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

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

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.

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.

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)