Oral Akynzeo® vs Standard of Care in Preventing CINV in High-risk MEC Patients (MyRisk)

Study Overview
=================
Brief Summary
-----------------
MyRisk: Efficacy and safety evaluation of oral Akynzeo® in patients receiving MEC at high risk of developing CINV based on a prediction tool. A multinational and multicenter study. Antiemetic guidelines recommendations are based on the emetogenic potential of the chemotherapy. Chemotherapy (CT) agents are divided in Highly, Moderately, Low and Minimally Emetogenic potential. In addition to type of chemotherapy, several patient-related risk factors can increase the risk of CINV (chemotherapy-induced nausea and vomiting). Currently, there is limited consensus surrounding the most relevant patient risk factors that may predict the risk of CINV. Based on a recent study by Dranitsaris et al. (Dranitsaris et al. Ann Oncol. 2017 Jun 1; 28(6):1260-1267.), eight (8) predictive factors have been identified and an algorithm has been developed to incorporate these factors into the optimal selection of prophylactic antiemetics: nausea and/or vomiting in the prior cycle of chemotherapy use of non-prescribed antiemetics at home in the prior cycle of chemotherapy platinum or anthracycline-based chemotherapy age < 60 years expectations for (anticipating) nausea and/or vomiting <7 h of sleep the night before chemotherapy history of morning sickness during previous pregnancy cycle of chemotherapy (A negative association between risk and number of cycles was identified where the hazard for CINV was highest in cycles 1 and 2, with a gradual decline and plateau from cycle 3 onward). The clinical application of this prediction tool has the potential to be an important resource for clinicians and may help to enhance patient care by optimizing the use of the antiemetics in a proactive manner.

Detailed Description
-----------------
Antiemetic guideline recommendations are based on the emetogenic potential of chemotherapy and involve 4 levels of classification of intravenous chemotherapy agents, i.e., high, moderate, low and minimal; these have been accepted by major organisations. Moderate emetogenic chemotherapy (MEC) results in acute vomiting in 30% to 90% of cancer patients in the absence of antiemetic therapy. In addition to the chemotherapy type, several patient-related risk factors and clinical characteristics can increase CINV risk. These can include use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, no complete CINV response in an earlier cycle, history of nausea/vomiting, (trait) anxiety, fatigue experience, and expectations of nausea/vomiting. Other studies have largely confirmed some of the key risk factors for CINV (history of vomiting during pregnancy, history of motion sickness, age, gender) and added other factors such as (chronic) alcohol consumption, body surface area, fewer hours slept the night prior to infusion, or advanced stage cancer. Currently, there is a limited consensus surrounding the most relevant patient risk factors that may predict CINV risk. Based on a recent study by Dranitsaris et al. eight predictive factors have been identified, and an algorithm has been developed to combine these patient-related risk factors into the optimal treatment of prophylactic antiemetics. These include: nausea and/or vomiting in the prior cycle of chemotherapy use of non-prescribed antiemetics at home in the prior cycle of chemotherapy platinum or anthracycline-based chemotherapy age < 60 years expectations for (anticipating) nausea and/or vomiting <7 h of sleep the night before chemotherapy history of morning sickness during previous pregnancy cycle of chemotherapy (A negative association between risk and number of cycles was identified where the hazard for CINV was highest in cycles 1 and 2, with a gradual decline and plateau from cycle 3 onward). Akynzeo®, an oral combination of the neurokinin 1 receptor antagonists (NK1 RA), netupitant and the 5-hydroxytryptamine (HT3) receptor antagonists (5-HT3 RA), palonosetron, is recommended by guidelines for the prevention of CINV. Akynzeo® has been evaluated in a multicentre, randomised, double-blind, double-dummy phase II clinical trial at various dose ranges among 694 cisplatin-treated cancer patients from 44 sites (two countries); each NEPA (netupitant-palonosetron) dose significantly improves CINV prevention in cancer patients. Similar results were obtained in another international, randomised, double-blind and parallel group phase III clinical trial; NEPA prevented CINV in patients receiving MEC. The current study primarily aimed to evaluate whether Akynzeo® leads to a higher response rate compared with standard care in MEC regimen-treated patients who are identified to be at high risk based on the algorithm.

Official Title
-----------------
MyRisk: Efficacy and Safety Evaluation of Oral Akynzeo® in Patients Receiving MEC at High Risk of Developing CINV Based on a Prediction Tool: A Multinational and Multicenter Study

Conditions
-----------------
Chemotherapy-induced Nausea and Vomiting

Intervention / Treatment
-----------------
* Drug: NEPA (300mg netupitant/0.5mg palonosetron)
* Drug: Granisetron, 2 mg (oral) or 1 mg (IV) OR Palonosetron, 0.5 mg (oral), 0.25mg (IV) OR Ondansetron, 16 mg (oral) or 8 mg (IV) OR Dolasetron 100 mg (oral) OR Tropisetron 5 mg (oral or IV)
* Drug: Dexamethasone, 8 mg (oral) or equivalent IV dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients aged ≥18 years Patients with a risk score of ≥ 13 as calculated by the algorithm - see 3.6.3.1. Baseline/screening: VISIT 0 Signed Informed consent Both sexes Patients with diagnosis of any cancer scheduled and intended to be treated for three consecutive cycles with a single dose of any IV MEC regimen, per cycle, including adjuvant or neo-adjuvant chemotherapy Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Use of Standard of Care defined as a 5-HT3 RA + Dexamethasone (or equivalent corticosteroid) based-regimen on day 1 of chemotherapy for CINV prevention Naïve and non- naïve to chemotherapy The enrolled women should be a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test done by health care team within 1-24 hours before dosing the antiemetic treatment in both arms and outcome recorded in the medical records Able to comply with study requirements Exclusion Criteria: Patients receiving highly emetogenic chemotherapy (including anthracycline+cyclophosphamide-based chemotherapy) Patients receiving oral moderately emetogenic chemotherapy drugs Patients receiving opioids within 2 weeks prior to trial enrollment (longer use allowed) Use of olanzapine as prophylaxis of CINV Patients scheduled to receive radiotherapy concurrently with chemotherapy Any illness or condition that, in the opinion of the physician, may confound the results of the study or pose unwarranted risks in administering the investigational product to the patient. Patients with mechanical risk factors for nausea (i.e. intestinal obstruction) Patients with liver disease (as nausea is a common presenting symptom) Patients with metabolic risk factors for nausea (i.e. electrolyte imbalances causing nausea/vomiting) Chronic treatment with steroids (with the exception of inhaled or topical steroids) Pregnancy and/or breast-feeding women Women of childbearing potential refusing to use effective contraception during the whole study treatment and up to one month after study treatment with Akynzeo® Use of Standard of Care including an NK-1 RA-based regimen to prevent CINV

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: interventional, open label, randomized, active controlled, parallel arms, multicenter and multinational study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEPA (300mg netupitant/0.5mg palonosetron) + Dexamethasone 8 mg<br>Oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination on Day 1 of each cycle. Dexamethasone (8 mg) will be administered on Day 1 of each cycle. | Drug: NEPA (300mg netupitant/0.5mg palonosetron)<br>* Oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination on Day 1 of each cycle.<br>* Other names: Akynzeo® capsules;Drug: Dexamethasone, 8 mg (oral) or equivalent IV dose<br>* Dexamethasone (8 mg) will be administered on Day 1 of each cycle.<br>* Other names: corticosteroid;|
| Active Comparator: Standard of care + Dexamethasone 8 mg<br>Dexamethasone (or equivalent corticosteroids) 8 mg administered by the oral route (or equivalent IV dose) on Day 1, approximately 1 hour before chemotherapy and one of the 5-HT3-RAs recommended by European Society for Medical Oncology (ESMO) and Multinational Association of Supportive Care in Cancer (MASCC) guidelines (standard of care), i.e. either: Granisetron, 2 mg (oral) or 1 mg (IV) OR Palonosetron, 0.5 mg (oral), 0.25mg (IV) OR Ondansetron, 16 mg (oral) or 8 mg (IV) OR Dolasetron 100 mg (oral) OR Tropisetron 5 mg (oral or IV) | Drug: Granisetron, 2 mg (oral) or 1 mg (IV) OR Palonosetron, 0.5 mg (oral), 0.25mg (IV) OR Ondansetron, 16 mg (oral) or 8 mg (IV) OR Dolasetron 100 mg (oral) OR Tropisetron 5 mg (oral or IV)<br>* Standard of care will be administered on Day 1 of each cycle.<br>* Other names: 5-HT3 RA;Drug: Dexamethasone, 8 mg (oral) or equivalent IV dose<br>* Dexamethasone (8 mg) will be administered on Day 1 of each cycle.<br>* Other names: corticosteroid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of complete responses over three cycles of chemotherapy after the start of the MEC administration | To evaluate if the use of NEPA (netupitant and palonosetron) in patients treated with IV moderately emetogenic chemotherapy and at high risk of CINV is more effective in preventing CINV than a standard of care antiemetics over three cycles of chemotherapy. | At the end of all three chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of acute (0 to 24 hours), delayed (>24 to 120 hours), and overall (0-120 hours) CINV indicators in each cycle of chemotherapy | Proportion of: No emetic episode during the acute, delayed, and overall phase and daily in each cycle Number of vomiting episodes during the acute, delayed, and overall phase in each cycle No rescue medication during the acute, delayed, and overall phase and daily in each cycle No significant nausea (maximum MAT scale = 2) during the acute, delayed, and overall phase and daily in each cycle; No nausea (MAT scale = 0) during the acute, delayed, and overall phase and daily in each cycle; Complete protection (no emetic episode, no rescue medication, and no significant nausea) during the acute, delayed, and overall phase and daily in each cycle Time 0 is defined as the start time of the chemotherapy administration on Day 1 of each of the three cycles. | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the predictive role of potential risk factors in the development of CINV over three cycles of chemotherapy | Analysis of the development of CINV as a dependent variable will be performed to identify additional potential risk factors of CINV thought to be increasing the risk of CINV in patients receiving MEC. The outcome measure is the development of CINV, defined as any occurrence of nausea or a vomiting episode. The data on the development of CINV will be taken from data collection tools, patients' diaries and MASCC Antiemesis Tool (MAT). | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the safety profile of the antiemetic drug over three cycles of chemotherapy - the frequency of adverse events (AE) | An overall summary of adverse events (AE) will be presented, including the frequency of patients with: Any treatment-emergent adverse event Any treatment-emergent adverse event related to a study drug Any treatment-emergent adverse event leading to chemotherapy dose reductions or interruptions Any treatment-emergent serious adverse event All AEs will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the safety profile of the antiemetic drug over three cycles of chemotherapy - the percentage of adverse events (AE) | An overall summary of adverse events (AE) will be presented, including the percentage of patients with: Any treatment-emergent adverse event Any treatment-emergent adverse event related to a study drug Any treatment-emergent adverse event leading to chemotherapy dose reductions or interruptions Any treatment-emergent serious adverse event All AEs will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the frequency of discontinuations due to adverse events | The frequency of discontinuations due to adverse events (AE) will be presented. All AEs leading to discontinuation will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the percentage of discontinuations due to adverse events | The percentage of patients with discontinuations due to adverse events (AE) will be presented. All AEs leading to discontinuation will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of frequency of on treatment deaths due to adverse events | The frequency of on treatment deaths due to adverse events (AE) will be presented. All AEs leading to on treatment deaths will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of the percentage of patients with on treatment death due to adverse events | The percentage of patients with on treatment death due to adverse events (AE) will be presented. All AEs leading to on treatment death will be summarized by their: Severity Seriousness Relationship to a drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Listings concerning the safety profile of the antiemetic drug over three cycles of chemotherapy | The following listings will be presented: All AEs (including pre-treatment AEs) Serious adverse events Adverse events resulting in withdrawn of study drug | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Exploration of the effect of CINV on daily activities and quality of life in patients receiving moderately-emetogenic chemotherapy over three cycles of chemotherapy | Evaluation of the effect of CINV on daily activities and quality of life that will be measured by using the Functional Living Index-Emesis (FLIE) questionnaire, a validated, nausea and vomiting specific, patient-reported outcome instrument. The Functional Living Index-Emesis (FLIE) has 18 questions. These questions are divided into two domains: Nausea (questions 1-9) and Vomiting (questions 10-18). The minimum score for any question is 0 and the maximum score is 100. Higher scores indicate less impairment on daily life as a result of nausea or vomiting. | At the end of all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - number of days with rescue medication administered for the treatment of CINV | Health economic endpoint, the number of days with rescue medication administered for the treatment of CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - daily doses of rescue medication administered for the treatment of CINV | Health economic endpoint, the daily doses of rescue medication administered for the treatment of CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the number of re-hydration bags | Health economic endpoint, the number of re-hydration bags given for at least grade 2 vomiting (more details below), will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the number of days of unplanned hospitalisations | Health economic endpoint, the number of days of unplanned hospitalizations related to CINV, will be evaluated during the study cycles All hospitalizations will be summarized according to the department of hospitalization (type of ward) | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the number of outpatient physician visits | Health economic endpoint, the number of outpatient physician visits and health care consultations due to CINV (e.g., general practitioner), will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the number of unplanned laboratory test | Health economic endpoint, the number of unplanned laboratory test including those at unplanned hospitalizations due to CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - discontinuation of chemotherapy treatment due to CINV | Health economic endpoint, the number of discontinuations of chemotherapy treatment due to CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the number of delays of chemotherapy administration due to CINV | Health economic endpoint, the number of delays of chemotherapy administration due to CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - the average length of delay of chemotherapy administration due to CINV | Health economic endpoint, the average length of delay (in days) of chemotherapy administration due to CINV, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). | 
| Evaluation of resource utilization and health economic outcome - days of absence from work | Health economic endpoint, the number of days of absence from work, will be evaluated during the study cycles | At the end of each cycle and after all 3 chemotherapy cycles. The length of a cycle depends on the treatment being given (cycles range from 2 to 6 weeks). |