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Development of Novel Immunotherapeutics 175 Figure 15 Diagram summarizing a clinical trial designed to evaluate safety and pharmacological response to a biomarker-guided investigational cancer vaccine. encompass substituted amino acids at primary MHC anchor residues, achieving an increased MHC-peptide half-life and consequently immunogenicity (18–20). Finally, the clinical trial design encompasses the biomarker-guided approach principle with a screening interval for evaluation of HLA and tumor antigen expression, followed by repeat prime-boost cycles as long as the patients do not progress under treatment and regular sample harvesting for comprehensive evaluation of biological response (Fig. 15). ADAPTIVE TRIAL DESIGNS IN EXPLORATORY PHASE One of the most interesting aspects characterizing the drug development process once it enters clinic is the antagonism between the speed of executing the clinical trials and budget constrains—a hallmark of the biopharmaceutical business prior to reaching proof of concept in man. This is particularly acute for investigational drugs that are first in class or truly innovative technologies. There are two categories of mistakes that plague early drug development in such circumstances. The first one is underestimating the need to thoroughly explore a new technology in clinic prior to randomized trials. This may result in an inadvertent design of key trials prior to optimizing the approach or defining the best opportunity in clinic. An extreme case of this scenario is stopping the development of a potentially viable drug without the appropriate data set to support it (e.g., failing to demonstrate achievement of a secondary clinical end point in a
176 Bot and Obrocea given indication without rigorous evaluation of “on-target” pharmacological effect that may have opened avenues toward alternate indications). Conversely, a second mistake consists in protracted clinical exploration of a technology that failed to meet key requirements in terms of expected pharmacological effects; again, in an extreme case, this may be due to simply not setting up certain minimal expectations in terms of on-target pharmacological effects or similar end points. In the case of investigational drugs that are first in class, the only benchmark may be represented by nonclinical exploratory data. Therefore, a key prerequisite for successful translation of a new technology or investigational drug is an appropriate design of the clinical exploratory program—a responsibility shared by a variety of departments such as research, development, clinical, operations, and regulatory. In addition to unavoidable hurdles associated with translating innovative technologies, an additional factor that needs to be taken into account is the molecular targeting nature of new investigational drugs. Therefore, the R&D process starts with the molecular target and there is very limited evidence on its applicability in terms of therapeutic approach and indication. Throughout development and once the project matures, both the therapeutic approaches (small molecule versus biomolecule, high throughput screening versus design) as well as indications start to clarify. From a mathematical standpoint, the number of variables and range of options should be kept at a higher end at the beginning, and will only narrow based on data sets achieved during nonclinical trials and later on based on clinical exploration of both target and investigational drugs. That is quite a different paradigm compared to conventional R&D processes in support of second- and third-generation drugs, where clinical indication at the beginning is a fixed parameter (e.g., new insulins for pulmonary inhalation) (Fig. 15). To enable a more optimal translational and clinical development of investigational cancer vaccines in an environment devoid of licensed compounds to date, we propose a different clinical exploration paradigm consistent with the basic tenets of translational medicine outlined above. The primary aim of this approach is to generate a relevant data set as early as possible during the clinical exploratory process to appropriately guide the subsequent development. There are several versions of the process that can be imagined to achieve that goal; one of them (Fig. 16) encompasses phase 1/2a trials aimed to test the pharmacological effect at various doses and/or in a variety of tumor types, in addition to confirming the safety profile—the latter with a somewhat diminished yet not abrogated importance. The key feature of this approach is an interim analysis time point when pharmacological response data are analyzed, and on the basis of the information generated, patient accrual continues in select dose/tumor type cohorts in a phase 2a program aimed to expand the pharmacological response data set and complement it with clinical outcome data. The decision to proceed with a narrow range of parameters can be made on lack of meeting preset success criteria at certain doses and/or in various tumor types; therefore, negative
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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Factoring in Antigen Processing in
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2 Outlining the Gap Between Preclin
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Preclinical Models and Clinical Sit
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Table 1 Examples of Preclinical Act
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Page 148 and 149: Multimodality Immunization Approach
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Page 225 and 226: 206 Index Antigenic peptides degrad
Page 227 and 228: 208 Index Chromogens, enzymatic act
Page 229 and 230: 210 Index Freund’s adjuvants. See
Page 231 and 232: 212 Index Langerhans cells, 133, 13
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