Olanzapine for Nausea/Vomiting Prophylaxis in Recipients of Hematopoietic Stem Cell Transplants

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to see if olanzapine helps to prevent nausea and/or vomiting (throwing up) when it is added to other medicines in subjects having stem cell transplants. Subjects will either be given olanzapine or an inactive pill (called a placebo) before getting any chemotherapy that is known to cause nausea and vomiting. During the study, the study coordinators will ask the subjects to complete surveys to understand if the patient is having nausea and vomiting, and if so, how bad it is making the patient feel. This trial will split subjects into two groups: one group will be given an inactive pill (placebo), and the other group will be given the active pill (olanzapine). Study coordinators will collect surveys every morning before chemotherapy and 5 days after the last dose of chemotherapy. These surveys may be given by members of the study team or possibly on a mobile device. Subjects may benefit from being in this research study because olanzapine may reduce the frequency or severity of chemotherapy-induced nausea and vomiting (CINV). The most common risks of using olanzapine include possibly becoming more tired, mild dizziness, mild low blood pressure, and mild muscle quivering. Other possible adverse effects include low blood pressure, muscle weakness, increased appetite, weight gain, constipation, and liver function test changes however these risks are less common in subjects with cancer. In addition, there may be a change detected in heart rhythm however subjects will be screened for this ahead of time.

Detailed Description
-----------------
Chemotherapy induced nausea and vomiting (CINV) occurs in up to 80% of patients on active therapy and remains a significant barrier to quality of life. CINV can alter electrolytes and enteral nutrition which can have a detrimental effect on patient adherence and health outcomes. Hematopoietic Stem Cell Transplant (HCT) patients are at increased risk for CINV because many of the conditioning regimens require multiple days of high-dose chemotherapy that are, in many cases, associated with highly-emetogenic potential. Thus, most conditioning regimens require a 3-drug regimen for optimal CINV prophylaxis. Current Standard of Care Current guidelines support the use of olanzapine in addition to a 3 drug CINV regimen for highly emetogenic chemotherapy, however some controversy remains as to olanzapine's place in therapy with moderately emetogenic chemotherapy. In HCT, current practice at University of North Carolina utilizes an neurokinin-1 receptor antagonist (NK1 RA), serotonin receptor antagonists (5-HT3 RA) and corticosteroid for CINV prophylaxis in conditioning regimens including moderate and highly emetogenic chemotherapy in accordance with American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommendations. Olanzapine, an atypical antipsychotic, antagonizes dopamine, serotonin, catecholamines, acetylcholine, and histamine receptors which helps prevent acute, breakthrough and delayed nausea. Olanzapine has shown benefit when used as prophylaxis in solid tumor patients receiving single-day highly emetogenic chemotherapy. The addition of olanzapine to 5HT-3 antagonist, NK-1 antagonist, and dexamethasone resulted in significantly more complete responses (CR) and more patients without CINV when compared to placebo in the acute, delayed and overall time periods. Data with olanzapine as CINV prophylaxis is not clear in HCT patients, but one retrospective study by Trifilio et. al. illustrates possible benefit in HCT. They compared an aprepitant-based regimen (aprepitant, ondansetron, and steroid) to an olanzapine-based regimen (olanzapine, ondansetron, and steroid) and found that patients in the olanzapine group had significantly less acute and delayed nausea. In addition, the olanzapine-based regimen required significantly less PRN rescue medication compared to the aprepitant based regimen. These results ultimately provided the foundation for the FOND-O study, a prospective trial that added olanzapine as part of CINV prophylaxis in both hematologic malignancies and HCT patients. The FOND-O study compared fosaprepitant, ondansetron, and dexamethasone (FOND) to fosaprepitant, ondansetron, dexamethasone and olanzapine (FOND-O). The inclusion of olanzapine resulted in significantly less delayed and overall nausea but did not affect the acute phase. While the FOND-O study was the first to look at utilizing olanzapine as part of 4 drug CINV prophylaxis in HCT, there were only 68 HCT patients included in the study. Only 24 allogeneic transplants and 44 autologous transplants were enrolled, and only 34 of these patients actually received olanzapine. In addition, the FOND-O study utilized an olanzapine dose of 10 mg on each day of chemotherapy continued through chemotherapy day 3. Rationale for Clinical Study The purpose of our proposed study is to build upon the FOND-O results by doing a prospective, randomized, placebo-controlled study, focused entirely on HCT recipients, and powered to detect olanzapine's potential role in CINV prophylaxis in recipients of HCT. Based upon the available literature in both solid and hematologic malignancies the benefit outweighs the risk of adding olanzapine to standard CINV prophylaxis. The primary endpoint is complete response- defined as no emesis and no more than minimal nausea starting with the first dose of highly or moderately emetogenic conditioning chemotherapy and continuing 5 days beyond the last dose of highly or moderately emetogenic conditioning chemotherapy. Secondary endpoints are defined explicitly

Official Title
-----------------
Addition of Olanzapine to Standard CINV Prophylaxis in Hematopoietic Stem Cell Transplant

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

Intervention / Treatment
-----------------
* Drug: Olanzapine 5 MG
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent was obtained to participate in the study and HIPAA authorization for the release of personal health information. Recipients receiving autologous or allogeneic HCT for any disease Any conditioning chemotherapy regimen considered a standard bone marrow transplantation conditioning regimen Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 The subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. Exclusion Criteria: Patients must not have started conditioning chemotherapy prior to consent. Note: test dose Busulfan is not part of conditioning chemotherapy Known allergy to olanzapine Baseline corrected QT interval ( QTc )>500 msec as calculated by the Fridericia formula Patients receiving post-transplant cyclophosphamide as planned graft-versus-host disease (GVHD) prophylaxis Pregnant or breastfeeding (NOTE: patients pregnant or breast-feeding are not eligible to proceed to transplant). Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. Treatment with any investigational drug within 7 days prior to registration. Subject is receiving prohibited medications (ciprofloxacin or fluvoxamine) that cannot be discontinued/replaced by an alternative therapy.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olanzapine Arm<br>Olanzapine 5mg tablet with chemotherapy, and 3 days after | Drug: Olanzapine 5 MG<br>* It will be a de-identified pill created by investigational drug services at University of North Carolina<br>* Other names: Zyprexa;|
| Placebo Comparator: Placebo Arm<br> | Drug: Placebo<br>* It will be a de-identified pill created by investigational drug services at University of North Carolina<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response | The number of subjects who completed the study and the overall rate of complete response were assessed. Complete response achievement requires all three of the following criteria for the entire duration of the study assessment period: 1. No emesis, 2. Response to PRO-CTCAE question In the last 24 hours, how often did you have nausea? is no higher than rarely and 3. Response to PRO-CTCAE question In the last 24 hours, what was the severity of your nausea at its worst? a score no higher than mild. | End of study assessment period, until 5 days after last chemotherapy administration (2- 12 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Rescue Medications Needed Acute | The total number of rescue medications needed acute was calculated, starting from the first dose of highly or moderately emetogenic conditioning chemotherapy and continuing for one day after the last dose of highly or moderately emetogenic conditioning chemotherapy. The rescue medication is defined as documented administration of an anti-emetic agent other than those that are scheduled for chemotherapy-induced nausea and vomiting (CINV) prophylaxis. | End of day 1 following last chemotherapy administration. (Up to day 2) | 
| Number of Subjects Achieving Minimal Nausea | To determine the number of subjects achieving minimal nausea was defined as the frequency of participants responded to the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) nausea question In the last 24 hours, how often did you have nausea? as rarely or less Starting with the first dose of chemotherapy and continuing for one day after the last dose of highly or moderately emetogenic conditioning chemotherapy. PRO-CTCAE of nausea scale includes categories: Never, Rarely, Occasionally, Frequently, Almost constantly To meet this endpoint the score reported for the Pro-CTCAE question for nausea frequency cannot exceed rarely and the score reported for the Pro-CTCAE question for nausea severity cannot exceed mild | Day 2-12 | 
| Frequency of Nausea in the Acute Phase | Starting with the first dose of highly or moderately emetogenic conditioning chemotherapy and continuing for one day after the last dose of highly or moderately emetogenic conditioning chemotherapy. Nausea was assessed using subjects' responses to the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) nausea questions. Scale: Never, Rarely, Occasionally, Frequently, Almost constantly. To meet this endpoint the score reported for the Pro-CTCAE question for nausea frequency cannot exceed rarely in the first 24 hours following receipt of chemotherapy. | End of day 1 following last chemotherapy administration (Up to day 2) | 
| Number of Subjects Achieved Emesis Endpoint in Acute Phase. | : The number of subjects who did not experience emesis, starting from the first dose of highly or moderately emetogenic conditioning chemotherapy and continuing for one day after the last dose of highly or moderately emetogenic conditioning chemotherapy. Met endpoint = 0 emesis. | End of day 1 following last chemotherapy administration. (Up to day 2) | 
| Frequency of Somnolence | The frequency of somnolence was determined as the number of patients who experienced somnolence based on Common Terminology Criteria for Adverse Events version 5 (CTCAE v5). The number of subjects has somnolence during the study period was counted. | Day 2-12 | 
| Safety Endpoint: Qtc Prolongation | Prolongation of corrected QTc interval graded as defined in Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Corrected QTc was calculated using Fredericia's Formula. Corrected QT interval (QTc) = QT interval / (60/Heart rate)^0.33. | Day 1 to 5 days after end of the chemotherapy (Days 2- 12). | 
| Number of Subjects Achieved Nausea Endpoint in the Delayed Phase. | Nausea was assessed using subjects' responses to the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) nausea questions, starting the second day after the completion of highly or moderately emetogenic conditioning chemotherapy and continuing through the fifth day after the completion of highly or moderately emetogenic chemotherapy. Scale: Never, Rarely, Occasionally, Frequently, Almost constantly. The number of subjects who experienced never or rarely nausea were considered as met the endpoint while those who experienced occasionally, frequently or almost constantly were considered as not met the endpoint. | Day 1 to 5 days after end of the chemotherapy (Days 2-12). | 
| Severity of Nausea in Delayed Phase | The severity of nausea in the delayed phase was defined as the response of the subject to the PRO- CTCAE nausea question. Starting the second day after the completion of highly or moderately emetogenic conditioning chemotherapy and continuing through the fifth day after the completion of highly or moderately emetogenic chemotherapy (PRO-CTCAE) Scale: Never, Rarely, Occasionally, Frequently, Almost constantly o meet the endpoint, the subject could not have answered a score as higher than mild in the period of time starting 24 hours after the last dose of chemotherapy and continuing until the 5th day following receipt of chemotherapy . | Day 2-12 | 
| Number of Emesis Episodes in Delayed Phase | The number of emesis episodes in acute phase was defined as the number of subjects with no emesis, 1 emesis, and 2 or more emesis. | Day 1 to 5 days after end of the chemotherapy ( Days 2-12). | 
| Total Number of Rescue Medications Needed -Delayed | The total number of rescue medications needed for breakthrough chemotherapy-induced nausea and vomiting were calculated, starting from the second day after the completion of highly or moderately emetogenic conditioning chemotherapy and continuing through the fifth day after the completion of highly or moderately emetogenic chemotherapy. The rescue medication is defined as documented administration of an anti-emetic agent other than those that are scheduled for CINV prophylaxis. | Day 1 to 5 days after end of the chemotherapy ( Days 2-12). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chemotherapy-induced Nausea and Vomiting, Chemotherapy, Nausea and Vomiting, Olanzapine