Clinical trial NCT04535141: Olanzapine for Nausea/Vomiting Prophylaxis in Recipients of Hematopoietic Stem Cell Transplants
Official title: Addition of Olanzapine to Standard CINV Prophylaxis in Hematopoietic Stem Cell Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chemotherapy-induced Nausea and Vomiting
Keywords: Chemotherapy-induced Nausea and Vomiting
Chemotherapy
Nausea and Vomiting
Olanzapine
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: University of North Carolina, Chapel Hill
First posted: 2020-09-01
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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

Eligibility criteria: Inclusion Criteria:

1. Written informed consent was obtained to participate in the study and HIPAA authorization for the release of personal health information.
2. Recipients receiving autologous or allogeneic HCT for any disease
3. Any conditioning chemotherapy regimen considered a standard bone marrow transplantation conditioning regimen
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
5. The subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee.

Exclusion Criteria:

1. Patients must not have started conditioning chemotherapy prior to consent. Note: test dose Busulfan is not part of conditioning chemotherapy
2. Known allergy to olanzapine
3. Baseline corrected QT interval ( QTc )\>500 msec as calculated by the Fridericia formula
4. Patients receiving post-transplant cyclophosphamide as planned graft-versus-host disease (GVHD) prophylaxis
5. Pregnant or breastfeeding (NOTE: patients pregnant or breast-feeding are not eligible to proceed to transplant).
6. 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.
7. Treatment with any investigational drug within 7 days prior to registration.
8. Subject is receiving prohibited medications (ciprofloxacin or fluvoxamine) that cannot be discontinued/replaced by an alternative therapy.

Primary outcomes:
measure: Number of Participants With Complete Response
timeFrame: End of study assessment period, until 5 days after last chemotherapy administration (2- 12 days)
Secondary outcomes:
measure: Total Number of Rescue Medications Needed Acute
timeFrame: End of day 1 following last chemotherapy administration. (Up to day 2)
measure: Number of Subjects Achieving Minimal Nausea
timeFrame: Day 2-12
measure: Frequency of Nausea in the Acute Phase
timeFrame: End of day 1 following last chemotherapy administration (Up to day 2)
measure: Number of Subjects Achieved Emesis Endpoint in Acute Phase.
timeFrame: End of day 1 following last chemotherapy administration. (Up to day 2)
measure: Frequency of Somnolence
timeFrame: Day 2-12
measure: Safety Endpoint: Qtc Prolongation
timeFrame: Day 1 to 5 days after end of the chemotherapy (Days 2- 12).
measure: Number of Subjects Achieved Nausea Endpoint in the Delayed Phase.
timeFrame: Day 1 to 5 days after end of the chemotherapy (Days 2-12).
measure: Severity of Nausea in Delayed Phase
timeFrame: Day 2-12
measure: Number of Emesis Episodes in Delayed Phase
timeFrame: Day 1 to 5 days after end of the chemotherapy ( Days 2-12).
measure: Total Number of Rescue Medications Needed -Delayed
timeFrame: Day 1 to 5 days after end of the chemotherapy ( Days 2-12).
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: UNC Hospital
state: North Carolina
Study officials:
affiliation: jonathan.Ptachcinski@unchealth.unc.edu
name: Jonathan Ptachcinski, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Monson T, Greer D, Kreikemeier E, Liewer S. Olanzapine as a rescue antiemetic in hematopoietic stem cell transplant. J Oncol Pharm Pract. 2020 Jun;26(4):918-922. doi: 10.1177/1078155219879215. Epub 2019 Oct 21.
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citation: Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Somerfield MR, Lyman GH. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Oct 1;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789. Epub 2017 Jul 31.
citation: Trifilio S, Welles C, Seeger K, Mehta S, Fishman M, McGowan K, Strejcek K, Eiten E, Pirotte C, Lucier E, DeFrates S, Mehta J. Olanzapine Reduces Chemotherapy-induced Nausea and Vomiting Compared With Aprepitant in Myeloma Patients Receiving High-dose Melphalan Before Stem Cell Transplantation: A Retrospective Study. Clin Lymphoma Myeloma Leuk. 2017 Sep;17(9):584-589. doi: 10.1016/j.clml.2017.06.012. Epub 2017 Jun 20.
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citation: Clemmons AB, Orr J, Andrick B, Gandhi A, Sportes C, DeRemer D. Randomized, Placebo-Controlled, Phase III Trial of Fosaprepitant, Ondansetron, Dexamethasone (FOND) Versus FOND Plus Olanzapine (FOND-O) for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients with Hematologic Malignancies Receiving Highly Emetogenic Chemotherapy and Hematopoietic Cell Transplantation Regimens: The FOND-O Trial. Biol Blood Marrow Transplant. 2018 Oct;24(10):2065-2071. doi: 10.1016/j.bbmt.2018.06.005. Epub 2018 Jun 13.
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