Emend and Ondansetron Compared to Ondansetron Alone to Prevent CINV in Glioma Patients Receiving Temozolomide

Study Overview
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Brief Summary
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Patients diagnosed with malignant glioma who are receiving temozolomide will be accrued in this open label, phase 2, randomized single institution trial of aprepitant in combination with ondansetron versus ondansetron alone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Sixty-eight (68) patients will be randomized to each arm of the study.

Detailed Description
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Sixty-eight (68) patients will be randomized to each arm of the study. Patient randomization will be stratified by grade of tumor (1 or 2 versus 3 or 4) and the number of prior progressions (0 or 1 versus 2). Within each of the 4 strata defined by these factors, a permuted block randomization scheme will be used to assign patients to receive either aprepitant in combination with ondansetron or ondansetron alone. Though the study is comparative, the goal of the study is to determine whether aprepitant is worthy of further investigation in this setting, and not to make definitive statements about the comparative effectiveness of ondansetron treatment with or without aprepitant.

Official Title
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A Randomized Open Label Phase II Trial of Aprepitant (Emend) in Combination With Ondansetron Compared to Standard 5HT3 Serotonin Antagonist (Ondansetron) in the Prevention of Acute and Delayed Chemotherapy Induced Nausea and Vomiting (CINV) in Glioma Patients Receiving a Temozolomide Based Regimen

Conditions
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Nausea, Vomiting, Glioma

Intervention / Treatment
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* Drug: aprepitant
* Drug: ondansetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed diagnosis of glioma (either low or high grade) and be either chemotherapy naïve or non-naïve and scheduled to receive temozolomide-based +/- Bevacizumab- based chemotherapy. Patients with recurrent disease whose diagnostic pathology confirmed glioma (either low or high grade) will not need re-biopsy. Age ≥ 18 years ≤ 2 prior chemotherapeutic regimens Patient is scheduled to receive temozolomide at either 150 mg/m2 or 200mg/m2 by mouth for 5 days out of a 28 day cycle +/- bevacizumab. Study participation will occur during the first cycle of the 5 day temozolomide course. An interval of at least 6 weeks between prior surgical resection and study enrollment Karnofsky ≥ 60%. Hematocrit > 29%, absolute neutrophil count (ANC) > 1,000 cells/µl, platelets > 100,000 cells/µl Serum creatinine < 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT) and bilirubin < 1.5 times upper limit of normal For patients on oral corticosteroids, they must be stable clinically on corticosteroids or tapered off prior to starting the study drug. For patients taking dexamethasone, the dose should not exceed 8 mg qd (or 4 mg twice a day), if clinically stable, and the dose should not be escalated over entry dose level, if clinically possible. The patient's dose of dexamethasone will be evaluated by the PI, the patient's study physician, and/or the study pharmacist on a case by case basis for safety. All doses of oral corticosteroids will be reduced by 50% to avoid drug to drug interactions with Aprepitant, unless oral corticosteroids are at physiologic dose (e.g. dexamethasone 1 mg, prednisone 10 mg, or cortisone 30 mg). It is recommended that oral corticosteroid doses be escalated back to full dose on Day 7 (2 days after Aprepitant is discontinued) based on Aprepitant half-life pharmacokinetic data, and expert clinical opinion. Signed informed consent approved by the Institutional Review Board prior to patient entry If sexually active, patients will take contraceptive measures for the duration of protocol treatment and continue until one month after treatment. The efficacy of hormonal contraceptives during and for 28 days following the last dose of Aprepitant may be reduced. Alternative or back-up methods of contraception must be used. Approved rescue medication for the treatment of nausea and vomiting is permitted at the discretion of the investigator. The rescue antiemetics allowed will include: ondansetron, granisetron and lorazepam. Exclusion Criteria: Pregnant or breast-feeding (While both aprepitant and ondansetron are classified as Category B drugs, an eligibility criteria for this study is that the patient be scheduled to receive a temozolomide-based chemotherapy regimen +/- bevacizumab, which are Category D and C drugs respectively. Therefore, while not considered necessary for the administration of the current study drugs, a pregnancy test should be a part of normal clinical care for the patients in this study, if the patient is determined to be of child-bearing potential.) No prior nitrosourea (e.g. lomustine, carmustine) Inability or unwillingness to understand or cooperate with study procedures Concurrent administration of CYP3A4 enzyme-inducing anti-epileptic drugs (EIAEDs) including phenytoin, phenobarbitol, carbamazepine, oxcarbazepine or primidone Prohibited medications: Patients taking CYP3A4 enzyme inducers and moderate or strong inhibitors will be excluded from this trial. Received any drug with potential anti-emetic effect within 24 hours prior to the start of study-designated chemotherapeutic agent: HT3 receptor or substance P/neurokinin 1(NK1) receptor antagonists; Dopamine receptor antagonists (metoclopramide); Phenothiazine anti-emetics (prochlorperazine, thiethylperazine and perphenazine); Diphenhydramine, scopolamine, chlorpheniramine maleate, trimethobenzamide; Haloperidol, droperidol, tetrahydrocannabinol, or nabilone Any vomiting, retching or NCI Common Toxicity Criteria v.4.0 grade 2-4 nausea 24 hours preceding chemotherapy Ongoing vomiting from any organic etiology Will receive radiotherapy of cranium within one week prior to or during the study

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: aprepitant+ondansetron<br>On day 1, patients will receive a single oral dose of Aprepitant 125 mg p.o, 1 hour before first dose of the 5-day oral temozolomide regimen. This will be followed by Aprepitant 80 mg p.o. on days 2 -5 (1 hour prior to temozolomide). Additionally, On days 1-5, patients receive a single dose of Ondansetron 30 minutes before the receiving their prescribed dose of 5-day oral temozolomide. | Drug: aprepitant<br>* On day 1, eligible patients will receive a single oral dose of Aprepitant 125 mg p.o, 1 hour before first dose of the 5-day oral temozolomide regimen. This will be followed by Aprepitant 80 mg p.o. on days 2 -5 (1 hour prior to temozolomide).<br>* Other names: Emend;Drug: ondansetron<br>* On Days 1-5, eligible patients will receive a single oral dose of Ondansetron, 30 minutes before first dose of the 5 -day oral temozolomide regimen.<br>* Other names: Zofran;|
| Active Comparator: ondansetron<br>On days 1-5, patients receive a single dose of Ondansetron 30 minutes before the receiving their prescribed dose of 5-day oral temozolomide. | Drug: ondansetron<br>* On Days 1-5, eligible patients will receive a single oral dose of Ondansetron, 30 minutes before first dose of the 5 -day oral temozolomide regimen.<br>* Other names: Zofran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving Complete Control (CC) | Complete control (CC): study days 1-7 (acute and delayed CINV) the proportion of patients achieving complete control (CC); defined as no emetic episode, no need for rescue medication during days 1-7; number of emetic episodes daily; time to first emetic episode; as captured by the MAT (MASCC Antiemesis Tool)/Osoba survey (MASCC refers to Multinational Association for Supportive Care in Cancer™). Severity of nausea and other toxicities measured daily by the NCI Common Toxicity Criteria (version 4.0). | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving an Acute and Delayed Complete Response (CR) | CR is the proportion of patients with no emetic episode and no rescue medication. (1) Assessed from the beginning of study day 1, CR is defined for acute CINV as no emetic episode and no use of rescue anti-nausea medication during the first 24 hours following chemotherapy administration. An emetic episode is defined as one episode of vomiting or a sequence of episodes in very close succession not relieved by a period of relaxation of at least 1 min, any number of unproductive emetic episodes (retches) in any given 5 minute period, or an episode of retching lasting <5 minutes combined with vomiting not relieved by a period of relaxation of at least 1 minute; (2) Complete response (CR) on study days 2-7 (delayed CINV) is defined as the proportion of patients achieving a CR during the delayed time period. The data will be captured by the validated ultinational Association of Supportive Care in Cancer (MASCC) Anti-emesis Tool (MAT)/Osoba survey. | 7 days | 
| Patient's Global Satisfaction With the Antiemetic Regimen | Patients' global satisfaction with the antiemetic regimen is measured using the Osoba survey, which was administered on days 1-7. This survey asks patients In the past 24 hours, did vomiting or dry heaves a) interfere with your appetite, b) affect your sleep, c) interfere with your physical activities, d) interfere with your social life, and e) interfere with your enjoyment of life? Patients responded on a scale of 1-4 ranging from 'Not at all' to 'Very much.' Global satisfaction was defined as responding 'Not at all' for all questions related to vomiting/retching for each study day. The proportion of patients responding 'Not at all' for all Osoba vomiting/retching questions over the study period is reported. | 7 days | 
| Time to Treatment Failure | Median time in days to first emetic episode or first need of rescue medication, whichever occurred first as measured by the MAT/Osoba survey, among those patients experiencing an emetic episode or need of rescue medication | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CINV, Chemotherapy induced nausea and vomiting, Glioma, Temozolomide, Temodar, Aprepitant, Emend, Ondansetron, Zofran, Pro00031206, Affronti, Peters, Duke, Preston Robert Tisch Brain Tumor Center