Feasibility of Olanzapine at REduced doSe in hIGHly Emetogenic chemoTherapy

Study Overview
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Brief Summary
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Olanzapine is frequently used off-label as an adjunct antiemetic in clinical oncology settings. North American oncology guidelines recommend it as salvage therapy and as add-on to the standard triple regimen; some suggest it may also be effective as an initial triple therapy (olanzapine replacing the NK-1 antagonist) based on phase II and III trials. This prospective, multi-center, open-label study aims to evaluate the feasibility of a large scale randomised controlled trial to compare the effectiveness and tolerability of 5mg orally once daily olanzapine in triple antiemetic therapy versus the standard treatment of aprepitant + ondansetron + dexamethasone in treatment-naive patients receiving the first cycle of a highly emetogenic chemotherapy. Secondary outcomes include effectiveness, tolerability and quality of life assessments. Effectiveness will be measured with complete response and complete remission rates in each treatment arms. Tolerability and patient quality of life will be evaluated with a standardised side effect form and validated questionnaires; ESAS-R and FLIE. The role of olanzapine-based triple therapy in prevention of chemotherapy-induced nausea and vomiting remains founded on low-quality evidence. To the investigator's knowledge, this study will be the first large scale direct comparison of 5mg olanzapine versus aprepitant in triple therapy.

Official Title
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FORESIGHT: Feasibility of Olanzapine at REduced doSe in hIGHly Emetogenic chemoTherapy: a Randomised Controlled Trial Against Aprepitant in Triple Therapy

Conditions
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Chemotherapy-induced Nausea and Vomiting

Intervention / Treatment
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* Drug: Zyprexa® (OLANZapine 5MG)
* Drug: Emend® (Aprepitant)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients receiving a first cycle of highly emetogenic chemotherapy (or having received one more than 2 years prior to randomisation) at the oncology outpatient clinic at Charles LeMoyne or Haut-Richelieu hospital between April 29th and September 20th 2019. 18 years old and over Patient receiving highly emetogenic chemotherapy ECOG from 0 to 2 inclusively Creatinine clearance ≥ 30ml/min; total bilirubin ≤ 1.5 x ULN, AST/ALT ≤ 3.0 x ULN Patient without electrolytic imbalance or corrected imbalance Signed written and informed consent Exclusion Criteria: Patient doesn't speak french or english Patient to receive treatment whose protocol includes a second dose of highly emetogenic chemotherapy before day 6 of the cycle Patient to receive chemotherapy treatment that already contains corticosteroids (dexamethasone or prednisone) given as antineoplastic Nausea or vomiting present ≤ 24h before randomisation Untreated brain metastases Severe cognitive disorder or dementia or inability to properly understand or document the presence of nausea or vomiting or the use of salvage therapy History of uncontrolled cardiac arrhythmia, unstable angina or known QT prolongation (> 500ms) Uncontrolled diabetes Patient to receive abdominal radiotherapy during the first cycle of chemotherapy Bowel obstruction, intestinal ileus or ascites present at cycle 1 Chronic alcoholism Severe uncontrolled psychologic disorder Patient taking antipsychotic treatment on a regular basis Patient taking drugs with a contraindication when administered concurrently with one of the protocol drugs Dysphagia (incapacity to swallow the pills included in the study) Hypersensitivity, severe reaction or allergy to one of the study treatments Participation in another research protocol Pregnancy or breastfeeding Subject that does not have a valid phone ou email address

Ages Eligible for Study
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Minimum 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment group<br>Olanzapine in combination with ondansetron and dexamethasone | Drug: Zyprexa® (OLANZapine 5MG)<br>* Olanzapine 5mg orally at bedtime for 4 days (starting the day before the chemotherapy) Ondansetron 16mg orally pre-chemotherapy on day 1 Dexamethasone 12mg orally pre-chemotherapy on day 1 Dexamethasone 8mg orally twice a day for 6 doses (starting on the morning of day 2)<br>* Other names: Zyprexa®;|
| Active Comparator: Standard treatment group<br>Aprepitant in combination with ondansetron and dexamethasone | Drug: Emend® (Aprepitant)<br>* Aprepitant 125mg orally pre-chemotherapy on day 1, then 80mg orally once daily on days 2 and 3 Ondansetron 16mg orally pre-chemotherapy on day 1 Dexamethasone 12mg orally pre-chemotherapy on day 1 Dexamethasone 8mg orally once daily for 3 doses (starting on the morning of day 2)<br>* Other names: Emend®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients recruited | At least 60 patients over 5 months meet the eligibility criteria and agree to participate. | 5 months | 
| Eligible patients' interest to participate | At least 35% of all eligible patients agree to participate | 5 months | 
| Completion of the diary | At least 75% of recruited patients complete 100% of their patient diary. | 5 months | 
| Cost | The total cost of the study does not exceed 10,000$ | 5 months | 
| Number of centres | The study can be done at two sites. | 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare effectiveness of olanzapine 5mg versus standard aprepitant in a triple antiemetic therapy in patients receiving a first cycle of highly emetogenic chemotherapy in regard of proportion of participant with complete response in the overall phase. | Overall phase was defined as 0 to 120 hours following initiation of chemotherapy. Complete response was defined as no nausea, no vomiting and no rescue therapy. Intensity of nausea episodes will be measured with a 0 to 10 visual scale. Intensity of vomiting episodes will be measured with a 0 to 10 visual scale. | 0 to 120 hours | 
| Compare effectiveness of olanzapine 5mg versus standard aprepitant in a triple antiemetic therapy in patients receiving a first cycle of highly emetogenic chemotherapy in regard of proportion of participant with complete remission in the overall phase. | Overall phase was defined as 0 to 120 hours following initiation of chemotherapy. Complete remission was defined as no vomiting and no rescue therapy. Intensity of vomiting episodes will be measured with a 0 to 10 visual scale. | 0 to 120 hours | 
| Compare tolerability of olanzapine 5mg versus standard aprepitant in a triple antiemetic therapy in patients receiving a first cycle of highly emetogenic chemotherapy in regard of prevalence of adverse events due to the antiemetic therapy in each arm. | Proportion of patients who experienced adverse events associated with each of the treatment arms. Adverse events obtained according to the ESAS-R questionnaire and a follow-up interview at the second cycle of chemotherapy. Definition and gradation of adverse events would be following the Common Terminology Criteria for Adverse Events (CTCAE) 5th edition. | During the complete duration of the first cycle of chemotherapy (1 cycle is 14 to 28 days) | 
| Compare patient's assessment of quality of life between those receiving olanzapine 5mg and those receiving standard aprepitant in a triple antiemetic therapy in patients receiving a first cycle of highly emetogenic chemotherapy. | Quality of life score obtained according to the FLIE questionnaire | 0 to 120 hours |