Pediatric Trials 23/04/2018. Disclosures. Nausea and Vomiting Control in Adults and Children: Mind the Gap! Learning Objectives

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1 Nausea and Vomiting Control in Adults and Children: Mind the Gap! Disclosures No relevant conflicts of interest Lee Dupuis, RPh, PhD May 5, Learning Objectives At the end of this presentation, attendees will be able to: 1) Describe guideline-consistent CIV prophylaxis for pediatric patients 2) Compare CIV control rates in adult and pediatric patients and 3) Identify possible explanations for the relatively low CIV control rate seen in pediatric patients.. guideline-based antiemetic treatment.. has largely alleviated acute emesis,... Rojas & Slusher. Cancer Treatment Reviews 2015; 41: newer drugs.are extremely effective in suppressing chemotherapy-induced nausea and vomiting to almost negligible levels.... Mehta et al. J Soc Health Diab 2016; 4: 57 Control of vomiting has improved markedly... attention should shift to control of nausea... Roila et al. Ann Oncol 2016; 27 (Supp 5): v Is the experience of children different? Pediatric Trials Palonosetron: Kovacs (Lancet Oncology 2016) 5 6 1

2 Pediatric Trial: Palonosetron Adult Trial: Palonosetron Study design Double blind, double dummy Non-inferiority phase 3 RCT G3 Subjects N=493 Ages 0-<17yr palonosetron 10 µg/kg IV once (max: 0.75 mg/dose) ± corticosteroid palonosetron 20 µg/kg IV once (max: 1.5 mg/dose) ± corticosteroid ondansetron 150 µg/kg/dose (max: 10.7 mg/dose) IV q4h x 3 ± corticosteroid Naïve or not to chemo Received MEC or HEC on day 1 52% received single day chemotherapy Complete response: no vomiting, no retching or use of rescue medication Lancet Onc 2009; 10: Adult trial: Palonosetron - HEC Study design Double-blind, double-dummy, stratified, parallel-group, active-comparator RCT Day 1: palonosetron 0.75 mg IV x 1 + dexamethasone 16 mg IV x 1 Day 2-3: dexamethasone 8 a mg IV OR 4 b mg PO once daily Day 1: granisetron 40 µg/kg IV x 1 + dexamethasone 16 mg IV x 1 Day 2-3: dexamethasone 8 a mg IV OR 4 b mg PO once daily Subjects N=1,114 Mean age = 58 yr Naïve to MEC and HEC Received HEC on day 1 Number receiving single-day chemo unknown Complete response: no emetic episodes and no rescue medication Palonosetron: Adults vs. Children Acute Complete Response Rate Adults PALONOSETRON +/- DEXAMETHASONE palonosetron: a 75% granisetron: a 73% a all patients received dexamethasone; b an unknown number of patients received dexamethasone Children palonosetron: b 51% ondansetron: b 41% 9 10 Pediatric Trial - Aprepitant Pediatric Trial Aprepitant Lancet Oncology 2015; 16: Study design Randomized, double blind, placebo-controlled trial Subjects N=302 Day 1: ondansetron + aprepitant 3 mg/kg (max: 125 mg) PO and 2 mg/kg (max: 80 mg) PO on days 2 and 3 ± dexamethasone IV Day 1: ondansetron + placebo ± dexamethasone IV Day 2-3: placebo ± dexamethasone IV 200 receiving HEC* : 99 : receiving MEC* : 53 : 49 Complete response: no vomiting, no retching and no use of rescue medication

3 Adult Trial Aprepitant Adult Trial Aprepitant HEC JCO 2003; 21: Study design Randomized, double blind, placebo-controlled trial Day 1: ondansetron 32 mg IV + dexamethasone 20 mg PO + placebo Day 2-4: dexamethasone 8 mg BID PO + placebo Day 1: ondansetron 32 mg IV + dexamethasone 12 mg PO + aprepitant 125 mg PO Day 2-3: dexamethasone 8 mg once/day PO + aprepitant 80 mg PO Subjects N=521 Mean age ~ 58 yr Cisplatin naïve Number receiving single-day chemo unknown Complete response: no emetic episodes and no rescue medication Aprepitant: Adults vs. Children Adults Children 5-HT3 a +/- DEXAMETHASONE +APREPITANT/PLACEBO - HEC Acute Complete Response Rate aprepitant: a 89% placebo: a 78% aprepitant: b 65% placebo: b 51% Antiemetic Agents Agent FDA Approval Date Adult Pediatric Aprepitant Palonosetron Ondansetron a all patients received dexamethasone; b 0 to 44% of patients received dexamethasone; Clinical Practice Guidelines - HEC Pediatric Oncology Group of Ontario 2017 children 6 months old receiving HEC which is not known or suspected to interact with aprepitant receive: granisetron or ondansetron or palonosetron + dexamethasone + aprepitant. Strong recommendation Moderate quality evidence Multinational Association of Supportive Care in Cancer/ESMO 2016 Children receiving HEC: 5-HT3 RA (granisetron, ondansetron, tropisetron or palonosetron) + dexamethasone + aprepitant American Society of Clinical Oncology 2017 Pediatric patients treated with high emetic risk antineoplastic agents should be offered a three-drug combination of a 5-HT 3 receptor antagonist + dexamethasone + aprepitant. MASCC level of confidence: high; MASCC level of consensus: high; ESMO level of evidence: II; ESMO grade of recommendation: B Type: evidence based, benefits outweigh harms; Quality of evidence: intermediate; Strength of recommendation: strong Pediatr Blood Cancer 2017; 64(10): e

4 Dexamethasone: Survey of 36 COG sites 2 NEVER used dexamethasone as an antiemetic 29 different dosing regimens in 34 sites 3 of 34 gave CPG-recommended dexamethasone dose Concerns: 19 Immediate adverse events: hyperglycemia (63%); hypertension (52%); bradycardia (46%); dyspepsia (24%); changes in mood/behaviour (9%) Late adverse events: invasive fungal infection; in HSCT - impaired engraftment; cancer relapse Pediatr Blood Cancer 2016;63: JPHO 2018 in press Aprepitant: Extemporaneous oral liquid 20 stable x 90 days refrigerated Support Care Cancer (2009) 17: Potential chemo-aprepitant interactions Moderate CYP3A4 inhibitor: Increases AUC of victim drug by 2- to 5-fold Clinically significant interaction: Geometric mean ratio (GMR) Cmax with/without < 0.8 or > 1.25 OR GMR AUC with/without < 0.8 to > 1.25 Aprepitant Chemotherapy Interactions: Clinically significant interaction: Possibly significant interaction: Possibly no clinically significant interaction: No clinically significant interaction: bosutinib PO cabazitaxel IV cyclophosphamide IV erlotinib (route NR) ifosfamide IV pazopanib PO thiotepa IV melphalan IV dinaciclib IV docetaxel IV vinorelbine IV Barriers to Controlling CINV Who is at higher risk of CINV? Treatment-related risk factors Chemotherapy emetogenicity pediatric vs adult Duration of chemotherapy block? 1-day vs. multiple Patient-related risk factors sex, age, history of motion sickness, genetics? Br J Clin Pharmacol. 2017; 83(10):

5 Feedback from Children It's nice & short an app that you can flip to now and then you don't wanna have to waste 20 minutes on it I think this is a good way for you to communicate with doctors and nurses because some kids are shy and don't want to talk to anybody, they would rather complete SSPedi than talk to someone Pediatric Nausea Assessment Tool (PeNAT) It's nice, short and it works! [Animations] add a little bit extra, something different; it's not just a list of questions Pharmacotherapy 2006; 26:1221 Adapted from: Wong D et al. Pediatric Nursing 1988;14: Severely Bothersome Symptoms Symptom Any Bother Severe Bother Any Symptom 99% 60% Pain 78% 22% The future... no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention and no nausea-related change in the child s usual appetite and diet. 22% had vomited yesterday or today 33% reported nausea Mild: 25% Moderate: 6% Severe 2% To get to the future... Provide CPG-consistent CIV prophylaxis Screen for symptom severity Equip patients to report nausea and vomiting severity and Listen and respond Acknowledgements Collaborators: Lillian Sung, Paula Robinson Jacqueline Flank, Jason Freedman CINV Guideline Panel members Team: Mila Khanna, Araby Sivananthan Ashlee Vennettilli Graduate Students: Priya Patel; Edric Paw Cho Sing