Phase I Oncology Drug Development Timothy A. Yap Jordi Rodon David S. Hong Editors 123 Phase I Oncology Drug Development Timothy A. Yap • Jordi Rodon • David S. Hong Editors Phase I Oncology Drug Development Editors Timothy A. Yap Jordi Rodon University of Texas MD University of Texas MD Anderson Cancer Center Anderson Cancer Center Houston Houston TX TX USA USA David S. Hong University of Texas MD Anderson Cancer Center Houston TX USA ISBN 978-3-030-47681-6 ISBN 978-3-030-47682-3 (eBook) https://doi.org/10.1007/978-3-030-47682-3 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword The Times—They Are A-Changin’ —Bob Dylan Nobel Laureate for Literature 2016 It is certainly no longer “the bad old days” in the field of oncology phase I clini- cal trials. The days of treating patients with advanced refractory cancer when all prior treatments have failed them with just the next phase I agent coming off the drug development assembly line are thankfully over. Potential new therapeutic entities are becoming available for phase I clinical trials at a rapid clip. Whether we are referring a patient for a possible phase I trial or consenting a patient for a phase I study, we must make sure we are offering our patients the best possible chance they will actually benefit from that new agent. In the “bad old days,” only about 1 in every 15 or so new agents tried actually had evidence of helping someone in a phase I trial. Today, it is thankfully at least 1 in every 3 new agents (that will provide clinical benefit for a patient). In fact, with bet- ter science, better patient selection, etc., if no participant in a phase I trial derives benefit from the new agent, one quickly wonders whether there is any future at all for that drug. Therefore, now, more than ever, it is critical that physicians trying to do their very best for their oncology patient be familiar with the very latest informa- tion on strategies for the most efficient ways to develop a new anticancer agent. Presently, it can make a real difference for patients, e.g., they have a greater chance of achieving clinical benefit in the phase I trial. Done properly, a patient’s participa- tion in a phase I clinical trial has a much higher likelihood of helping them (30% today versus 3% in the past). Therefore, in this day and age, to do the best for our patients with advanced cancer, our patients should be offered participation in a phase I clinical trial. In this volume Phase I Oncology Drug Development, three of our most outstand- ing physician investigators (Timothy Yap, David Hong, and Jordi Rodon) have done all of us a service by assembling a most important perspective on what we all should know about present-day phase I clinical trials. v vi Foreword The authors in this volume cover perspectives from multiple distinguished mul- tinational experts. They, first of all, remind us not to forget the basics like good pharmacokinetic/pharmacodynamic principles and how a great biomarker wins the day for giving our patients the best chance for clinical benefit. They also give the best chance for FDA approval. Other very helpful topics covered in this volume include: (a) Differences in interactions required with different regulatory agencies (for the USA and for the European Union) (b) What pharmacokinetic and pharmacodynamic data should look like in various preclinical models before proceeding to a phase I clinical trial (c) Strategies for the selection of patients most likely to benefit from a phase I agent (d) Dose–response relationships for new molecularly targeted immuno-oncology agents or epigenetic modifying agents (e) Tips on how state-of-the-art preclinical studies (e.g., CRISPR/Cas9, organ- oids) can be used for target discoveries and for the validation of that target as a driver. These techniques can “de-risk” a compound and give our patients the best chance for clinical benefit (f) How to set up an outstanding phase I unit so patients do not have to travel far away from home (g) Novel trial designs: for studying dose escalation (including Bayesian optimal interval (BOIN) design) and selecting the proper dose to take forward into expansion cohorts (h) The critical area of attribution and management of toxicities (i) Important consideration for situations that might alter pharmacokinetics. This includes designs with consideration for food effects, drug–drug interactions, and organ impairment (j) Beautifully detailed description of the development of biomarkers, including imaging and regulatory requirements (k) Discussion of various new endpoints for detecting early signs of efficacy in the phase I trial (l) Special consideration for the development of novel technologies (e.g., anti- body–drug conjugate, novel formulations) (m) A unique discussion of phase I combinatorial drug development strategies (n) How molecular profiling of patients in a phase I setting can inform unexpected results of finding an actionable target, which is incredibly helpful for their care, and which may have implications for their relatives (e.g., germline mutations) (o) Special strategies for phase I trials for immunotherapeutics, including unique patient selection and agent-specific designs (e.g., with STING agonists, Toll- like receptor agonists), as well as combination strategies for such agents (p) Novel phase I trial designs involving multiple types of radiation (q) Special consideration for phase I trials for patients with hematologic malignancies Foreword vii Throughout the volume, there are multiple successful and unsuccessful examples of therapeutic development. These are very helpful examples. There are also some incredibly helpful tables and diagrams to emphasize important points. In summary, this is a must-read volume for all those who want to provide the very best possibilities for their patients with advanced cancer. The editors and authors have given us their very best. Yes, the times in phase I trials, they are a-changin’. Daniel Von Hoff Translational Genomics Research Institute Phoenix, AZ USA Contents 1 The Development of a Drug: A Pharmaceutical Drug Development Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Michael Lahn 2 Paradigms in Cancer Drug Development: A Universe with Many Galaxies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Cinta Hierro and Jordi Rodon 3 Preclinical Studies to Enable First in Human Clinical Trials . . . . . . . 45 Rajesh Chopra and Florence I. Raynaud 4 Practicalities of Setting Up a Phase I Clinical Trial Unit Within an Academic Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 David S. Hong, Kathrina L. Marcelo-Lewis, and Patricia LoRusso 5 Novel Trial Designs for Early Phase Clinical Trials . . . . . . . . . . . . . . . 85 Chia-Chi Lin 6 Examining Performance of Phase I Designs: 3+3 Versus Bayesian Optimal Interval (BOIN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Kenneth R. Hess and Bryan M. Fellman 7 Considerations for the Attribution and Management of Toxicities in Phase I Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Pedro C. Barata and David S. Hong 8 Strategies for Incorporating Pharmacokinetic Studies into Oncology Phase I Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Lingzhi Wang, Wan Qin Chong, Pei Shi Ong, and Boon Cher Goh ix x Contents 9 Development of Pharmacodynamic Biomarkers for Phase I Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 María Vieito, Itziar Gardeazabal, Ignacio Matos, and Elena Garralda 10 Efficacy Considerations in Phase I Trials . . . . . . . . . . . . . . . . . . . . . . . 159 Kanan Alshammari, Kirsty Taylor, and Lillian L. Siu 11 Considerations for the Development of Novel Chemotherapies and Antibody Drug Conjugates in Phase I Trials . . . . . . . . . . . . . . . . 185 Vivek Subbiah and Roman Groisberg 12 Development of Molecularly Targeted Agents in Early Phase Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Pedro C. Barata and Timothy A. Yap 13 Incorporating Precision Medicine into Phase I Clinical Trials . . . . . . 221 Funda Meric-Bernstam 14 Incorporating Circulating Biomarkers into Clinical Trials . . . . . . . . 233 Filip Janku 15 Development of Immunotherapeutic Strategies for Early Phase Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Patricia Martin-Romano, Roman Chabanon, Adrien Procureur, Sandrine Aspeslagh, and Sophie Postel-Vinay 16 Radiotherapy Considerations and Strategic Approaches in Phase I Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Lauren E. Colbert, Ying Yuan, Jaap D. Zindler, Clifton D. Fuller, and Charles R. Thomas 17 The Paradigm of Early Phase Studies in Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Vishwanath Sathyanarayanan and Swaminathan P. Iyer 18 Pharmacokinetic Considerations for Organ Dysfunction Clinical Trials in Early Drug Development . . . . . . . . . . . . . . . . . . . . . 313 Analia Azaro, Mehmet Esat Demirhan, Joann Lim, and Jordi Rodon Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Chapter 1 The Development of a Drug: A Pharmaceutical Drug Development Perspective Michael Lahn Abstract Clinical investigation of New Molecular Entities (NME) in oncology is chang- ing. Drivers of this transformation are advances in pharmacological platforms, such as antibody technology, changes in the regulatory framework to accelerate approval of new treatments, and rapid scientific discovery. As a result of this transformation the estab- lished drug development process is being modified and continues to adapt. Today signifi- cant resources are being moved towards early clinical development and NME have to show early promise of therapeutic activity. The ideal NME targets specific pathways, for which diagnostic tools can be developed to select or enrich patients for the treatment with NME. This chapter reviews the critical steps enabling the early phase clinical develop- ment from the perspective of a pharmaceutical drug developer. The required steps include non-clinical pharmacokinetic (PK) studies, pharmacokinetic/pharmacodynamic (PK/ PD) models, pharmacology and toxicology studies, and biomarker development plans. Keywords Drug development · First in human dose studies · Immuno-oncology · Kinase inhibitors · Targeted agents · Regulatory approval · Antibody · Biomarkers Key Points 1. Drug Development in Oncology is undergoing adaptation in response to new scientific discoveries. 2. Resources are invested earlier in clinical development to reduce attrition for new molecular entities (NME). 3. Success for identifying NME early appears to depend on the selection of specific targets that can be readily assessed in patients 4. Regulatory framework is evolving to respond to the changes in the clinical inves- tigation of NME. 5. Pharmaceutical drug development continues to search for the right model that will allocate the relevant resources in the overall drug development in a timely manner. M. Lahn (*) iOnctura SA, Geneva, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2020 1 T. A. Yap et al. (eds.), Phase I Oncology Drug Development, https://doi.org/10.1007/978-3-030-47682-3_1