Journal Club

1
Journal Club

• October 23, 2007
• Leigh Marcus, MD
• Inspired by the TV series 24

2
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
3
The Dreaded Call

• The non formulary guy is not returning your page

133 pm
4
The Question

• Is there any additional agent in our
  armamentarium to alleviate, if not prevent, CINV?

252pm
5
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

6
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

702 pm
7
Aprepitant

• Substance P, regulatory peptide, caused emesis
  when injected into ferrets
• Neurokinin-1 (NK-1) antagonist
• 1931 vonEuler/Gaddum in equine brain and intestine

8
Aprepitant

• CNS (nucleus tractus solitarii and area postrema)
• GI tract (vagal afferents)
• vascular relaxation

9
Physiology

• SM NK-1 receptor, which is a G-protein receptor
  coupled to the inositol phosphate signal
  transduction pathway
• VM NO--gt inc cAMP and cGMP

10
Search Strategy

• Multicenter
• Randomized
• Double-blind
• Placebo controlled
• Clinical trial
• Aprepitant

1117pm
11
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

12
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

13
Phase 1

• first time test in humans
• studies in a small number of patients 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

14
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

15
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
• Expenive

16
Phase 4

• FDA
• Post-marketing to broaden indications
• Long-term safety

17
The Study

• Parallel groups
• Cisplatin naïve, scheduled for gt70mg/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

18
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

19
Figure 1 052 Study Trial
20
Treatment Groups
21
Cisplatin

• Single most emetogenic chemotherapeutic agent
  (Level 5 at gt50mg/m2)
• 50 who receive will get CINV (Hesketh gt90)

22
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

23
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)

24
VAS
25
Other endpoints

• 1. No emesis
• 2. No use of rescue therapy
• 3. Complete protection
• -no emesis, no rescue tx, nausea VASlt25mm
• 4. Total control
• -no emesis, no rescue tx, nausea VASlt5mm
• 5. Impact of CINV on daily life
• -FLIEgt108
• 6. No significant nausea
• -VASlt25
• 7. No nausea
• -VASlt5

26
Follow-Up

• Study site telephone contact Days 2-6
• Tolerability PE (vital signs and weights),
  laboratory, EKGs
• RTC Days 6 and 8, and between Days 19-29

27
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

28
Outcome

• Complete response
• 62.7 aprepitant (163 of 260 pts)

• 43.3 standard therapy (114 of 263 pts)

29
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

• 329AM

30
Secondary Analyses
31
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

32
Outcome

• Complete Response
• 72.7 aprepitant
• Plt0.001

• 52.3 standard therapy

• Take home point 20 percentage point difference!

505AM
33
Secondary Analyses
34
FLIE

• measured by total score
• minimal or no impact on daily life

35
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

36
Differences 052 Study

• Treatment-by-sex interaction significant plt0.001
• Only in standard arm, females CR 38.8 vs males
  60.5
• Smaller female pt since most CA ENT
• Gail and Simons Test not significant
  qualitative, pgt0.5
• 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

37
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

38
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 plt0.05
• Clinical significance, randomly assigned
• Therefore, needed 470 pt to have plt0.05

39
Efficacy analysis

• 052 Study 521 patients
• Latin Study 523 patients
• OUR SAMPLE SIZES WERE 500 PTS
• SIGNIFICANCE OF Plt0.001
• -did not need to enroll as many

40
What about the children?

• 052 study included 6 males between 12-17 yrs
• gt40kg
• Sarcoma, cisplatin naive
• Modified version of aprepitant vs standard
  treatment with mg/kg
• CR in 3/3 aprep vs 2/3 stnd

41
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

42
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

43
You act!

• 730AM rounds
• You ask the Heme/Onc Attending if Aprepitant
  would be an option for N.V.
• TO BE CONTINUED!!!!!

12noon
44
References

• Jack VanHoff, MD
• Hesketh, P. Defining the Emetogenicity of Cancer
  Chemotherapy Regimens Relevance to Clinical
  Practice. The Oncologist 19994(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
  2003214112-4119.
• 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 2003973090-3098.
• 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
  200545857-860.
• http//www.vivo.colostate.edu/hbooks/pathphys/dige
  stion/stomach/vomiting.html