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Phase I Cancer Clinical Trials
Phase I Cancer Clinical Trials
A Practical Guide

SECOND EDITION n

EDITED BY

ELIZABETH A. EISENHAUER

CHRIS TWELVES

MARC BUYSE

1
1
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Library of Congress Cataloging-in-Publication Data

Phase I cancer clinical trials : a practical guide / edited by Elizabeth A. Eisenhauer,
Chris Twelves, Marc Buyse.—Second edition.
p. ; cm.
Preceded by Phase I cancer clinical trials : a practical guide / Elizabeth A. Eisenhauer, Christopher Twelves,
Marc Buyse. 1st ed. 2006.
Includes bibliographical references and index.
ISBN 978–0–19–935901–1 (alk. paper)
I. Eisenhauer, Elizabeth A., editor. II. Twelves, Chris, editor. III. Buyse, Marc E., editor.
IV. Eisenhauer, Elizabeth A. Phase I cancer clinical trials.
[DNLM: 1. Neoplasms—therapy. 2. Clinical Trials, Phase I as Topic—methods. QZ 266]
RC267
616.99′400724—dc23
2014034346

This material is not intended to be, and should not be considered, a substitute for medical or other professional advice.
Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while
this material is designed to offer accurate information with respect to the subject matter covered and to be current as of
the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules
for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must
therefore always check the product information and clinical procedures with the most up-to-date published product
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The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy
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consequence of the use and/or application of any of the contents of this material.

9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
 CONTENTS

Preface ╇ vii

Contributors ╇ix

1. Introduction ╇ 1
Elizabeth A. Eisenhauer
2. Preclinical Data and Requirements ╇ 9
Sophie Postel-Vinay, Jean-Charles Soria, and
Elizabeth A. Eisenhauer
3. Phase 0 Clinical Trials ╇ 44
Shivaani Kummar and James H. Doroshow
4. Basics of Phase I Design: First-in-Human Studies ╇ 57
Donna M. Graham, Aaron R. Hansen, Elizabeth A. Eisenhauer,
and Lillian L. Siu
5. Ethical Issues in First-in-Human Phase I Cancer Trials ╇ 91
Elizabeth A. Eisenhauer
6. Phase I Trials in Special Populations and Circumstances ╇ 104
Rajiv Kumar, Chris Twelves, and Udai Banerji
7. Phase I Trials of Immunotherapeutics ╇ 149
Christy Ralph, Emma King, Chris Twelves,
and Christian Ottensmeier
8. Statistical Designs for First-in-Man Phase I Cancer Trials ╇ 170
Xavier Paoletti and Marc Buyse
9. Writing the Protocol ╇ 200
Penelope A. Bradbury and Elizabeth A. Eisenhauer
10. Practical Aspects of Pharmacokinetics and Pharmacodynamics ╇ 227
Chris Twelves, Maria Jove, and Paul Loadman
v i  C ontents

11. Process, Pitfalls, and Logistics of Phase I Trials 273

Elizabeth A. Eisenhauer, Chris Twelves, Hayley Farmer, and Philip Ross
12. Reporting and Interpreting Results 308
Lesleigh S. Abbott, Elizabeth A. Eisenhauer, and Lesley K. Seymour

Appendix: Useful Web Resources 339

Index 343
 PREFACE

This is an exciting time in cancer research, with the number and type of potential
new cancer agents increasing exponentially. Phase I trials are a critical first step
in the study of novel cancer therapeutic approaches in humans. Their primary
goals are to identify the recommended dose, schedule and pharmacologic and
pharmacodynamics behavior of new agents or new combinations of agents and
to describe the adverse effects of treatment.
In cancer therapeutics, such studies have particular challenges. In general,
because of the nature of the effects of treatment, most such studies are con-
ducted in patients with advanced malignancy, rather than in healthy volunteers.
Further, the endpoints of these trials are usually measures adverse effects rather
than molecular target or anti-tumor effects. In addition to the goals noted above,
increasingly phase I trials are seen as a key step in identifying the effects of new
drugs, often targeted to affect a specific aberrant protein or pathway, on the
markers of that effect—through tissue biopsies, circulating measures or imaging
evaluations. Furthermore, as new agents in cancer are expected to have maximal
effects in biologically defined subgroups of patients, phase I trials provide the
opportunity to begin to evaluate the new drug’s impact in patients selected based
on such putative biomarkers. These factors render the design, conduct, analysis
and ethical aspects of phase I cancer trials unique and this book addresses all of
these in depth.
The publication of the second edition of this book has updated many topics to
reflect changes in the decade since the first edition and also includes sections and
chapters dealing with new and evolving areas of importance including phase 0 trials,
phase I evaluation of immunological therapies, biomarker driven trial design, phase I
trials in pediatric populations and including those with hematological malignancies.
Phase I Cancer Clinical Trials: A Practical Guide is a unique resource for a com-
prehensive understanding of the design and methods for trials of the first studies
v i i i  P reface

of new therapeutic cancer agents in human subjects. This new edition provides
updated and expanded information from a wide array of international experts
that will ensure it is useful to oncology trainees, as well as those in more senior
positions, and workers in related clinical specialities such as research nurses,
pharmacists and data mangers who are vital to the effective delivery of phase
I trials as well as statisticians and translational laboratory scientists whose
specialist input is increasingly important in early clinical trials.
Elizabeth Eisenhauer, MD, FRCPC
Chris Twelves, B Med Sci, MD, FRCP
Marc Buyse, ScD
September 2014
 CONTRIBUTORS

Lesleigh S. Abbott, MD╇ James H. Doroshow, MD╇

Division of Hematology/Oncology Center for Cancer Research
Department of Pediatrics Division of Cancer Treatment and
Children’s Hospital of Eastern Ontario Diagnosis
Assistant Professor National Cancer Institute
University of Ottawa Bethesda, Maryland
Ottawa, Ontario, Canada
Elizabeth A. Eisenhauer,
Udai Banerji, MBBS, MD, DNB, MD, FRCPC╇
MRCP, PhD, FRCP Head, Department of Oncology
The Institute of Cancer Research Queen’s University
The Royal Marsden Hospital Medical Director, Oncology Program
Sutton, United Kingdom Kingston General Hospital
Penelope A. Bradbury, MBBCh, Cancer Centre of Southeastern
FRACP, MD╇ Ontario
Associate Professor Kingston, Ontario, Canada
Department of Medicine Hayley Farmer, BSc (Hons), PhD╇
University of Toronto Cancer Research UK Centre for Drug
Medical Oncologist Development
Princess Margaret Cancer Centre London, United Kingdom
Toronto, Ontario, Canada
Donna M. Graham, MBBCh╇
Marc Buyse, ScD╇ Department of Medicine
Founder and Chairman University of Toronto
International Drug Development Division of Medical Oncology and
Institute Hematology
Louvain-la-Neuve, Belgium Princess Margaret Cancer Centre
Associate Professor of Biostatistics Toronto, Ontario, Canada
Universiteit Hasselt
Diepenbeek, Belgium
x  C ontributors

Aaron R. Hansen, MBBS Christian Ottensmeier, MD, PhD

Department of Medicine Cancer Sciences Division
University of Toronto Department of Medical Oncology
Division of Medical Oncology and University of Southampton
Hematology Southampton University Hospitals
Princess Margaret Cancer Centre Southampton, United Kingdom
Toronto, Ontario, Canada
Xavier Paoletti, PhD
Maria Jove, MD Biostatistics
Clinical Research Fellow INSERM U900
Leeds Institute of Cancer and Institut Curie
Pathology Paris, France
St. James’s Institute of Oncology
Sophie Postel-Vinay, MD
Leeds, United Kingdom
Clinical Fellow
Emma King, BMSc (Hons), Institut Gustave Roussy
MBChB, PhD, FRSC-ORLHNS Villejuif, France
CRUK Senior Lecturer Head and
Christy Ralph, MD
Neck Surgery
Associate Professor
University of Southampton
Leeds Institute of Cancer and
Southampton, United Kingdom
Pathology
Rajiv Kumar, MD St. James’s Institute of Oncology
The Institute of Cancer Research Leeds, United Kingdom
The Royal Marsden Hospital
Philip Ross, BSc (Hons), MSc
Sutton, United Kingdom
Cancer Research UK Centre for Drug
Shivaani Kummar, MD Development
Division of Cancer Treatment and London, United Kingdom
Diagnosis
Lesley K. Seymour, MD, PhD
National Cancer Institute
NCIC Clinical Trials Group
Bethesda, Maryland
Professor of Oncology
Paul Loadman, BSc (Hons), PhD Queen’s University
Professor in Pharmacokinetics and Kingston General Hospital
Drug Metabolism Kingston, Ontario, Canada
School of Life Sciences
Lillian L. Siu, MD, FRCPC
Institute of Cancer Therapeutics
Professor of Medicine
University of Bradford
University of Toronto
Bradford, United Kingdom
Drug Development Program
Princess Margaret Cancer Centre
Toronto, Ontario, Canada
C ontributors  xi

Jean-Charles Soria, MD, PhD Chris Twelves, BMedSci, MD,

Chief of Service, Institut de FRCP
Cancérologie Professor of Clinical Pharmacology
Director of the SIRIC Socrates Project and Oncology
Professor of Medicine Head, Section of Clinical Cancer
Institut Gustave Roussy Research Groups
Villejuif, France Leeds Institute of Cancer and
Pathology
St. James’s Institute of Oncology
Leeds, United Kingdom
 1

Introduction
ELIZABETH A. EISENHAUER ■

1 .1 ╇ D R U G D E V E LO PM E N T I N CAN CER

The development of new agents for cancer therapy is an orderly and systematic
process. Beginning with a preclinical body of data that includes evidence for effi-
cacy, toxicology, and mechanism of action, the classical clinical development of
a new agent proceeds through three steps or “phases.” These steps have as their
major goals: (a) establishment of a recommended dose and schedule; (b) dis-
covery of whether the drug shows any preliminary evidence of activity in spe-
cific tumor types (or subtypes); and, finally, (c) determination of whether the
new agent alone, or in combination, has a meaningful impact on survival or other
measures of efficacy in cancer patients. In all phases of investigation, compilation
of drug safety and other data also takes place. Table 1.1 outlines these steps and
highlights the types of questions, trial design, and endpoints that are typically
associated with each in cancer drug development.

1.1.1╇ Historical perspective—Cytotoxic

chemotherapy development

Historically, this phased process of clinical development dates to the dawn of

the era of cytotoxic chemotherapy in the 1960s. As summarized in an historical
review by Chabner and Roberts [1]â•„, early research into the relationship between
dose and cell kill by Schabel and Skipper [2,3] provided the foundation for the
strategy of giving the highest tolerable dose in clinical studies, and in fact laid the
foundations for research in high-dose chemotherapy with stem cell support that
occupied a great deal of clinical research activity in the 1980s and 1990s. Thus,
 Table 1.1. Cancer Trial Goals, Designs, and Endpoints
Phase Goal Question(s) Design Usual outcome Issues for targeted agents
measure(s)
(primary endpoint)
I Determine What is maximum dose that Non-randomized Toxic effects using Is dosing to toxicity appropriate
recommended can be safely administered? Dose escalation standard criteria or necessary?
dose for fur- What is pharmacokinetic Can direct measures of target
ther evaluation behavior? effect be utilized to determine dose?
Can seamless transition to
phase II be undertaken?
Should the population be
restricted by molecular genotype?
II Determine if What is the response rate Non-randomized Objective response Is phase II necessary? Can there be
sufficient evi- of the drug in a defined (some phase seamless transition from phase II to III
dence of bio- population? II trials may be through randomized designs? If
logical effect to Does it surpass a preset randomized) tumor regression is not anticipated,
continue drug minimum? Multistage what endpoints are appropriate for
development enrollment non-randomized trials screening
to allow early for efficacy? Should population be
stopping restricted to those expressing target?
How should biomarker for efficacy be
defined and identified?
III Determine Does the treatment Randomized Survival How should population be enriched for
relative effi- incorporating the new drug Early stopping Relapse-free survival expression of relevant biomarker or
cacy of new produce improved survival rules for extreme Quality of life target?
versus standard or freedom from relapse? differences measures How to combine/sequence with other
treatment Is the new treatment superior allowed agents?
in terms of quality of life?
Introduction3

phase I trials employing dose escalation to achieve levels of the “maximum toler-
ated dose” of the cancer agent became the norm [4,5], not only because of the
preclinical science, but also because the toxic effects that limited dose, usually
myelosuppression, provided evidence of the biological effects that were desired
of the new agent on the tumor.
Following completion of phase I trials, phase II evaluation, designed to screen
new drugs for signals of antitumor activity meriting further investigation, uti-
lized tumor regression, defined by objective standard measures, as the primary
endpoint [6,7].
Finally, phase III trials in which the new agent was evaluated (alone or incorpo-
rated into combination) in comparison with standard treatment, provided a mecha-
nism for unbiased assessment of the impact of the new drug in randomized designs
that utilized clinically meaningful endpoints of relapse-free or overall survival.

1.1.2 Drug development of molecular targeted therapeutics

Some decades later, although many new cytotoxic drugs and other agents iden-
tified by empirical screening and other means have continued to enter clinical
trials, the landscape of new anticancer agents has changed. Therapeutic agents
entering the clinic that are rationally designed or selected to affect specific intra-
cellular and extracellular targets thought to be relevant to malignant transforma-
tion are commonplace. In this new era of “molecular targeted therapy,” questions
have been posed about the appropriateness of applying the same clinical devel-
opment paradigm and utilizing the same endpoints as are employed for cytotoxic
drugs. Agents that are targeted to molecular aberrations in cellular and extracel-
lular pathways or to immune modulatory targets may be devoid of traditional
toxic effects, may not cause tumor regression, and may have effects only in molec-
ularly defined subpopulations. Although it is generally agreed that phase III trials
utilizing clinical endpoints are the final vital step in the development of newer
agents, special attention needs to be paid to how the early clinical evaluation of
such novel agents should most rationally proceed. Some of the questions that
face targeted therapies are highlighted in the final column of Table 1.1.

1 .2 S P E C I A L R O LE O F FI R ST- I N - HUMA N P HA S E I
T R I A L S : F I N D I NG THE DO SE AND S CHEDULE

Regardless of the debate about the endpoints and design of trials testing dif-
ferent types of cancer agents, it remains the case that phase I first-in-human
cancer trials are a critical first step in cancer drug development [8]‌. They are
4 P hase I C ancer C l inica l T ria l s

small-sample-size, generally non-randomized, dose-escalation studies that

define the recommended dose for subsequent study of a new drug in each sched-
ule tested; they also provide the opportunity for important early observations
about the drug’s safety, pharmacokinetic behavior, and preliminary evidence of
antitumor activity in humans. The recommended dose is based on observations
of toxic effects, pharmacokinetic outcomes, or other measures of drug effects, as
this book will describe. A wealth of preclinical information is utilized to inform
phase I trial starting dose and design. Furthermore, statistical and other research
have been undertaken to address issues of safety, ethics, and efficiency in the trial
conduct and dose-escalation methodologies.
As the subsequent development path for a drug is heavily dependent on the
information garnered from phase I trials, it is critically important to assure that
the design, conduct, and analysis of these trials are rigorous. Rushing to finish
phase I trials, inclusion of patients very different from those who will be treated
in later studies, or taking a poorly justified decision at the end of phase I (e.g.,
choosing a schedule based only on convenience rather than one supported by
other data) may paradoxically increase the overall time of subsequent drug devel-
opment or jeopardize the drug’s future altogether. The history of gemcitabine
provides an example of this.
When the phase I trials of gemcitabine were originally conducted, it was rec-
ognized early on that schedule played a very prominent role in the dose of drug
that could be delivered and in its toxic effects: the daily×5 schedule was fraught
with significant flu-like effects, and only relatively small doses could be admin-
istered [9]‌. When the dose was given as a 30-minute infusion for three of four
weeks, more drug could be delivered per cycle, and myelosuppression, particu-
larly thrombocytopenia, was dose-limiting. The latter schedule was thus selected
for further development and the recommended phase II dose was 790 mg/m2
(rounded to 800 mg/m2 in initial phase II trials) [10]. However, as is often the
case in phase I trials, heavily pretreated patients made up the population enrolled,
and dose escalation was very conservative, resulting in a large number of patients’
being treated at low doses without any toxicity, and very few patients were treated
near the recommended dose. When gemcitabine began its phase II evaluation
at the recommended dose, little in the way of toxic effects was seen, and doses
were first escalated to 1000 mg/m2, then to 1250 mg/m2 [11–14]. In the end,
the phase I trial was repeated in non–small cell lung cancer patients who were
treatment-naïve: a dose of 2200 mg/m2 was recommended [15], although many
continued to use single-agent doses in the range of 1000 mg/m2 (the dose that
was in fact approved for use in pancreatic carcinoma in the United States in 1996).
It is possible that if phase I trials were undertaken today with gemcitabine, the
same issues could arise; citing these experiences is not intended to fault the deci-
sions taken at the time, which were carefully considered. However, this historical
Introduction5

example serves to highlight how important it is that the phase I trials that deter-
mine the dose for future studies be designed to include appropriate numbers and
types of subjects in order to limit the risk of making inaccurate recommenda-
tions. Otherwise, considerable time and effort will need to be invested when the
drug is undergoing phase II investigation to refine dosing, leading to potential
delays in the overall drug development process.

1 .3 D I F F E R EN CE S B E TW E E N CAN CER
A N D O T H E R THE R APE U TI C AR E AS

Unlike most other therapeutic areas, studies of cancer therapeutics usually are
conducted first in patients with the disease rather than in normal healthy volun-
teers. The major reason for this is that anticancer agents often cause substantial
toxic effects, or may need to be given in doses producing such effects, which are
thought to be inappropriate for healthy subjects. Furthermore, the pharmaco-
logical behavior of drugs may differ between patients and healthy subjects. Thus,
cancer drugs are first studied in cancer patients to assure that knowledge of dos-
ing and pharmacology is acquired in the population in which the drugs will be
used. An important exception to this has been the rise in interest in so-called
phase 0 trials, which may enroll healthy volunteers (or cancer patients) to evalu-
ate microdoses of new drugs to address specific questions for which answers in
human subjects are necessary before full phase I investigation can begin.
The study of cancer patients in a phase I setting poses unique ethical issues.
Patients who have disease for which no active therapy remains who are offered
participation in phase I trials may view this as an opportunity to help future
patients, but more often they are hopeful that this treatment may prove effective
in controlling their disease. While this may indeed be possible, it is not the goal
of the phase I trial to establish efficacy, but rather dosing and safety information.
This and other ethical issues associated with phase I trials in an advanced-disease
population oblige investigators, institutions, and sponsors to address these
through appropriate review of the study protocol and development of a process
of trial conduct and consent that is rigorous, balanced, and in compliance with
internationally accepted standards.

1 .4 W H AT TH I S B O O K W I LL D O

This updated second edition will describe the process of phase I development
for cancer agents, from the preclinical information required before a new agent
is given to humans for the first time, through to generation of the final phase
6 P hase I C ancer C l inica l T ria l s

I study report. The book’s main focus is on first-in-human trials, although some
sections address combination phase I trials and other special circumstances or
populations. Agents that have direct effects on cancer and its tissue environment
are emphasized, but special sections on immunological agents highlight key dif-
ferentiating features of these agents in early clinical and in preclinical investiga-
tion. Regulatory, ethical, and practical issues are covered. Chapter 2 describes the
non-human (preclinical) data that should be in place before human testing may
begin. Chapter 3, new in this edition, highlights the rising role of phase 0 trials in
cancer drug development. Chapters 4 through 6 offer theoretical considerations
in phase I trial design, ethics and conduct, including issues surrounding special
populations. Chapter 7, also new in this edition, describes the special consider-
ations for phase I studies of immunotherapeutics. Chapter 8 provides a broad
overview of statistical phase I designs, while ­chapters 9 through 12 give practical
information and examples covering protocol development, trial conduct, phar-
macokinetic (PK) and pharmacodynamic (PD) assay development, and how to
report the final study in its published form. Finally, the Appendix offers useful
resources for the clinician or investigator interested in studying new therapies or
combinations of agents in a first-in-human assessment.

1 .5 P H A S E I T E R M S AN D NO R M S
A D OP T E D F O R TH I S B O O K

As is described in Chapter 4, some terms used in the phase I literature may have
more than one definition. The term “maximum tolerated dose” (MTD) is high-
lighted as the most important example. There are variations in the definition of
MTD, which frequently have led to confusion. In Europe, MTD is typically the
dose level at which a pre-specified allowable number of patients with dose limit-
ing toxicity (DLT) is exceeded (i.e., is above the recommended dose), whereas in
the United States the MTD is typically meant to be the dose level at which the
incidence of DLT is at or below the acceptable threshold (i.e., may be equivalent
to the dose recommended for further evaluation).
To avoid this confusion, it has been suggested that the dose at which escala-
tion ceases because of the observation of a critical number of DLT events be
referred to as the “maximum administered dose (MAD),” rather than the MTD.
In this book, MAD will be used for clarity—except when citing publications.
Another advantage of using MAD instead of MTD is that dose escalation may
cease before dose-limiting toxicity is observed. In particular, this may be the
case when biological agents that are not expected to induce toxicity are tested
in phase I; in such cases, the term MTD may be misleading and suggest that
Introduction7

dose escalation was stopped for toxicity, while the term MAD means exactly
what it states—the highest dose administered (whether for toxicity reasons or
others).
The other term that will be used consistently in this book is “recommended
phase II dose” (RP2D). In some settings the term “maximum tolerated dose”
has been used to describe the highest dose tolerable recommended for further
evaluation. It is felt however, that much greater clarity and precision is con-
veyed when this is described by RP2D, and this will be the approach adopted
in this book.

R E F E R E N C ES

1. Chabner BA, Roberts RG Jr. Timeline: Chemotherapy and the war on cancer. Nat
Rev Cancer. 2005;5:65–72.
2. Skipper HE, Schabel FM Jr, Wilcox WS. Experimental evaluation of potential anti-
cancer agents. XIII. On the criteria and kinetics associated with “curability” of exper-
imental leukaemia. Cancer Chemother Rep. 1964;35:1–111.
3. Skipper HE, Griswold DP. Frank Schabel. 1918–1983. Cancer Res. 1984;44:871–872.
4. Carter SK. Clinical trials in cancer chemotherapy. Cancer. 1977;40 (Suppl. 1):
544–547.
5. EORTC New Drug Development Committee. EORTC Guidelines for phase I trials
with single agents in adults. Eur J Cancer Clin Oncol. 1985;21:1005–1007.
6. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treat-
ment. Cancer. 1981;47:207–214.
7. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the
response to treatment in solid tumors (RECIST Guidelines). J Natl Cancer Inst.
2000;92:205–216.
8. Critical role of phase I clinical trials in cancer treatment. J Clin Oncol.
1997;15:853–859.
9. O’Rourke TJ, Brown TD, Havlin K, et al. Phase I clinical trial of gemcitabine given
as intravenous bolus on 5 consecutive days. Eur J Cancer. 1994;30A:417–418.
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