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 Cisplatin-The 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 GroupsDay Standard Therapy Aprepitant Group
1 ondansetron 32mg IV
dex 20mg po
aprepitant 125mg po
ondansetron 32mg IV
dex 12mg po
2 dex 8mg po twice daily
aprep 80mg po
dex 8mg po daily
3 dex 8mg po twice daily
aprep 80mg po
dex 8mg po daily
4 dex 8mg po twice daily
dex 8mg po daily
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 emesis2. No use of rescue therapy3. Complete protection
-no emesis, no rescue tx, nausea VAS<25mm4. Total control
-no emesis, no rescue tx, nausea VAS<5mm5. Impact of CINV on daily life
-FLIE>1086. No significant nausea
-VAS<257. 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 of 260 pts)
• 43.3% standard 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 AnalysesP<0.001 Aprepitant Standard
Therapy
Acute
<24 hours post chemo
82.8% 68.4%
Delayed
>24 hours post chemo
67.7% 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
• P<0.001
• 52.3% standard therapy
•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• 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