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