Phase I Oncology Drug Development

352 Pages·2020·5.48 MB·English

by  Timothy A. Yap, Jordi Rodon, David S. Hong

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
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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