| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epithelial ovarian cancer |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 aim is to assess the feasibility of delivering IP chemotherapy (either carboplatin or cisplatin, in combination with paclitaxel) to patients who have been optimally debulked at delayed primary surgery following IV chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
Endpoints for Selecting Intraperitoneal Arm after Randomisation of 150 Patients:
• 9-month progression rate post randomisation
• Completion rate of treatment (based on toxic effects and feasibility)
• Toxic effects
Long-term Comparison of All Patients Allocated to the Two Intraperitoneal Arms after randomisation of 300 patients:
• Progression-free survival
• Toxic effects
• Quality of life
Endpoints for the Phase III:
Primary Endpoint:
• Progression free survival
Secondary Endpoints:
• Overall survival
• Toxic effects
• Quality of life
• Correlative biological studies
• Economic evaluation
• Outcomes associated with variation in nursing-related practices
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must fulfill all of the following criteria to be eligible for admission to the study:
Histologically proven epithelial ovarian, primary serous type peritoneal or fallopian tube carcinoma. Patients with ovarian cancer of the clear cell histology are eligible.
Initial stage of disease (at diagnosis based on clinical/imaging assessment): FIGO Stage IIB-III. Patients with stage IV disease are also eligible if the only criterion for stage IV disease is presence of a pleural effusion that is confirmed to be associated with positive cytology for ovarian cancer.
Patients must have completed a minimum of 3 and a maximum of 4 cycles of platinum-based neoadjuvant chemotherapy prior to their first debulking surgery.
Surgical treatment prior to randomisation:
• Initial Diagnosis: Biopsy or limited excision only (no debulking attempted).
• The patient’s first cytoreductive (debulking) surgery must be after neoadjuvant chemotherapy (Delayed Primary Debulking). The delayed primary debulking surgery must be completed no more than 4 weeks after commencing administering of the last cycle of neoadjuvant chemotherapy and must be completed no more than 6 weeks prior to randomisation.
• Surgery will include total abdominal hysterectomy, bilateral salpingo-ophorectomy, omentectomy and any additional procedures required to achieve maximal cytoreduction with residual disease of 1 cm or less as assessed by the surgeon at the end of surgery.
ECOG performance status 0, 1 or 2 within 7 days prior to randomisation.
Age > 18 years. An upper age limit for eligibility will not be instituted. Investigators should ensure that enrolled patients can be expected to receive protocol therapy. Treatment modifications based only on older age are not permitted.
Life expectancy greater than or equal to 12 weeks.
Adequate hematological, renal and hepatic functions as defined by the following required laboratory values obtained within 7 days prior to randomization.
granulocytes > 1.5 x 109/l
platelets > 100 x 109/l
serum creatinine < UNL (upper normal limit) or >UNL to < 1.25 UNL provided measured creatinine clearance is > 60 ml/min (1 ml/sec)
serum bilirubin < UNL (upper normal limit)
AST (SGOT) or ALT (SGPT) < 2.5 UNL (upper normal limit)
Radiology requirements: must be done after debulking surgery and should be performed prior to first cycle of protocol therapy. Radiologic requirements will be accepted if performed within 14 days of day 1 of cycle 1 of protocol therapy if scheduling does not permit their completion prior to commencing protocol therapy).
chest x-ray or thoracic CT scan
abdominal/pelvic CT scan or MRI (ultrasound is not an acceptable substitute)
other x-rays or scans as clinically indicated
Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires. The baseline assessment must be completed prior to the first cycle of protocol therapy. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
Patient consent must be obtained according to local Institutional requirements. The patient must sign the consent form prior to randomisation.
Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomised on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
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|
| E.4 | Principal exclusion criteria |
Patients who fulfill any of the following criteria are not eligible for admission to the study:
Patients who have received any prior therapy for ovarian cancer, except for neoadjuvant platinum-based chemotherapy and surgery as described in the protocol.
Patients with borderline ovarian tumours (i.e. tumours of low malignant potential) alone.
Patients with a mucinous tumour.
Patients with a history of other malignancy, except adequately treated non-melanoma skin cancer or curatively treated in situ carcinoma of the cervix or other solid tumours curatively treated with no evidence of disease for > 5 years.
Patients with uncontrolled atrial or ventricular arrhythmias including 2nd or 3rd degree heart block unless managed with implanted pacemaker. Patients with a history of 1st degree heart block will be eligible.
Documented myocardial infarction within the 6 months preceding randomization (pre-treatment ECG evidence only of infarct will not exclude patients).
Patients diagnosed with a bowel obstruction.
Serious illness or medical condition which would not permit the patient to be managed according to protocol, including but not limited to:
prior allergic reactions to drugs containing cremophor or to compounds chemically related to cisplatin, paclitaxel or carboplatin. NOTE: non-IgE mediated hypersensitivity reactions to taxanes are not considered allergic reactions for the purpose of this criterion. Patients who have had mild-moderate hypersensitivity reactions to taxanes who have been successfully rechallenged with taxanes following premedication during neoadjuvant treatment are considered eligible. Patients who
have had severe hypersensitivity reactions to taxanes requiring their discontinuation or who have not been successfully rechallenged following moderate hypersensitivity reactions will, however be considered ineligible as they should not receive paclitaxel under these circumstances
symptomatic congestive heart failure within the preceding 6 months or other conditions which would lead to a contraindication of a high-volume saline diuresis
history of significant neurologic or psychiatric disorder which would impair the ability to obtain consent
active uncontrolled infection
persistent peripheral neuropathy or hearing loss > Grade 2 resulting from prior therapy
extensive intraperitoneal adhesion intra- or post-operatively which would impede intraperiteoneal treatment delivery
Concurrent treatment with other experimental drugs or anticancer therapy.
Note: Patients may undergo intra-operative randomisation during the surgery performed as the delayed primary debulking procedure in order to facilitate catheter placement in the event that the patient is randomized to receive intraperitoneal therapy. These patients must meet all the above criteria at the time of randomisation. Furthermore, in such patients, criteria related to patient safety with protocol therapy must be reviewed following surgery and within 7 days prior to beginning protocol therapy to determine that the patient continues to meet eligibility criteria. This includes, but is not limited to, the criteria for minimum organ function, performance status, absence of bowel obstruction and serious illness.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase II:
Nine month progression rate post randomisation.
Phase III:
Progression free survival. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Route of administration: 1)intravenous vs intraperitoneal; 2)comparison of chemotherapy schedules |
|
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
| The last visit of the last subject undergoing the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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