| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-Sensitive Recurrent Ovarian Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
|
| 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 |
• Phase Ib: to define the maximum tolerated dose (MTD)/ recommended Phase II of E7080 administered in combination with carboplatin + gemcitabine in patients with platinum-sensitive recurrent ovarian cancer.
• Phase II: to evaluate the safety and tolerability of E7080 administered in combination with carboplatin + gemcitabine, compared with carboplatin + gemcitabine alone, in patients with platinum-sensitive recurrent ovarian cancer.
|
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the Phase II portion of the study is to make a preliminary assessment of the efficacy of E7080 administered in combination with carboplatin + gemcitabine, compared with carboplatin + gemcitabine alone, in patients with platinum-sensitive recurrent ovarian cancer. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be entered in the study only if they meet all of the following criteria:
1. Female patients ≥18 years of age.
2. Histologically or cytologically confirmed ovarian epithelial, fallopian tube, or primary peritoneal cavity cancer that was treated with and was sensitive to one prior platinum-based chemotherapy regimen for Stage III or Stage IV disease.
3. Documentation of biochemical relapse defined by CA125 criteria (measurable or non-measurable by RECIST criteria), more than six months since completion of first-line platinum-based chemotherapy requiring treatment with further platinum-based chemotherapy. CA125 criteria for relapse (GCIG criteria) are the finding of 2 serum CA125 levels with samples taken at least 1 week apart and no greater than 3 months apart:
•≥2 x ULN in patients with an elevated pre-treatment serum CA125 level followed by normalization on treatment and prior to progression
OR
•≥ 2X nadir value for patients with an elevated pre-treatment CA125 that never normalizes.
4. GOG performance status of 0 or 1
5. Life expectancy ≥3 months
6. Patients must have recovered from effects of any major surgery within 28 days from the first dose of study treatment.
7. Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing.
•Absolute neutrophil count (ANC) ≥1.5 x 109/L
•Platelet count ≥100 x 109/L
•Hemoglobin ≥9 g/dL
•Serum creatinine ≤1.5 X ULN and/or creatinine clearance >50 mL/min per the Cockcroft and Gault formula;
•Total serum bilirubin ≤1.5 X ULN
•Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) ≤2.5 X ULN, and ≤5 X ULN in cases of liver metastasis
•PT/International normalized ratio (INR) ≤1.5 X ULN
•PTT ≤ 1.1 X ULN
8. Blood pressure must be well-controlled (≤140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy;
9. Patients should have a negative pregnancy test at screening in pre-menopausal women and women <2 years after the onset of menopause. Pre-menopausal women must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year;
10. Before study entry, written informed consent must be obtained from patient prior to performing any study-related procedures. |
|
| E.4 | Principal exclusion criteria |
Patients will not be entered in the study for any of the following reasons:
1. Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives or avoidance of pregnancy measures;
2. Prior anti-angiogenic therapy with anti-VEGFR inhibitors; bevacizumab is allowed;
3. Prior gemcitabine;
4. Subjects with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein ≥1 g/24 hours will be ineligible.
5. Ovarian nonepithelial cancer, including malignant mixed Müllerian tumors and borderline tumors (e.g., tumors of low malignant potential);
6. Other malignancy within 5 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence;
7. History of, or known carcinomatous meningitis;
8. Are currently receiving any other treatment for the tumor (including palliative radiotherapy) aside from control of symptoms;
9. Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade ≤1, except for peripheral neuropathy (Grade 1 or 2 are permitted) or alopecia;
10. Received chemotherapy, biological therapy, hormonal therapy, targeted therapy, or radiotherapy within the 30 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade ≤1, except for peripheral neuropathy (Grade 1 or 2 are permitted) or alopecia;
11. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if ≥7 days have passed;
12. The use of anti-coagulants such as Vitamin K antagonists, unfractionated heparin, or low molecular weight heparin;
13. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
14. Significant cardiovascular impairment (history of congestive heart failure > New York Heart Association (NYHA) Grade II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
15. Any history of cerebral vascular accident (CVA) or transient ischemic attack (TIA) unless they have had no evidence of active disease for at least 6 months prior to randomization
16. Active hemoptysis (defined as bright red blood of ½ teaspoon or more) within the 30 days prior to study entry;
17. History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within the 6 months prior to enrolment;
18. History of bleeding diathesis or coagulopathy;
19. History of an allograft requiring immunosuppression;
20. Known positive human immunodeficiency virus (HIV), known surface antigen positive for hepatitis B or hepatitis C positive;
21. Hypersensitivity to E7080 and/or E7080 chemical derivative; or
22. Have any other uncontrolled infection or medical condition that would interfere with the conduct of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary exploratory efficacy endpoint will be the median biomarker-based progression-free survival (B-PFS), defined as the time from the date of randomization of a patient until the sooner of (1) the date of first documented biomarker CA125 relapse according to CA125 level, or (2) the date of such patient’s death due to any cause. |
|
| 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 | No |
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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
|
| Last Patient Last Visit (LPLV) |
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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