Transcript Journal Club - Yale University

Journal Club
October 23, 2007
Leigh Marcus, MD
Inspired by the TV series: 24
The Case
• N.V. is a 14yr F hx
osteosarcoma
• “Kytril kid,” although she
still gets extreme
chemotherapy-induced
nausea and vomiting,
especially after end of tx
• Hx “bounce-back”
secondary to dehydration
after CINV
12noon
The Dreaded Call
• The non formulary guy is not returning your
page
1:33 pm
The Question
• Is there any additional
agent in our
armamentarium to
alleviate, if not
prevent, CINV?
2:52pm
Nausea and Vomiting 101
• Physiologically, nausea is typically associated with decreased
gastric motility and increased tone in the small intestine
• The chemoreceptor trigger zone
• Visceral afferents from the gastrointestinal tract (vagus or
sympathetic nerves) - these signals inform the brain of such
conditions as GI distention and mucosal irritation
• Visceral afferents from outside the gastrointestinal tract -signals
from bile ducts, peritoneum, heart and other organs
• Afferents from extramedullary centers in the brain - it is clear
that certain psychic stimuli (odors, fear), vestibular disturbances
(motion sickness) and cerebral trauma can result in vomit
The night goes on
• Still no return page
• As you gripe to your med/peds colleague during your
Indian food dinner in the PICU conference room, he
offers a suggestion to review the adult literature on
Aprepitant
• You head to micromedex, and then to pubmed.com
7:02 pm
Aprepitant
• Substance P,
regulatory peptide,
caused emesis when
injected into ferrets
• Neurokinin-1 (NK-1)
antagonist
• 1931
vonEuler/Gaddum in
equine brain and
intestine
Aprepitant
• CNS (nucleus tractus
solitarii and area
postrema)
• GI tract (vagal
afferents)
• vascular relaxation
Physiology
• SM: NK-1
receptor, which is
a G-protein
receptor coupled
to the inositol
phosphate signal
transduction
pathway
• VM: NO--> inc
cAMP and cGMP
Search Strategy
•
•
•
•
•
•
Multicenter
Randomized
Double-blind
Placebo controlled
Clinical trial
Aprepitant
11:17pm
Articles
• The Oral Neurokinin-1 Antagonist Aprepitant for
the Prevention of Chemotherapy-Induced
Nausea and Vomiting: A Multinational,
Randomized, Double-Blind, Placebo-Controlled
Trial in Patients Receiving High-Dose CisplatinThe Aprepitant Protocol 052 Study Group
• Addition of the Neurokinin 1 Receptor Antagonist
Aprepitant to Standard Antiemetic Therapy
Improves Control of CINV; Results from a
randomized, double-blind, placebo-controlled
trial in Latin America
Clinical Trial
• Any investigation in human subjects
intended to discover or verify the clinical,
pharmacokinetic, and/or other
pharmacodynamic (study of interactions
between drugs and living structures)
effects of an investigational product,
and/or to identify any adverse reactions to
an investigational product, with the object
of ascertaining its safety and/or efficacy
Phase 1
• first time test in humans
• studies in a small number of patient’s with
advanced cancer refractory to standard therapy
(20-100), usually in a hospital setting where they
can be closely watched should there be any side
effects
• purpose of these studies is to determine how the
experimental drug is absorbed, metabolized,
and excreted in humans
• beneficial effects of the drug and what types of
side effects occur as the dosage of the drug is
increased
Phase 2
• Provide pharmaceutical company and the FDA
with comparative information about the relative
safety of the experimental drug, the proper
dosage needed to treat the condition, and the
drug's effectiveness; least SE
• several months to a few years and may involve
up to hundreds of patients
• “open label,” or not blinded; can be randomized
to 2 different doses
Phase 3
• large-scale testing provides the
pharmaceutical company as well as the
FDA with a more thorough understanding
of the drug's effectiveness, benefits/risks,
and range/severity of possible adverse
side effects
• Compare to standard therapy
• Lasts several years, thousands of pts
• Expen$ive
Phase 4
• FDA
• Post-marketing to
broaden indications
• Long-term safety
The Study
•
•
•
•
•
Parallel groups
Cisplatin naïve, scheduled for >=70mg/m2
18yrs age and over
Histiologic solid tumors
Modified intent-to-treat
– Not all were included in efficacy analysis b/c not all randomized
patients finished study
-deaths prior to study initiation or finish
-received incorrect drug/wrong combination
-pt did not provide results
-40 pts data excluded after found “unreliable after
audit”
Modified Intent-to-treat
• 1. all patients who received cisplatin
• 2. took study drug
• 3. had at least one post treatment
assessment
• offers bias, although was acceptable in our
case…
Figure 1 052 Study Trial
Treatment Groups
Day
Standard Therapy
1
ondansetron 32mg IV aprepitant 125mg po
dex 20mg po
ondansetron 32mg IV
dex 12mg po
dex 8mg po twice
aprep 80mg po
daily
dex 8mg po daily
dex 8mg po twice
aprep 80mg po
daily
dex 8mg po daily
dex 8mg po twice
dex 8mg po daily
daily
2
3
4
Aprepitant Group
Cisplatin
• Single most
emetogenic
chemotherapeutic
agent (Level 5 at
>50mg/m2)
• 50% who receive will
get CINV (Hesketh
>90%)
Dexamethasone
• Corticosteroid
• Aprepitant increases dex levels
approximately two-fold
• Could confound efficacy and safety profile,
therefore 50% reduction of dex dose in
aprepitant arm
• Dex plasma exposure comparable
Primary Endpoint
• Complete response (no
emesis and no rescue
therapy) 5 days s/p
cisplatin
• Patients kept diaries and
used horizontal visual
analog scale 100mm
• Day 6 Functional Living
Index-Emesis
questionnaire (quality of
life)
VAS
Other endpoints
1. No emesis
2. No use of rescue therapy
3. Complete protection
-no emesis, no rescue tx, nausea VAS<25mm
4. Total control
-no emesis, no rescue tx, nausea VAS<5mm
5. Impact of CINV on daily life
-FLIE>108
6. No significant nausea
-VAS<25
7. No nausea
-VAS<5
Follow-Up
• Study site telephone
contact Days 2-6
• Tolerability: PE (vital
signs and weights),
laboratory, EKG’s
• RTC Days 6 and 8,
and between Days
19-29
Latin study
• 569 randomized
patients
– 44 not in efficacy
analysis
– 2 not in safety analysis
• 8 countries:
Argentina, Brazil,
Chile, Colombia,
Guatemala, Mexico,
Peru, Venezuela
Outcome
• Complete response:
• 62.7% aprepitant (163 • 43.3% standard
of 260 pts)
therapy (114 of 263
pts)
Outcome
• Aprepitant protected
two-thirds from CINV
after cisplatin with no
rescue meds in 5
days
• Standard therapy
protected less than
half
• 19% point difference
•3:29AM
Secondary Analyses
P<0.001
Aprepitant
Acute
82.8%
<24 hours
post chemo
Delayed
67.7%
>24 hours
post chemo
Standard
Therapy
68.4%
46.8%
052 study group
• 530 randomized
– 521 in efficacy
analysis
– 516 in safety analysis
• Multinational: USA
and 14 countries
• FDA requires studies
take place in USA
Outcome
• Complete Response:
• 72.7% aprepitant
• 52.3% standard
therapy
• P<0.001
•Take home point: 20 percentage point difference!
5:05AM
Secondary Analyses
P<0.001
Aprepitant
Standard
Therapy
Acute phase
89.2%
78.1%
Delayed phase
75.4%
55.8%
FLIE
Aprepitant
Standard
74%
64.3%
• measured by total score
• “minimal or no impact on daily life”
Differences: Latin Trial
• CYP3A4-metabolized chemotherapy (etoposide,
vinca alkaloids, taxanes) had greater serious
adverse events
• 26/164 aprepitant vs 14/164 standard
• Aprepitant and no CYP3A4 agents had less
serious adverse events
• Asthenia/fatigue, diarrhea, dizziness, hiccups
*CYP3A4 showed no difference with serious
adverse events in 052 study: further publication
Differences: 052 Study
• Treatment-by-sex interaction significant p<0.001
• Only in standard arm, females CR 38.8% vs
males 60.5%
• Smaller # female pt since most CA ENT
• Gail and Simon’s Test not significant qualitative,
p>0.5
– qualitative or crossover interactions occur when one
treatment is superior for some subsets of patients and
the alternative treatment is superior for other subsets
*No difference in Latin study: further publication
Final Answer
•
•
•
•
•
•
1043 patients overall
523 from aprepitant
520 from standard
ARR set at 15%, but actually had 20%
NNT = 5
CI 95% 4-6
Remember…
• Modified to treat was acceptable because the exclusions
where not related to study drug
• 15% pt difference anticipated between treatment groups
for primary endpoint of CR to yield p<0.05
– Clinical significance, randomly assigned
– Therefore, needed 470 pt to have p<0.05
Efficacy analysis
• 052 Study: 521 patients
• Latin Study: 523 patients
*OUR SAMPLE SIZES
WERE 500+ PTS
*SIGNIFICANCE OF
P<0.001
-did not need to enroll as
many
What about the children?
• 052 study included 6
males between 12-17 yrs
• >40kg
• Sarcoma, cisplatin naive
• Modified version of
aprepitant vs standard
treatment with mg/kg
• CR in 3/3 aprep vs 2/3
stnd
Why children are different
• Recall that there may be an association
when used with CYP3A4 agents
• Pediatric oncology commonly uses these
agents concomitantly
• Safety unknown
• Adolescents vs infants
N.V. case
• Decrease hospital
cost by decreasing
stay
• Preventing return to
hospital
• Decrease patient
anxiety and fear,
along with discomfort
• Increases quality of
life
You act!
• 7:30AM rounds
• You ask the
Heme/Onc Attending
if Aprepitant would be
an option for N.V.
• TO BE
CONTINUED!!!!!
12noon
References
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Jack VanHoff, MD
Hesketh, P. Defining the Emetogenicity of Cancer Chemotherapy Regimens:
Relevance to Clinical Practice. The Oncologist 1999;4(3):191-196.
Hesketh PJ, Grunberg SM, Gralla RJ, et al. The Oral Neurokinin-1 Antagonist
Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A
Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients
Receiving High-Dose Cisplatin-The Aprepitant Protocol 052 Study Group. J Clin
Oncol 2003;21:4112-4119.
Poli-Begelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the Neurokinin 1
Receptor Antagonist Aprepitant to Standard Antiemetic Therapy Improves Control of
CINV; Results from a randomized, double-blind, placebo-controlled trial in Latin
America. Cancer 2003;97:3090-3098.
Simeon Ramsey 12/13/00 The neuropeptide Substance P.
Smith A, Repka T, Weigel B.Aprepitant for the control of Chemotherapy induced
nausea and vomiting in adolescents. Pediatr Blood Cancer 2005;45:857-860.
http://www.vivo.colostate.edu/hbooks/pathphys/digestion/stomach/vomiting.html