Page 369 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 18 Clinical Trials and Developmental Therapeutics 347

as more information regarding efficacy and KIT localization and weeks, however, would be randomized to drug continuation or
c-kit mutation status became available, newly accrued dogs were discontinuation (placebo) and followed with monthly reevalua-
tions. This would ensure all dogs had a chance to respond to the
randomized proportional to the predicted response probability.
VetBooks.ir drug and enrich the population likely to respond, and a positive
result would be clinical response noted in the run-in phase or a
Randomized Discontinuation Trials
statistical difference in PFR between groups in the second stage.
This phase II design was proposed for evaluating the efficacy of
newer targeted agents that are thought to have disease-stabiliz- Personalized Medicine
ing activity (cytostatic) in contrast to disease-regressing activity
of more traditional cytotoxic chemotherapeutics. Several reviews Advancements in genomic, proteomic, and epigenetic profiling
of this trial design are recommended. 83–85 Trials that evaluate have created new opportunities to tailor cancer treatments to
growth-inhibiting agents in tumors with a variable natural history individual patient and tumor molecular characteristics; this field
seem ideally suited for randomized discontinuation trials (RDTs) is known as personalized or molecular-based medicine. The goals
because the “no treatment effect” is hard to control in these cases. of personalized medicine approaches include improving outcomes
In essence, these trials serve to enrich and homogenize the static by revealing disease drivers, toxicity, susceptibilities, and resistance
agent for those patients likely to benefit from it. RDTs involve profiles unique to the individual patient. Molecular profiling
a two-stage trial design, wherein the first stage involves a “run- approaches have been employed to stratify and prescribe therapies
in” phase in which all patients receive the cytostatic agent under for human oncology patients. The most successful examples to
investigation. At the end of the run-in phase, assessment of disease date have been in the identification of HER2 overexpression in
response is made. If a response is noted, the subject continues on breast cancer and the oncogenic bcr–abl translocation in chronic
the investigational drug, whereas if progression (or excess toxicity) myelogenous leukemia and the prescription of monoclonal anti-
is noted, the subject is removed from trial and allowed to receive bodies (trastuzumab, Herceptin) and TKIs (imatinib, Gleevec)
alternative treatment. Those patients who meet stable disease cri- against these key pathways (also the basis for Bayesian approaches
teria enter the second stage of the RDT and are randomized to previously mentioned). 86–88 Veterinary oncology has also ben-
continue on the investigational drug or placebo (the discontinu- efited from molecular-based approaches, most notably in the tar-
ation arm). Then, at predetermined times, follow-up determina- geting of c-kit mutations in canine mast cell tumors. 48,89 TKIs
tions are made. Endpoints in stage II of the trial at these follow-up (toceranib and masitinib) have shown clinical utility against mac-
intervals are “stable or better” versus “progression.” Time-to-event roscopic disease and have been approved by the FDA for use in
measures may be applied as well (e.g., PFS, TTP), although this this setting. Although both agents are nonselective inhibitors that
takes more time to complete. If a subject progresses in the second also have activity against other key pathways (e.g., vascular endo-
stage, the code can be broken, and if that subject is in the pla- thelial growth factor receptor 2 [VEGFR2] for toceranib), their
cebo group, the investigational drug can be reinstituted. Therefore approval marks an important step forward in veterinary tumor
there are two ways for RDTs to be stopped: there are a substantial biology-based therapeutics and sets the stage for future directed
number of objective responses noted in the run-in phase making research in other tumor types.
a second stage unnecessary, or the number of subjects progress- The field of personalized medicine expands beyond patient
ing in the second stage differs statistically between the treatment prescription to also include the study of patient pharmacogenom-
and placebo groups. It becomes intuitive that the length of the ics and pharmacometabolics, the genetic variation of response
run-in phase is critical to RDTs: if it is too long, some initially and metabolism of novel agents or medications. These include
responding patients progress during the late stage of the run-in the study of individual patient single nucleotide polymorphisms
and are missed (therefore increasing subject numbers); if it is too (SNPs) in key metabolic pathways (cytochrome p450) and the
short, insufficient enrichment occurs (not enough time for non- measurement of metabolites in blood and urine. An example of
responders to progress) and the randomization might as well have this in veterinary oncology is the use of multidrug resistance gene
been done at the outset. The two major advantages of RDTs are 1 (MDR1) mutation analysis in certain herding breeds (e.g., col-
that all subjects receive the drug up front so that every patient is lies and shelties) before initiating MDR1 substrate chemothera-
given a chance to respond to the drug (something that is popular peutic agents (e.g., doxorubicin and vincristine).
with patients [or companion animal owners]) and enrichment of Newer personalized medicine approaches based on com-
likely responders may increase power and decrease subject num- plex mathematical algorithms have been created that include a
bers. Potential disadvantages of RDTs include the ethics of discon- broader base of tumor characteristics to define potential treat-
tinuation (but the design can allow reinstitution), the potential for ments. The use of pretreatment biopsies to create prospective
a carryover effect of the drug after discontinuation (unlikely for molecular profiles has been modeled by the COTC in veterinary
most targeted agents), and failure to detect short duration activity patients and found to be achievable in a practical clinical win-
(but this would likely be a clinically irrelevant duration anyway). dow. More recently, so called “liquid biopsy” techniques have
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RDTs can be improved by combining other modifications of been developed whereby tumor DNA in blood is used to detect,
clinical trials, such as interim analysis and Bayesian analysis, and track, and develop personalized treatment protocols in cancer
by using active controls. For purposes of illustration, an RDT in patients. The publication of the canine genome and the advent
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veterinary medicine that the authors have considered would be the of high-throughput technologies have enabled the field of vet-
investigation of a cytostatic agent in dogs with pulmonary meta- erinary oncology to describe canine cancer biology and charac-
92
static OSA. All dogs would enter the run-in phase, receive the terize potential therapeutic targets more globally. This creates
cytostatic drug for 4 weeks, and then be evaluated for response. the opportunity for personalized medicine investigations in the
From what we already know about the natural history of OSA dog to inform novel therapy development for both veterinary and
in dogs, most (probably 80%) of dogs that did not receive treat- human oncology patients using these algorithmic approaches. In
ment would progress in that period. Those that were stable at 4 addition, strong cancer breed predilections support “breed-based”