Page 365 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 18 Clinical Trials and Developmental Therapeutics 343

progression-free rate (PFR) at predetermined time points. Again, forward into phase III trials; so called “pick-the-winner” trials.
26
comparative oncology models may more expediently define TTP Although often not sufficiently powered for direct comparisons,
they may use a less rigorous statistical assessment, such as setting
or PFR because of compressed progression times in veterinary
VetBooks.ir patients. These measures can also more accurately define efficacy the p-value at 10% and using 1-tailed analyses.
in the minimal residual disease (MRD) setting such as trials inter-
rogating novel adjuvant therapies for canine osteosarcoma (OSA) Phase III Trials (Pivotal/Confirming Trials)
in the postamputation setting. For gauging response to immu-
notherapeutics, expanded response criteria have been published It has been suggested that if phase II trials are “learning” trials,
that help define methods of capturing unique response patterns phase III trials are “confirming” trials. These larger, random-
45
observed in patients receiving these agents, which can be used in ized, blinded, and controlled trials have the goal of comparing a
conjunction with RECIST or WHO methods. 38,39 new drug or combination with standard-of-care therapies. They
Secondary endpoints that may be evaluated in phase II trials are often performed by large cooperative groups, which ensures
include QOL assessments, comparative cost of therapy, days of greater case accrual, and FDA pivotal trials require multiinstitu-
hospitalization, validated surrogate biomarkers or measures of a tional involvement. An example of a multicenter phase III trial
molecular effect such as dephosphorylation of a growth factor would be the randomized comparison of liposome-encapsulated
receptor, 20,21 changes in microvessel density or regulatory T-cell cisplatin (SPI-77) versus standard-of-care carboplatin in dogs
40
46
number, or target modulation that is linked to clinical out- with appendicular OSA. No difference was observed between
come. Importantly, phase II trials serve to expand knowledge of treatment groups, despite SPI-77 allowing five times the MTD
25
cumulative or long-term toxicities associated with new agents that of native cisplatin to be delivered in a liposome-encapsulated
may not be observed in short-term phase I trials designed to eluci- form. True phase III trials are not common in veterinary oncology
date acute toxicity. An example of this in the veterinary literature because of their size and expense, with the exception of multicenter
involved a combined phase I/II trial simultaneously investigating “registration” trials that have formed the basis for New Animal
the safety of liposome-encapsulated doxorubicin (LED) while Drug Applications with the FDA Center for Veterinary Medicine
comparing its activity with native doxorubicin in cats with vac- (FDA-CVM). 47–49 Pivotal trials have included the registration of
41
cine-associated sarcomas. Unexpectedly, the MTD established the first approved veterinary oncology agents, two tyrosine kinase
for LED in the acute phase I component of the trial was found to inhibitors (TKIs; Palladia, Zoetis; Kinavet, AB Sciences) for the
result in delayed and dose-limiting nephrotoxicity after long-term treatment of mast cell tumors. 47,48 TKIs showed improvement in
follow-up in the phase II component of the trial. Such discoveries PFS over placebo controls, and these trials define the process for
are key to defining an agent’s therapeutic window with repeated expanding future efforts in veterinary oncology drug approval.
administrations.
New clinical trial concepts have entered into use in great part Sample Size and Power
because of a recent initiative of the US Food and Drug Adminis- The overriding function of clinical research is to provide a defini-
tration (FDA) to allow for “preclinical studies to provide evidence tive answer to a clinical question. However, it is possible that,
necessary to support the safety of administering new compounds once complete, clinical trial conclusions may be incorrect based
to humans.” These are known as phase 0 trials, and they precede on chance or design error. Chance error results when an erroneous
42
the traditional trials defined previously. 43,44 The role of phase 0 inference is drawn from a study sample group that is not actually
trials in cancer drug development is for biomarker and assay devel- representative of an entire patient population. Accounting for this
opment/validation and evaluation of target modulation. Phase 0 potential error is essential in prospective clinical trial design, and
trials allow for the systematic deprioritization of investigational its first critical step is to articulate the study hypothesis. Type I
50
agents that exhibit excessive toxicity or fail to show expected bio- or α error (false positive) occurs if an investigator rejects the null
logic effects and are used to direct dose selection for future studies. hypothesis when it is actually true. 45,50 This is also referred to as
They represent first-in-species trials, usually of a small number of the study’s level of significance. Type II or β error (false negative)
patients, and utilize lower and likely subtherapeutic drug doses. occurs when one fails to reject the null hypothesis when it is actu-
Comparative oncology trials allow the unique opportunity to ally incorrect. Type I and II errors are due to chance and cannot
answer the preclinical questions necessary to advance an agent. be avoided completely, although steps can be taken to reduce their
Phase 0 trials are “proof of concept” studies, wherein PK parame- potential effect by increasing sample size and augmenting study
ters are measured along with PD effects within target tissues, such design or measurements.
as the tumor itself. These trials can also define surrogate markers Power is the ultimate measure of a clinical trial’s results and
of target effect, therapeutic response, or metabolites in surrogate also must be prospectively controlled. Power is defined as 1 – β,
tissues or fluids, such as blood or urine. Assessment of PK/PD the probability of correctly rejecting the null in the sample if the
relationships allow for a much broader understanding of new drug actual effect in the population is equal to (or greater than) the
mechanism, therefore informing phase I/II trial design. effect size. 45,50 Power is governed by sample size, with the goal
being to enroll enough patients to accurately allow for a difference
Controlled Phase II Trials to be seen between groups. Power is irrelevant if the results are sta-
Sometimes referred to as phase IIB trials, these tend to be con- tistically significant, but if not, it is important to ensure the study
trolled, blinded, and randomized investigations of two or more had adequate numbers to detect a difference between groups. If
novel regimens that identify promising agents to send to phase a study to detect the difference between two cancer treatments is
III trials for additional evaluation. Randomized phase II trials can designed with an α of 0.05, then the principal investigator (PI) has
be as simple as randomizing standard-of-care plus or minus the set 5% as the maximum chance of incorrectly rejecting the null
addition of a new drug. Another approach is to randomize sub- hypothesis if it is true. This is the level of doubt the PI is willing
jects into multiple treatment arms or schedules with only enough to accept when statistical tests are used to compare the two treat-
power to make inferences as to which is the best drug to take ments. If β is set at 0.10, the PI is willing to accept a 10% chance