered that exploratory INDs offer more than decisions on whether to move a drug forward in the clinical testing hierarchy.
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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 compound 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)
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10 IMPROVING THE QUALITY OF CANCER CLINICAL TRIALS FIGURE 1 Whole-body biodistribution imaging. Time points 1, 2, and 3 show a radiolabeled bio-distribution study of a therapeutic agent as it targets an abdominal tumor.
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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.
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In the figure, 1–4 represent exploratory INDs dependent on chemistry, manufacturing, and controls (CMC) and pharmacology/toxicology.
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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.
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He pointed out that even drug sponsors might balk at the high hospital and surgeon expenses linked to doing the tumor biopsies as was done for Dr. Doroshow's exploratory IND study.
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IND Sponsor • National Cancer Institute Repository • Pharmaceutical Industry Laboratory for Trial Monitor Pharmacodynamic • Investigator Analysis Pathology Laboratory REGULATORY Laboratory CLINICAL LABORATORY for Tissue AGENCY Handling and Processing Research Interventional Drug Bioethics Imaging Radiology Development Clinic Patient Laboratory for Education Review imaging Medical Oncologists Pharmacokinetic studies to determine Analysis feasibility of obtaining biopsies Research Nursing Documentation of patient understanding Clinical Nursing Schedule tumor of the nature of biopsies: the clinical trials Data Managers coordinate with times for drug administration Social Workers FIGURE 3 NCI integrated Phase 0 research team. 15 SOURCE: Doroshow presentation (October 4, 2007)
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It is also standard in Phase I cancer studies to have adaptive trials with dose escalation schemes dependent on observed toxicity at each stage, she said. Adaptive trial designs can also be used to make a seamless transition between phases in cancer clinical trials, Dr.
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The so-called "stopping boundary" for superiority of an experimental agent is usually very conservative and therefore most Phase III trials accrue to their maximally targeted sample sizes. Less commonly used adaptive trials are those that have adaptive borrowing, adaptive randomization, adaptive study populations, or adaptive accrual rates.
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. TABLE 2 Study Results -- Drug Combinations in Acute Myeloid figure 4 Leukemia Drug Combination Complete Response by Day 50 Idarubicin/Cytarabine 10/18 = 56% Troxicitabine/Cytarabine 3/11 = 27% Troxicitabine/Idarubicin 0/5 = 0% SOURCES: Berry presentation (October 4, 2007)
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His experience with a number of patient groups suggests that adaptive trials will encourage more patients to enroll in cancer clinical studies because patients perceive such trials as offering them better treatment in addition to providing more efficient drug development.
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Dr. Berry pointed out that FDA Deputy Director Janet Woodcock stated at a recent conference that "improved utilization of adaptive and Bayesian methods" could help resolve the low success rate of and expense of Phase III clinical trials. He added that in the past 7 years, MD Anderson has had more than 200 adaptive trials that used Bayesian techniques.
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From page 21... ...
Because analyses of interim data in adaptive trial designs may reveal the need to enlarge a study population, they are not necessarily always more efficient. In fact, some investigators have shown that standard group sequential designs are always more efficient than the start-small type of adaptive design (Tsiatis, 2003)
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She concluded by stating that concerns about study integrity should be addressed before adaptive designs become more widely used to change sample size in Phase III trials. "I haven't seen any solution to this problem," she said.
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Agreements often have to be forged among different industry partners and academic institutions for the development of combination treatments that target multiple cancer pathways. To aid this process and foster early clinical trials of investigational drug combinations, the NCI turned to its Cancer Therapy Evaluation Program (CTEP)
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In addition, doses used in preclinical tests and endpoints may not be relevant for the clinical situation. Cancer clinical trial endpoints are usually patient survival or progression-free survival, but these endpoints are rarely used to evaluate for synergy in preclinical studies of drug combinations.
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with one that acts on the receptor for VEGF. Another approach is to combine an agent that targets a specific cancer growth factor, such as human epidermal growth factor receptor 2, or HER-2, in breast cancer with another compound that plays a critical role downstream from the activation of that target, such as mTOR (mammalian target of rapamycin)
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But these biomarkers are often lacking, and without them, interpreting the results of clinical trials of combination targeted cancer drugs is especially problematic. To illustrate this point, Dr.
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A response rate of greater than 30 percent would occur if the combination is more favorable than the individual agents. But without predictive markers for response to each of the three drugs, as well as predictors of response to the combination, researchers cannot conclude who is likely to benefit from the combination treatment and whether it is more beneficial than individual agents.
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He focused on how to model molecular heterogeneity to enhance multidrug clinical trial design. He summarized the efforts by the Greater Bay Area Consortium, which consists of investigators at the University of California, San Francisco, the University of California, Berkeley, LBNL, and SRI International, in collaboration with investigators at MD Anderson Cancer Center and pharmaceutical company GlaxoSmithKline.
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, ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog) , FGFR1 (fibroblast growth factor receptor 1)
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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 combinations should be tested preclinically based on the likelihood that they will have synergistic effects.
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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.
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Dr. Gray summarized the strength of this modeling approach by pointing 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.
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, AKT (v-akt murine thymoma viral oncogene homolog) , AMP (Adenosine Monophosphate)
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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.
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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.
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This understanding of the microenvironment of myeloma tumors explains why a proteasome inhibitor drug such as bortezomib is more effective 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.
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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)
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, NPI0052 (proteasome inhibitor) , p38 MAPK (mitogen activated protein kinase 14)
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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 Approved in May 2007. See http://www.cancer.gov/cancertopics/druginfo/ fda-doxorubicin-HCL-liposome.
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