Anticancer drug development guide : preclinical screening, clinical trials, and approval

466 Pages·2004·17.151 MB·English

by  Beverly A Teicher, Paul A Andrews

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A D D G
NTICANCER RUG EVELOPMENT UIDE
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C D D D
ANCER RUG ISCOVERY AND EVELOPMENT
Beverly A. Teicher, Series Editor
Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004
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Jamali, 2004
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edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004
Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D.
Figg and Howard L. McLeod, 2004
Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval,
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
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Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins,
edited by Nicholas B. La Thangue and Lan R. Bandara, 2002
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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
Krzysztof Appelt, 2001
Farnesyltransferase Inhibitors in Cancer, edited by Saïd M. Sebti and Andrew D. Hamilton,
2001
Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P.
Farrell, 2000
Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999
Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other
Diseases, edited by J. Silvio Gutkind, 1999
Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999
Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999
Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval,
edited by Beverly A. Teicher, 1997
Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997
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A D
NTICANCER RUG
D G
EVELOPMENT UIDE
P S , C T , A
RECLINICAL CREENING LINICAL RIALS AND PPROVAL
S E
ECOND DITION
Edited by
B A. T ,
EVERLY EICHER PhD
Vice President and
Director of Oncology Portfolio
Genzyme Corporation
Framingham, MA
P A. A ,
AUL NDREWS PhD
Senior Director, Preclinical Sciences
Aton Pharma Inc.
Tarrytown, NY
H P
UMANA RESS
T , N J
OTOWA EW ERSEY
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© 2004 Humana Press Inc.
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Due diligence has been taken by the publishers, editors, and authors of this 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
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Library of Congress Cataloging-in-Publication Data
Anticancer drug development guide : preclinical screening, clinical trials, and approval / edited by Beverly A. Teicher,
Paul A. Andrews.—2nd ed.
p. ; cm. — (Cancer drug discovery and development)
Includes bibliographical references and index.
ISBN 1-58829-228-2 (alk. paper)
1. Antineoplastic agents—Development.
[DNLM: 1. 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.C5A6722 2004
616.99'4061—dc22
2003024925
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For the beautiful ones
Emily and Joseph
Katie and Matt
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P
REFACE
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. We are
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 L1210 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
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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
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C
ONTENTS
Preface......................................................................................................................... vii
Contributors...................................................................................................................xi
Value-Added eBook/PDA ..........................................................................................xiv
Part I: In Vitro Methods
1 High-Volume Screening.......................................................................................3
Michel Pagé
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
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