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

Study Description

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Brief Summary:

The objectives of the study are: 1) Primary: Assess CINV efficacy of Aprepitant in combination with Ondansetron vs. Ondansetron alone in preventing acute and delayed CINV (Complete Control (CC): days 1-7) in brain tumor patients during adjuvant temozolomide therapy; and 2) Secondary: To assess the efficacy of Aprepitant in combination with Ondansetron vs Ondansetron alone in preventing acute CINV in brain tumor patients during the acute period (first 24 hours) of receiving adjuvant temozolomide therapy; 3)Secondary: To assess the efficacy of Aprepitant in combination with Ondansetron vs. Ondansetron alone in preventing delayed CINV (days 2-7); 4) Secondary: To assess the safety and tolerability of Aprepitant administered concomitantly with Ondansetron; 5) Exploratory: To assess the time to treatment failure of Ondansetron treatment with and without Aprepitant; 6) Exploratory: To explore the effects of age, gender, chemotherapy history, and concomitant glucocorticoid on the efficacy of Ondansetron treatment with and without Aprepitant; 7) Exploratory: To explore the impact of Aprepitant on quality of life and daily function.

Condition or disease	Intervention/treatment	Phase
Nausea; Vomiting; Glioma	Drug: Aprepitant; Drug: Ondansetron	Phase 2

Detailed Description:

One hundred and thirty-six (136) malignant glioma patients receiving temozolomide will be accrued in this open labeled phase II randomized single institution trial of Aprepitant in combination with Ondansetron vs. Ondansetron alone for the prevention of acute and delayed CINV. Sixty-eight (68) patients will be randomized to each arm of the study. Patient randomization will be stratified by grade (I/II vs. III/IV) and the number of prior progressions (0/1 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 Ondansetron with or without Aprepitant.

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	136 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	June 24, 2014
Actual Primary Completion Date :	April 13, 2017
Actual Study Completion Date :	April 21, 2017

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Emend (Aprepitant) and Ondansetron Regimen; Aprepitant in combination with Ondansetron on Days 1-5 of a 5-day oral temozolomide regimen	Drug: Aprepitant; 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).; Other Name: Emend; Drug: Ondansetron; 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.; Other Name: Zofran
Active Comparator: Ondansetron Alone Regimen; Ondansetron alone on Days 1-5 of a 5-day oral temozolomide regimen	Drug: Ondansetron; 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.; Other Name: Zofran

Outcome Measures

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Primary Outcome Measures :

1. Proportion of patients achieving an acute and delayed complete response (CR) [ Time Frame: 7 days ]
   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.

Secondary Outcome Measures :

1. Proportion of patients achieving complete control (CC) [ Time Frame: 7 days ]
   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).
2. Patient's global satisfaction with the antiemetic regimen [ Time Frame: 7 days ]
   Patient's global satisfaction with the antiemetic regimen as measured by the Osoba survey. This survey will be administered at baseline and for day 1 (acute period) and for days 2-7 (delayed period) to determine overall global satisfaction (Acute and delayed combined to determine overall CC, days 1-7).
3. Time to treatment failure [ Time Frame: 7 days ]
   First emetic episode or first need of rescue medication, whichever occurred first as measured by the MAT/Osoba survey, which indicates time of first emetic episode or rescue medication.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, North Carolina
The Preston Robert Tisch Brain Tumor Center at Duke
Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Katy Peters

Merck Sharp & Dohme Corp.

Investigators

Principal Investigator:	Mary Lou Affronti, DNP, RN, MHSc, ANP	Duke University
Principal Investigator:	Katherine B Peters, MD, PhD	Duke University

More Information

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Additional Information:

The Preston Robert Tisch Brain Tumor Center 

Duke Cancer Institute 

Responsible Party:	Katy Peters, Assistant Professor, Duke University
ClinicalTrials.gov Identifier:	NCT01450826 History of Changes
Other Study ID Numbers:	Pro00031206
First Posted:	October 12, 2011
Last Update Posted:	February 14, 2018
Last Verified:	February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Katy Peters, Duke University:

Chemotherapy induced nausea and vomiting; CINV; Glioma; Temozolomide; Temodar; Aprepitant; Emend	Ondansetron; Zofran; Pro00031206; Affronti; Peters; Duke; Preston Robert Tisch Brain Tumor Center

Additional relevant MeSH terms:

Glioma; Nausea; Vomiting; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Signs and Symptoms, Digestive; Signs and Symptoms; Temozolomide; Dacarbazine; Ondansetron	Aprepitant; Fosaprepitant; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Antipruritics; Dermatologic Agents; Serotonin Antagonists; Serotonin Agents