ANTICANCER DRUG DEVELOPMENT GUIDE

CANCER DRUG DISCOVERY AND DEVEwPMENT

Beverly A. Teicher, Series Editor

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Second Edition, edited by Beverly A. Teicher and Paul A. Andrews, 2004 Handbook of Cancer Vaccines, edited by Michael A. Morse, Timothy M. Clay, and Kim

H. Lyerly, 2004 Drug Delivery Systems in Cancer Therapy, edited by Dennis M. Brown, 2003 Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Cell Cycle Inhibitors in Cancer Therapy: Current Strategies, edited by Antonio Giordano and

Kenneth J. Soprano, 2003 Chemoradiation in Cancer Therapy, edited by Hak Choy, 2003 Fluoropyrimidines in Cancer Therapy, edited by YouceJ M. Rustum, 2003 Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins,

edited by Nicholas B. La Thangue and Lan R. Bandara, 2002 Tumor Targeting in Cancer Therapy, edited by Michel Page, 2002 Hormone Therapy in Breast and Prostate Cancer, edited by V. Craig Jordan and

Barrington J. A. Furr, 2002 Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and

KrzysztoJ Appelt, 2001 Famesyltransferase Inhibitors in Cancer, edited by Said M. Sebti and Andrew D. Hamilton,

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Farrell,2000 Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 Signaling Networks and Cell Cycle Control: The Molecular Basis oj Cancer and Other

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edited by Beverly A. Teicher, 1997 Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997

ANTICANCER DRUG

DEVELOPMENT GUIDE

PRECLINICAL SCREENING, CLINICAL TRIALS, AND APPROVAL

SECOND EDITION

Edited by

BEVERLY A. TEICHER, PhD Vice President and Director of Oncology Portfolio Genzyme Corporation Framingham, MA

PAUL A. ANDREWS, PhD Senior Director, Preclinical Sciences Aton Pharma Inc. Tarrytown, NY

H UMANA PRESS TOTOWA, NEW JERSEY

ISBN 978-1-4684-9841-7 ISBN 978-1-59259-739-0 (eBook) DOI 10.1007/978-1-59259-739-0

© 2004 Humana Press Inc. Softcover reprint of the hardcover 1 st edition 2004 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512

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All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. Due diligence has been taken by the publishers, editors, and authors ofthis book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication.

All articles, comments, opinions, conclusions, or recommendations are those of the author(s) , and do not necessarily reflect the views of the publisher.

Cover design by Patricia F. Cleary.

Cover illustration: from Fig. I in Chapter 14, "Discovery ofTNP-470 and Other Angiogenesis Inhibitors," by Donald E. Ingber, in Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, Humana Press, 1997.

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Library of Congress Cataloging-in-Publication Data

Anticancer drug development guide: preclinical screening, clinical trials, and approval 1 edited by Beverly A. Teicher, Paul A. Andrews.-2nd ed.

p. ; cm. - (Cancer drug discovery and development) Includes bibliographical references and index.

Additional material to this book can be downloaded from http://extras.springer.com. ISBN 978-1-4684-9841-7

I. Antineoplastic agents-Development. [DNLM: I. Antineoplastic Agents-standards. 2. Clinical Trials. 3. Drug Approval. 4. Drug Design. 5. Drug

Evaluation, Preclinical. QV269 A62953 2004] I. Teicher, Beverly A. , 1952- . II. Andrews, Paul A. III. Series. RC271.C5A67222004 616.99'4061-dc22

2003024925

For the beautiful ones

Emily and Joseph

Katie and Matt

PREFACE

This unique volume traces the critically important pathway by which a "molecule" becomes an "anticancer agent." The recognition following World War I that the administration of toxic chemicals such as nitrogen mustards in a controlled manner could shrink malignant tumor masses for relatively substantial periods of time gave great impetus to the search for molecules that would be lethal to specific cancer cells. Weare still actively engaged in that search today. The question is how to discover these "anticancer" molecules. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition describes the evolution to the present of preclinical screening methods. The National Cancer Institute's high-throughput, in vitro disease-specific screen with 60 or more human tumor cell lines is used to search for molecules with novel mechanisms of action or activity against specific phenotypes. The Human Tumor Colony-Forming Assay (HTCA) uses fresh tumor biopsies as sources of cells that more nearly resemble the human disease.

There is no doubt that the greatest successes of traditional chemotherapy have been in the leukemias and lymphomas. Since the earliest widely used in vivo drug screening models were the murine L 1210 and P388 leukemias, the community came to assume that these murine tumor models were appropriate to the discovery of "antileukemia" agents, but that other tumor models would be needed to discover drugs active against solid tumors. Several solid tumor models were developed in mice that are still widely used today and have the advantage of growing a tumor in a syngeneic host. In the meantime, a cohort of immunodeficient mice was developed, including nude, beige, and SCID mice, allowing the growth of human tumor cell lines and human tumor biopsies as xenografts in the mice. Through the great advances in our knowledge of intracellular communication by secreted growth factors, cytokines, chemokines, and small molecules, the importance of the normal cellular environment, both stromal and organal, to the growth of malignant tumors has come to the fore. Now preclinical tumors in which malignant cells are implanted into the organ of origin, that is, in the orthotopic site, add this additional level of sophistication to drug discovery. In addition, new endpoints for preclinical testing, such as quantified tumor cell killing and detection of tumor cells in sanctuary sites, have been developed.

Of the hundreds of thousands of molecules passing through the in vitro screens, few reach clinical testing. In the United States, the FDA must grant permission to enter new investigational agents into human testing, whether the clinical testing is sponsored by an academic investigator, the NCI, or the pharmaceutical industry. Patient safety is the foremost concern. Nonclinical safety testing programs need to be carefully designed to allow identification of potential hazards so that they can be appropriately monitored and so that safe starting doses can be selected. The ongoing costs and timelines for toxicology studies need to be realistically factored into overall development plans so that clinical testing is not unnecessarily delayed. The phase I clinical trial allows the initial study of a candidate therapeutic's pharmacokinetics, pharmacodynamics, toxicity profile, and tolerated dose. In phase II clinical trials, the goal becomes demonstration of disease-

vii

viii Preface

specific activity. In phase III clinical trials, statistically significant clinical benefit in well-designed and adequate clinical trials is required for success and FDA marketing approval. Phase III trial designs and statistical plans need to be appropriate relative to the current standard therapy for the intended indication. Poorly conceived and poorly executed clinical development can sabotage promising agents with recognizable activity. Much of the world's community of physicians and investigators now participate in clinical trials of potential new anticancer agents; however, the century-old goal of discovering molecules that control the growth and spread of malignancies as well as being viable as therapeutics in humans remains elusive.

The systems for finding molecules to manage malignancy are in place worldwide and our knowledge of cell growth and regulation is increasing daily; thus, one must remain optimistic of success in cancer drug discovery. This volume provides a guide for navigating the treacherous path from molecule discovery to a commercial therapy. This development path is mined with ample opportunity for failure. For anticancer drug development programs to succeed, promising compounds need to be expeditiously and intelligently selected; toxicology programs need to be thorough, relevant, timely, and informative; clinical development needs to be focused and executed with the highest scientific and administrative integrity; and FDA regulations and guidance have to be understood and followed. It is our hope that Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition will help all those engaged in developing new treatments for this dread disease to avoid the pitfalls that await. Our friends, colleagues, and family members who are burdened with a diagnosis of cancer await your successes.

Beverly A. Teicher, PhD

Paul A. Andrews, PhD

CONTENTS

Preface ......................................................................................................................... vii Contributors ................................................................................................................... xi Value-Added eBook/PDA .......................................................................................... xiv

Part I: In Vitro Methods

1 High-Volume Screening ....................................................................................... 3 Michel Page

2 High-Throughput Screening in Industry ............................................................ 23 Michael D. Boisclair, David A. Egan, Kety Huberman,

and Ralph Infantino

3 The NCI Human Tumor Cell Line (60-Cell) Screen: Concept, Implementation, and Applications .................................................. 41

Michael R. Boyd

4 Human Tumor Screening ................................................................................... 63 Axel-R. Hanauske, Susan G. Hilsenbeck, and Daniel D. Von Hoff

Part II: In Vivo Methods

5 Murine L1210 and P388 Leukemias .................................................................. 79 William R. Waud

6 In Vivo Methods for Screening and Preclinical Testing: Use of Rodent Solid Tumors for Drug Discovery .......................................... 99

Thomas Corbett, Lisa Polin, Patricia LoRusso, Fred Valeriote, Chiab Panchapor, Susan Pugh, Kathryn White, Juiwanna Knight, Lisa Demchik, Julie Jones, Lynne Jones, and Loretta Lisow

7 Human Tumor Xenograft Models in NCI Drug Development ....................... 125 Michael C. Alley, Melinda G. Hollingshead, Donald J. Dykes,

and William R. Waud

8 NCI Specialized Procedures in Preclinical Drug Evaluations ........................ 153 Melinda G. Hollingshead, Michael C. Alley, Gurmeet Kaur,

Christine M. Pacula-Cox, and Sherman F. Stinson

9 Patient-Like Orthotopic Metastatic Models of Human Cancer ....................... 183 Robert M. Hoffman

10 Preclinical Models for Combination Therapy ................................................. 213 Beverly A. Teicher

11 Models for Biomarkers and Minimal Residual Tumor ................................... 243 Beverly A. Teicher

ix

x Contents

12 Spontaneously Occurring Tumors in Companion Animals As Models for Drug Development .................................................................................. 259

David M. Vail and Douglas H. Thamm

Part III: Nonc1inical Testing to Support Human Trials

13 Nonclinical Testing: From Theory to Practice ................................................ 287 Denis Roy and Paul A. Andrews

14 Nonclinical Testing for Oncology Drug Products ........................................... 313 Paul A. Andrews and Denis Roy

15 Nonclinical Testing for Oncology Biologic Products ..................................... 325 Carolyn M. Laurenfot, Denis Roy, and Paul A. Andrews

Part IV: Clinical Testing

16 Working With the National Cancer Institute ................................................... 339 Paul Thambi and Edward A. Sausville

17 Phase I Trial Design and Methodology for Anticancer Drugs ........................ 351 Patrick V. Acevedo, Deborah L. Toppmeyer, and Eric H. Rubin

18 Phase II Trials: Conventional Design and Novel Strategies in the Era of Targeted Therapies .................................................................. 363

Keith T. Flaherty and Peter J. O'Dwyer

19 Drug Development in Europe: The Academic Perspective ............................. 381 Chris Twelves, Mike Bibby, Denis Lacombe, and Sally Burtles

20 The Phase III Clinical Cancer Trial ................................................................. 401 Ramzi N. Dagher and Richard Pazdur

21 Assessing Tumor-Related Symptoms and Health-Related Quality of Life in Cancer Clinical Trials: A Regulatory Perspective ....................................... 411

Judy H. Chiao, Grant Williams, and Donna Griebel

22 The Role of the Oncology Drug Advisory Committee in the FDA Review Process for Oncologic Products .................................. .421

Leslie A. Vaccari

23 FDA Role in Cancer Drug Development and Requirements for Approval .................................................................................................. 429

Susan Flamm Honig

Index ................................................................................................................. 443

CONTRIBUTORS

PATRICK V. ACEVEDO, MD • The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

MICHAEL C. ALLEY, PhD. Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD

PAUL A. ANDREWS, PhD· Aton Pharma Inc., Tarrytown, NY

MIKE BIBBY, PhD, DSc, CBiol, FIBiol· Tom Connors Cancer Research Centre, University of Bradford, West Yorkshire, UK

MICHAEL D. BOISCLAIR, PhD· OSI Pharmaceuticals Inc., Farmingdale, NY

MICHAEL R. BOYD, MD, PhD • Cancer Research Institute, University of South Alabama, Mobile, AL

SALLY BURTLES, BSc, PhD • Division of Drug Development, Cancer Research UK, London, UK

JUDY H. CHIAO, MD • Oncology Clinical Research and Development, Aton Pharma Inc., Tarrytown, NY

THOMAS CORBETT, PhD • Division of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI

RAMZI N. DAGHER, MD· Division of Oncology Drug Products, Food and Drug Administration, Rockville, MD

LISA DEMCHIK, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

DONALD J. DYKES, BS • Cancer Therapeutics, Southern Research Institute, Birmingham, AL

DAVID A. EGAN, PhD· OSI Pharmaceuticals Inc., Farmingdale, NY

KEITH T. FLAHERTY, MD· Developmental Therapeutics Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

DONNA GRIEBEL, MD· Division of Oncology Drug Products, Food and Drug Administration, Rockville, MD

AXEL-R. HANAUSKE, MD, PhD • Section of Medical Oncology, AK St. George, Hamburg, Germany

SUSAN G. HILsENBECK, PhD • Section of Biostatistics, Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX

ROBERT M. HOFFMAN, PhD • AntiCancer Inc., San Diego, CA; Department of Surgery, University of California at San Diego, La Jolla, CA

xi

xii Contributors

MELINDA G. HOLLINGSHEAD, DVM, PhD • Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD

SUSAN FLAMM HONIG, MD· Division of Oncology Drug Products, Food and Drug Administration, Rockville, MD

KETY HUBERMAN, MS· OSI Pharmaceuticals Inc., Farmingdale, NY

RALPH INFANTINO, BS • OSI Pharmaceuticals Inc., Farmingdale, NY

JULIE JONES, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

LYNNE JONES, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

GURMEET KAUR, MS • Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD

JUIWANNA KNIGHT, BA· Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

DENIS LACOMBE, MD, MSc· New Drug Development Program, European Organization for Research and Treatment of Cancer, Brussels, Belgium

CAROLYN M. LAUREN~OT, PhD· Cato Research Ltd., Rockville, MD

LORETTA LISOW, BA· Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

PATRICIA LoRusso, DO • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

PETER J. O'DWYER, MD • Developmental Therapeutics Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

CHRISTINE M. PACULA-COX, MS· Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD

MICHEL PAGE, PhD • Department of Medical Biology, Faculty of Medicine, Universite Laval, Sainte-Foy, Quebec, Canada

CHIAB PANCHAPOR, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

RICHARD PAZDUR, MD· Division of Oncology Drug Products, Food and Drug Administration, Rockville, MD

LISA POLIN, PhD • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

SUSAN PUGH, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

DENIS RoY, PhD· Cato Research Ltd., San Diego, CA

Contributors

ERIC H. RUBIN, MD • The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

EDWARD A. SAUSVILLE, MD, PhD· Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD

xiii

SHERMAN F. STINSON, PhD • Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD

BEVERLY A. TEICHER, PhD· Oncology Discovery and Research, Genzyme Corporation, Framingham, MA

PAUL THAMBI, MD • Medical Oncology Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD

DOUGLAS H. THAMM, VMD· Department of Medical Sciences, School of Veterinary Medicine; Comprehensive Cancer Center, University of Wisconsin, Madison, WI

DEBORAH L. TOPPMEYER, MD • The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

CHRIS TWELVES, BMedSci, MB ChB, MD, FRCP (London & Glasgow) • New Drug Development Program, European Organization for Research and Treatment of Cancer, Brussels, Belgium; and Tom Connors Cancer Research Center, University of Bradford, Bradford, West Yorkshire, UK

LESLIE A. V ACCARI, BSN, RAC • Cato Research Ltd., Rockville, MD

DAVID M. VAIL, DVM· Department of Medical Sciences, School of Veterinary Medicine, Comprehensive Cancer Center, University of Wisconsin, Madison, WI

FRED V ALERIOTE, PhD • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

DANIEL D. VON HOFF, MD· Departments of Medicine, Pathology and Molecular and Cellular Biology, Arizona Cancer Center, University of Arizona, Tucson, AZ

WILLIAM R. W AVD, PhD • Cancer Therapeutics, Southern Research Institute, Birmingham, AL

KATHRYN WHITE, BS • Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI

GRANT WILLIAMS, MD • Division of Oncology Drug Products, Food and Drug Administration, Rockville, MD

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