RCT of Olanzapine for Control of CIV in Children Receiving Highly Emetogenic Chemotherapy

Study Overview
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Brief Summary
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Chemotherapy-induced nausea and vomiting (CINV) are among the most bothersome symptoms during cancer treatment according to children and their parents. Most children receiving highly emetogenic chemotherapy (HEC), including those receiving hematopoietic stem cell transplant (HSCT) conditioning, experience CIV despite receiving antiemetic prophylaxis. Olanzapine improves CINV control in adult cancer patients, has a track record of safe use in children with psychiatric illness, does not interact with chemotherapy and is inexpensive. We hypothesize that the addition of olanzapine to standard antiemetics will improve chemotherapy-induced vomiting (CIV) control in children receiving highly emetogenic chemotherapy

Official Title
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Randomized Controlled Trial of Olanzapine for the Control of Chemotherapy-induced Vomiting in Children Receiving Highly Emetogenic Chemotherapy

Conditions
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Vomiting in Infants and/or Children, Nausea, Hematopoietic System--Cancer, Oncology

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Planned receipt of HEC or cyclophosphamide ≥ 1 g/m2/day (≥ 33 mg/kg/day) for cancer treatment or autologous or allogeneic HSCT conditioning.81,82 Examples of HEC are: busulfan IV (myeloablative dosing), carboplatin ≥175mg/m²/dose, cisplatin ≥12mg/m²/dose, cytarabine ≥3g/m²/day, melphalan >140mg/m², methotrexate ≥12g/m²/dose and thiotepa ≥300mg/m²/dose. Plan for inpatient admission from administration of first study drug dose until 24 hours following administration of last study drug dose. Body weight of at least 12.5 kg 2.5 to < 18 years of age. Note that the minimum age requirement corresponds to an approximate body weight of 12.5 kg. Samples for all laboratory tests will be obtained within one week prior to administration of the first chemotherapy dose of the study chemotherapy block or the first HSCT conditioning dose: Plasma creatinine within 1.5 times the upper limit of normal for age. Amylase within age-appropriate limits Plasma conjugated bilirubin within ≤ 3x upper limit of normal for age unless attributable to Gilbert's Syndrome ALT ≤ 5x upper limit of normal for age Baseline ECG within the month prior to study drug administration without known clinically significant abnormalities including pathologic prolongation of QTc A plan for scheduled, round-the-clock receipt of ondansetron, granisetron or palonosetron for antiemetic prophylaxis during administration of chemotherapy or HSCT conditioning. Negative pregnancy test if female of childbearing potential Patients of childbearing potential must consent to use adequate contraception (males and females) or agree to practice abstinence Parent or child able to speak a language in which the (modified Pediatric Adverse Event Rating Scale (PAERS) is available. Optional: Child participants in the optional assessment of nausea severity must be 4 to 18 years of age. Child and a parent/guardian must be English, Spanish or French-speaking. The Pediatric Nausea Assessment Tool58 (PeNAT) is validated in English-speaking children 4 to 18 years old with an English-speaking parent/guardian and has been translated into Spanish and French. The MAT is available in English, Spanish and French.

Ages Eligible for Study
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Minimum Age: 30 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Olanzapine<br>Standard antiemetics plus olanzapine | Drug: Olanzapine<br>* olanzapine 0.1 mg/kg/dose (maximum 10 mg/dose) by mouth as a single daily dose based on actual body weight<br>|
| Placebo Comparator: Placebo Oral Tablet<br>Standard antiemetics plus placebo | Drug: Placebo Oral Tablet<br>* Placebo tablets that look like olanzapine and will be dosed as if they are olanzapine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of CIV control during the acute phase | Complete CIV control is no vomiting/retching and no use of breakthrough antiemetic agents during phase | up to 8 days | 
| Rate of CIV control during the acute phase | Partial control is defined as no more than two vomits or retches during any 24-hr period | up to 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete and partial CINV control | Complete CIV control is no vomiting/retching and no use of breakthrough antiemetic agents during phase, Partial control is defined as no more than two vomits or retches during any 24-hr period | up to 1 month | 
| Safety profile of olanzapine based on toxicities | Based on descriptive statistics on reported toxicities. | up to 1 month | 
| Safety profile of olanzapine based on weight | Based on descriptive statistics on reported body weight | up to 1 month | 
| Safety profile of olanzapine based on Pediatric Adverse Event Rating Scale (PAERs) | Based on descriptive statistics on reported PAERs, will describe the most reported and most bothersome adverse events reported in the PAERs questionnaire. | up to 1 month | 
| Safety profile of olanzapine based on prolactin | Based on descriptive statistics on reported prolactin, will report incidence of abnormal prolactin values comparing the two arms | up to 1 month | 
| Safety profile of olanzapine based on amylase | Based on descriptive statistics on reported amylase, will report incidence of abnormal amylase values comparing the two arms | up to 1 month | 
| Safety profile of olanzapine based on creatine phophotase | Based on descriptive statistics on reported creatine phophotase, will report incidence of abnormal creatine phophotase values comparing the two arms | up to 1 month | 
| Safety profile of olanzapine based on triglycerides | Based on descriptive statistics on reported triglycerides, will report incidence of abnormal triglyceride values comparing the two arms | up to 1 month | 
| Impact of olanzapine on HSCT outcomes on incidence of veno-occlusive disease | Looking at incidence of veno-occlusive disease | From first HSCT conditioning dose until 100 days post-HSCT | 
| Impact of olanzapine on HSCT outcomes on incidence of GVHD | Looking at incidence of GVHD between the two arms | From first HSCT conditioning dose until 100 days post-HSCT | 
| Impact of olanzapine on HSCT outcomes on severity of GVHD | Comparing the incidence of the different maximal grades of GVHD between the two arms | From first HSCT conditioning dose until 100 days post-HSCT | 
| Association between PeNAT and MASCC Antiemesis Tool (MAT) scores | taking maximum daily PeNAT scale score and maximum nausea experience in MAT will estimate the degree of association between PeNAT and MAT | up to 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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olanzapine, vomiting, children, adolescents, bone marrow transplant, supportive care