Safety and Antiemetic Efficacy of Akynzeo Plus Dexamethasone During Radiotherapy and Concomitant Weekly Cisplatin

Inclusion Criteria:

1. The patient has a diagnosis of cervical cancer.
2. The patient understands the nature and purpose of this study and the study proceduresand has signed informed consent.
3. The patient is aged ≥ 18 years.
4. The patient must be both chemo- and radiotherapy (RT) naïve. NB: previously lowvoltage RT or electron RT for non-melanoma skin cancers is allowed.
5. The patient is scheduled to receive fractionated radiotherapy and concomitant weeklycisplatin at a dose of ≥ 40 mg/m2 for at least five weeks.
6. Brachy therapy is scheduled to be initiated after the third cycle of weekly cisplatin,and preferentially after the fifth week of treatment.
7. Chemotherapy with an emetic risk potential of minimal or mild (up to 30%) is allowedon days 1-4 (see ref. 14).
8. The patient has a WHO Performance Status of ≤ 2.
9. Hematologic and metabolic status must be adequate for receiving weekly cisplatin in adose of ≥ 40 mg/m2, and meet the following criteria:

• Total neutrophils ≥ 1500/mm3 (Standard units : ≥1.5 x 109/L)
• Platelets ≥ 100,000/mm3 (Standard units: ≥100.0 x 109/L)
• Bilirubin ≤ 1.5 x ULN (Upper Limits of Normal)
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 xULN
• GFR ≥ 50 ml/min

10. The patient is able to read, understand, and complete questionnaires and dailycomponents of the Patient Diary for each study cycle.
11. For patients of childbearing potential, urine human chorionic gonadotropin (hCG) (urine dipstick pregnancy test) or blood hCG results must be negative at screening,and these patients must agree to one of the following methods of contraception:

• Hormonal contraceptives (contraceptive pills, implants, transdermal patches,hormonal vaginal devices or injections with prolonged release).
• Male partner who is sterile prior to the patient's entry into the study and isthe sole sexual partner for that patient.
• Complete abstinence from intercourse for two weeks before study entry andthroughout the study period plus a period after the trial to account forelimination of the drug (minimum of eight days). Abstinence is only an acceptablecontraception form, when it reflects the usual and preferred lifestyle of thepatient.

Exclusion Criteria:

1. The patient has a current malignant diagnosis other than cervical cancer, withexception of non-melanoma skin cancers.
2. The patient is pregnant or lactating.
3. The patient has experienced emesis (i.e., vomiting and/or retching) or clinicallysignificant nausea (defined as nausea graded as moderate or severe) in the 24 hourspreceding the first dose of study medication.
4. The patient has a history active peptic ulcer disease, gastrointestinal obstruction,gastrointestinal carcinoma, increased intracranial pressure, hypercalcemia, or anyuncontrolled medical condition (other than malignancy) which in the opinion of theInvestigator may confound the results of the study, represent another potentialetiology for emesis and nausea (other than CINV/RINV) or pose an unwarranted risk tothe patient.
5. The patient has a known hypersensitivity or contraindication to palonosetron, another 5-HT3 receptor antagonist, dexamethasone, or netupitant.
6. The patient has previously received an NK1 receptor antagonist.
7. The patient has received an investigational drug in the previous 30 days or isscheduled to receive any investigational drug during the study period.
8. The patient has taken/received any medication of moderate or high emetogenic potentialwithin the 48 hours prior to the first dose of study medications. Opiate drugs forcancer pain will be permitted if the patient has been on a stable dose and has notexperienced emesis or clinically significant nausea from the narcotics in the 24 hourspreceding the first dose of study medication.
9. The patient has taken/received any medication with known or potential antiemeticactivity within the 24-hour period prior to receiving study drugs. This includes, butis not limited to:

• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron,tropisetron, ramosetron). Palonosetron is not permitted within 7 days prior toreceiving study drugs.
• Benzamide / benzamide derivatives (e.g., metoclopramide, alizapride).
• Benzodiazepines (except if the patient is receiving such medication for sleep oranxiety and has been on a stable dose for at least seven days prior to the firstdose of study medications).
• Phenothiazines (e.g., prochlorperazine, promethazine, metopimazine, fluphenazine,perphenazine, thiethylperazine, chlorpromazine).
• Butyrophenone (e.g., haloperidol, droperidol).
• Corticosteroids (e.g., dexamethasone, methylprednisolone, prednisolone; with theexception of topical steroids for skin disorders, inhaled steroids forrespiratory disorders).
• Anticholinergics (e.g., scopolamine).
• Antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine).
• Domperidone.
• Cannabinoids.
• Mirtazapine.
• Olanzapine.

10. The patient has taken/received strong or moderate inhibitors of CYP3A4 within seven (7) days prior to administration of study drugs (see Section 10.3.1., "Inhibitors ofCYP3A4").
11. The patient has taken/received inducers of CYP3A4 within thirty (30) days prior to theadministration of study drugs (see Section 10.3.2., "Inducers of CYP3A4").