Rolapitant as an Antiemetic in Malignant Glioma Patients Receiving Radiotherapy and Temozolomide

Study Overview
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Brief Summary
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The purpose of this phase 2 study is to assess the efficacy and patient satisfaction of oral rolapitant plus ondansetron vs. oral ondansetron monotherapy in malignant glioma (MG) patients receiving standard of care radiation (RT) and temozolomide (TMZ) therapy. This is a randomized phase 2 trial of rolapitant plus ondansetron vs. ondansetron monotherapy for the prevention of chemo-radiation induced nausea and vomiting in primary MG subjects receiving RT and concomitant multi-dose TMZ.

Detailed Description
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All eligible subjects should receive a planned total dose of 54-60 gray (GY) of radiation and 75 mg/m2 of TMZ daily for a total of six weeks. Patients will be randomized to receive one of two antiemetic treatment sequences: sequence A that involves administration of ondansetron alone for 3 weeks followed by a single dose of rolapitant (day 22) plus daily ondansetron for 3 weeks or sequence B that involves a single dose of rolapitant (day 1) plus daily ondansetron for 3 weeks followed by 3 weeks of daily ondansetron alone. The study has one primary endpoint: complete response (CR) rate. Participation in this study may result in reduced chemo-radiation induced nausea and vomiting, however, risks include the common side effects of rolapitant including decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, and anemia.

Official Title
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Phase II Randomized Study to Evaluate Efficacy, Patient Satisfaction, and Compliance of the Oral Combination of Rolapitant (Varubi®) Plus Ondansetron vs. Ondansetron Monotherapy in Malignant Glioma Patients Receiving Radiotherapy (RT) and Concomitant Temozolomide

Conditions
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Chemo-radiation Induced Nausea and Vomiting

Intervention / Treatment
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* Drug: Rolapitant
* Drug: Ondansetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically-confirmed, newly-diagnosed malignant glioma (glioblastoma, gliosarcoma, anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, or anaplastic oligodendroglioma) and are scheduled to receive radiotherapy (for a total of 54-60 Gy) and concomitant daily temozolomide therapy (at a dose of 75 mg/m^2 for one complete 6-week cycle). Age ≥ 18 years Karnofsky ≥ 60% or ECOG 0-2 Hematocrit >29%, Absolute Neutrophil Count >1,000 cells/mm^3, platelets >100,000 cells/mm^3 Serum creatinine <1.4 mg/dl, bilirubin <1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 x ULN. For subjects with known liver metastases ≤ 5 x ULN, and alanine aminotransferase (ALT) ≤ 2.5 x ULN. For subjects with known liver metastases ≤ 5 x ULN For patients on higher than physiological level of corticosteroids, they must have been on a stable dose for 1 week prior to initiating study drug, and the dose should not be escalated over entry dose level, if clinically possible Ability and willingness to give informed consent Female patients of childbearing potential must have a negative pregnancy test at Screening Female patients of childbearing potential must agree to use an acceptable method of birth control from the signing of informed consent and to continue its use during the study and for at least 90 days after the final dose Male patients must agree to use an acceptable form of birth control from study Day 1 through at least 90 days after the final dose Exclusion Criteria: Co-medications that may interact with rolapitant as reviewed by Duke Preston Robert Tisch Brain Tumor investigator pharmacist. Co-medications that are contraindicated in patients on rolapitant including pimozide, thioridazine, carbamazepine, colchicine, dabigatran (Pradaxa), edoxaban (Savaysa), fosphenytoin, metoprolol, phenobarbital, phenytoin, primidone, and warfarin Inability or unwillingness to cooperate with the study procedures Prophylactic medication for the prevention of nausea and vomiting 24 hours prior to the start of radiation therapy through the full course of radiation therapy is prohibited, with the exception of the study drug. Corticosteroids will be allowed for treatment of cerebral swelling Previous participation in any clinical trial involving rolapitant Any vomiting, retching, dry heaves, or clinically significant nausea (i.e., NCI Common Toxicity Criteria version 4.0 grade 2-4 nausea) caused by any etiology in the 24 hrs. preceding day 1 of the study intervention (ondansetron or ondansetron with rolapitant) as scheduled to begin on day 1 of radiation and chemotherapy. Or a patient who has a history of anticipatory nausea and vomiting. Ongoing vomiting from any organic etiology Received rolapitant within 21 days prior to study enrollment Prior cancer chemotherapy or radiotherapy Any current treatment, medical history, or uncontrolled condition, other than malignancy, (e.g., alcoholism or signs of alcohol abuse, seizure disorder, medical or psychiatric condition) that, in the opinion of the investigator, would confound the results of the study or pose any unwarranted risk in administering study drug to the subject Patient has a known hypersensitivity to the administration of rolapitant or its excipients Patient has a history of severe renal or hepatic impairment, severe bone marrow suppression, or systemic infection Patient is a woman with a positive serum pregnancy test at Screening, is pregnant, breast-feeding, or is planning to conceive children within the projected duration of the study treatment Patient has taken the following agents within the last 48 hours prior to the start of treatment with study drug: 5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.). Benzamides (metoclopramide, alizapride, etc.) Domperidone Cannabinoids Natural Killer (NK)-1 antagonist (aprepitant) Benzodiazepines (lorazepam, alprazolam, etc.) herbal medications or preparations in doses designed to ameliorate nausea or emesis Patient has taken phenothiazines (prochlorperazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine, etc.) for any indication within the last 48 hours prior to the start of treatment with study drug Palonosetron is not permitted within 7 days prior to administration of investigational product Patient must not have been dosed with a test drug or blinded study drug in another investigational study within 30 days or 5 half-lives of the biologic activity of the test drug, whichever is longer, before the time of first study dose Patient who is receiving investigational agent(s) as part of another clinical study at the time of screening or who anticipates receiving investigational agent(s) during their scheduled radiotherapy and concomitant daily temozolomide therapy (Any exception to this criteria will be noted in a study Memo to File)

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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence A<br>Daily ondansetron alone for 3 weeks, followed by the use of rolapitant (one dose on day 22) plus continued daily ondansetron for 3 weeks. | Drug: Rolapitant<br>* single 180 mg dose by mouth<br>* Other names: Varubi;Drug: Ondansetron<br>* 8 mg by mouth daily<br>* Other names: Zofran;|
| Active Comparator: Sequence B<br>Single dose of rolapitant (one dose on day 1) plus daily ondansetron for 3 weeks, followed by daily ondansetron alone for 3 weeks. | Drug: Rolapitant<br>* single 180 mg dose by mouth<br>* Other names: Varubi;Drug: Ondansetron<br>* 8 mg by mouth daily<br>* Other names: Zofran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate as Measured by Antiemesis Tool (MAT) | The Complete Response rate is defined as the proportion of participants with no emetic episode or the use of rescue medication during the first two weeks of radiation therapy and concomitant Temozolomide. The Complete Response rate will be assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT). | Weeks 1 and 2 | 
| Complete Response (CR) Rate as Measured by MAT With Supplemental Nurses Notes | The Complete Response rate is defined as the proportion of participants with no emetic episode or the use of rescue medication during the first two weeks of radiation therapy and concomitant Temozolomide. The Complete Response rate will be assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) MAT and nurse notes if MATs are missing. | Weeks 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Preferring Rolapitant in Combination With Ondansetron Versus Ondansetron Alone | The number of participants who prefer rolapitant plus ondansetron over ondansetron alone, as determined by response to the question with Which nausea medication regimen was I most satisfied with? | Weeks 1-6 | 
| Week 3 Patient Satisfaction: Effectiveness | Mean effectiveness scores at week 3 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The effectiveness subscale score was computed from the 3 items corresponding to effectiveness. The resulting effectiveness score is measured from 0-100 with higher scores corresponding to higher effectiveness. | Weeks 1-3 | 
| Week 3 Patient Satisfaction: Convenience | Mean convenience scores at week 3 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The convenience subscale score was computed from the 3 items corresponding to convenience. The resulting convenience score is measured from 0-100 with higher scores corresponding to higher convenience. | Weeks 1-3 | 
| Week 3 Patient Satisfaction: Overall Satisfaction | Mean overall satisfaction scores at week 3 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The overall satisfaction subscale score was computed from the 3 items corresponding to overall satisfaction. The resulting overall satisfaction score is measured from 0-100 with higher scores corresponding to higher overall satisfaction. | Weeks 1-3 | 
| Week 6 Patient Satisfaction: Effectiveness | Mean effectiveness scores at week 6 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The effectiveness subscale score was computed by summing the 3 items corresponding to effectiveness. The resulting effectiveness score is measured from 0-100 with higher scores corresponding to higher effectiveness. | Weeks 4-6 | 
| Week 6 Patient Satisfaction: Convenience | Mean convenience scores at week 6 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The convenience subscale score was computed from the 3 items corresponding to convenience. The resulting convenience score is measured from 0-100 with higher scores corresponding to higher convenience. | Weeks 4-6 | 
| Week 6 Patient Satisfaction: Overall Satisfaction | Mean overall satisfaction scores at week 6 using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) patient satisfaction survey. The overall satisfaction subscale score was computed from the 3 items corresponding to overall satisfaction. The resulting overall satisfaction score is measured from 0-100 with higher scores corresponding to higher overall satisfaction. | Weeks 4-6 | 
| Chemoradiation-induced Nausea (cRIN) Rate Over First Two Weeks | The cRIN-CR rate is defined as the proportion of participants who did not use rescue medication for nausea. The cRIN-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT). | Weeks 1 and 2 | 
| Chemoradiation-induced Nausea (cRIN) Rate Over First Two Weeks and Supplemented by Nurses Notes | The cRIN-CR rate is defined as the proportion of participants who did not use rescue medication for nausea. The cRIN-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT) and nurses notes if MATs were missing. | Weeks 1 and 2 | 
| Chemoradiation-induced Vomiting (cRIV) Rate Over First Two Weeks | The cRIV-CR rate is defined as the proportion of participants without use of rescue medication for vomiting. The cRIV-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT). | Weeks 1 and 2 | 
| Chemoradiation-induced Vomiting (cRIV) Rate Over First Two Weeks With Supplemental Nurses Notes | The cRIV-CR rate is defined as the proportion of participants without use of rescue medication for vomiting. The cRIV-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT) and nurse notes if MATS are missing. | Weeks 1 and 2 | 
| Chemoradiation-induced Nausea (cRIN) Rate Over All Six Weeks | The cRIN-CR rate is defined as the proportion of participants who did not use rescue medication for nausea. The cRIN-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT). | Weeks 1-6 | 
| Chemoradiation-induced Vomiting (cRIV) Rate Over All Six Weeks | The cRIV-CR rate is defined as the proportion of participants without use of rescue medication for vomiting. The cRIV-CR rates were assessed via the modified Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT). | Weeks 1-6 | 
| Ondansetron Medication Compliance Weeks 1-3 | Percentage of participants who adhered to ondansetron treatment for more than 21 days during weeks 1-3. | Weeks 1-3 | 
| Ondansetron Medication Compliance Weeks 4-6 | Percentage of participants who adhered to ondansetron treatment for more than 21 days during weeks 4-6. | Weeks 4-6 | 
| Proportion of Participants With Grade 3, 4 or 5 Treatment-related Adverse Events | The proportion of participants with grade 3, 4 or 5 adverse events (severe, life-threatening, or fatal) possibly, probably or definitely related to administration of Rolapitant or Ondansetron. Adverse events will be collected from start of treatment through the end of the two-week period following chemoradiation (or until 30 days after the last dose of rolapitant is given in Sequence A). CTCAE version 4 was used to grade adverse events. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malignant glioma, temozolomide, temodar, radiation, emesis, nausea, vomiting, chemotherapy, Affronti, Peters, 00076418