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 1:33 pm

4. The Question Is there any additional agent in our armamentarium to alleviate, if not prevent, CINV? 2:52pm

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 7:02 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--> inc cAMP and cGMP

10. Search Strategy Multicenter Randomized Double-blind Placebo controlled Clinical trial Aprepitant 11:17pm

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 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

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 Expen$ive

16. Phase 4 FDA Post-marketing to broaden indications Long-term safety

17. 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”

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 DayStandard TherapyAprepitant Group 1ondansetron 32mg IV dex 20mg po aprepitant 125mg po ondansetron 32mg IV dex 12mg po 2dex 8mg po twice daily aprep 80mg po dex 8mg po daily 3dex 8mg po twice daily aprep 80mg po dex 8mg po daily 4dex 8mg po twice daily dex 8mg po daily

21. Cisplatin Single most emetogenic chemotherapeutic agent (Level 5 at >50mg/m2) 50% who receive will get CINV (Hesketh >90%)

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 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

26. 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

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 3:29AM

30. Secondary Analyses P<0.001AprepitantStandard Therapy Acute <24 hours post chemo 82.8%68.4% Delayed >24 hours post chemo 67.7%46.8%

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 P<0.001 52.3% standard therapy Take home point: 20 percentage point difference! 5:05AM

33. Secondary Analyses P<0.001AprepitantStandard Therapy Acute phase89.2%78.1% Delayed phase75.4%55.8%

34. FLIE AprepitantStandard 74%64.3% 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 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

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 p<0.05 –Clinical significance, randomly assigned –Therefore, needed 470 pt to have p<0.05

39. 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

40. 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

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! 7:30AM 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 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