| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036902 |
| E.1.2 | Term | Prophylaxis against radiation induced nausea and vomiting |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008229 |
| E.1.2 | Term | Cervical cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to compare an antiemetic regimen consisting of fosaprepitant dimeglumine (Ivemend®), palonosetron (Aloxi®), and dexamethasone (active arm) and a regimen consisting of palonosetron, dexamethasone, and placebo (control arm) with respect to efficacy; the proportion of subjects with no vomiting, i.e. sustained no emesis rate - during five weeks of fractionated (5 days a week) radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.</ |
|
| E.2.2 | Secondary objectives of the trial |
| 1. To compare the fosaprepitant regimen and the control regimen in terms of the proportion of subjects with complete response in the 7 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2. 2. To compare the fosaprepitant regimen and the control regimen in terms of the proportion of subjects with no significant nausea during five weeks (35 days) (of treatment as above) 3. To compare the fosaprepitant regimen and the control regimen with respect to complete response in the 35 days following initiation of treatment as above. 4. To compare the fosaprepitant regimen and the control regimen in terms of the proportion of subjects with no nausea during five weeks (35 days) (of treatment as above). 5. To compare the fosaprepitant regimen and the control regimen in terms of the number of days to first emetic episode. 6. To compare quality of life using the FLIE questionnaire. 7. To compare tolerability of both regimens. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 procedures and has signed informed consent. 3. The patient is aged > 18 years. 4. The patient must be both chemo- and radiotherapy naïve. 5. The patient is scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2 for at least five weeks, and planned brachy therapy should preferentially be scheduled after the fifth week of treatment. 6. Chemotherapy with an emetic risk potential of minimal or mild (up to 30%) is allowed on days 1-4 (see ref. 17). 7. The patient has a WHO Performance Status of ≤ 2. 8. Hematologic and metabolic status must be adequate for receiving weekly cisplatin in a dose 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 x ULN • GFR ≥ 50 ml/min 9. The patient is able to read, understand, and complete questionnaires and daily components of the Patient Diary for each study cycle. 10. For patients of childbearing potential, urine human chorionic gonadotropin (hCG) (urine dipstick pregnancy test) results must be negative at screening, and these patients must agree to one of the following methods of contraception: • Male partner who is sterile prior to the patient’s entry into the study and is the sole sexual partner for that patient. • Double-barrier method of contraception consisting of spermicide with either condom or diaphragm. • Complete abstinence from intercourse for two weeks before study entry and throughout the study period plus a period after the trial to account for elimination of the drug (minimum of eight days). Oral contraceptives (e.g., oral, injectable, trans dermal, or implantable) are NOT considered safe because of potential lowered ethinyloestradiol exposures when co-administered with fosaprepitant and dexamethasone (see Appendix 1, p230).</ |
|
| E.4 | Principal exclusion criteria |
| 1. The patient has a current malignant diagnosis other than cervical cancer, with exception of non-melanoma skin cancers. 2. The patient is aged ≤ 18 years. 3. The patient is scheduled to receive less than five weeks of fractionated radiotherapy and concomitant weekly cisplatin. 4. The patient has been previously treated with radiotherapy, and/or chemotherapy. 5. The patient has a WHO Performance Status of > 2. 6. Hematologic and metabolic status are inadequate, i.e. • 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 • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 x ULN • GFR ≤ 50 ml/min 7. The patient is unable to read, understand, and complete the forms required for the study. 8. The patient is pregnant or lactating. 9. The patient with a reproductive potential refuses to use adequate contraception. 10. The patient has experienced emesis (i.e., vomiting and/or retching) or clinically significant nausea in the 24 hours preceding the first dose of study medication. 11. The patient has a history active peptic ulcer disease, gastrointestinal obstruction, gastrointestinal carcinoma, increased intracranial pressure, hypercalcemia, or any uncontrolled medical condition (other than malignancy) which in the opinion of the Investigator may confound the results of the study, represent another potential etiology for emesis and nausea (other than CINV/RINV) or pose an unwarranted risk to the patient. 12. The patient has a known hypersensitivity or contraindication to palonosetron, another 5-HT3 receptor antagonist, dexamethasone, or any component of fosaprepitant. 13. The patient has previously received an NK1 receptor antagonist. 14. The patient has received an investigational drug in the previous 30 days or is scheduled to receive any investigational drug other than the study medication during the study period. 15. The patient has taken/received any medication of moderate or high emetogenic potential within the 48 hours prior to the first dose of study medications. Opiate drugs for cancer pain will be permitted if the patient has been on a stable dose and has not experienced emesis or clinically significant nausea from the narcotics in the 24 hours preceding the first dose of study medication. 16. The patient has taken/received any medication with known or potential antiemetic activity within the 24-hour period prior to receiving study drugs. This includes, but is not limited to: • 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron). Palonosetron is not permitted within 7 days prior to receiving study drugs. • Benzamide / benzamide derivatives (e.g., metoclopramide, alizapride). • Benzodiazepines (except if the patient is receiving such medication for sleep or anxiety and has been on a stable dose for at least seven days prior to the first dose of casopitant investigational product and study medications). • Phenothiazines (e.g., prochlorperazine, promethazine, metopimazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine). • Butyrophenone (e.g., haloperidol, droperidol). • Corticosteroids (e.g., dexamethasone, methylprednisolone, prednisolone; with the exception of topical steroids for skin disorders, inhaled steroids for respiratory disorders). • Anticholinergics (e.g., scopolamine). • Antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine). • Domperidone. • Cannabinoids. • Mirtazapine. • Olanzapine. 17. Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 prior to administration of study drugs (see Section 10.3.1., “Inhibitors of CYP3A4 and CYP3A5”). 18. Has taken/received inducers of CYP3A4 and CYP3A5 within fourteen days prior to the administration of study drugs (see Section 10.3.2., “Inducers of CYP3A4 and CYP3A5”). 19. Is taking the anti-diabetic agent repaglinide or the diuretic torsemide. Investigators are advised to exercise caution if including patients taking the anti-diabetic agents rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and amodiaquine, as the metabolite of fosaprepitant is a potential inhibitor of CYP2C8 (See Section 10.3.4., “Exclusion and Necessary Caution with CYP2C8 Substrates”).</ |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the 'sustained no emesis rate' during five weeks of fractionated (5 days a week) radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2. Sustained no emesis during five weeks means that the study subject is free from vomiting episodes in the interval beginning at infusion of first dose of cisplatin untill 7 days after the infusion of the fifth dose of cisplatin.</ |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. To compare the fosaprepitant dimeglumine regimen and the control regimen in terms of the proportion of subjects with complete response (defined as no vomits, no dry retches and no need for rescue medication) in the 7 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
2. To compare the fosaprepitant dimeglumine regimen and the control regimen in terms of the proportion of subjects with no significant nausea (none or mild nausea) during five weeks (35 days) of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
3. To compare the fosaprepitant dimeglumine regimen and the control regimen with respect to complete response (defined as no vomits, no dry retches and no need for rescue medication) in the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
4. To compare the fosaprepitant dimeglumine regimen and the control regimen in terms of the proportion of subjects with no nausea during five weeks (35 days) of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
5. To compare the fosaprepitant dimeglumine regimen and the control regimen in terms of the number of days to first emetic episode.
6. To compare quality of life using the FLIE questionnaire.
7. To compare tolerability of both regimens.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Study will be closed when all 230 patients are enroled, and the last patient has completed the follow-up visit.< |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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