E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with an histologically confirmed diagnosis of ovarian sex-cord stromal tumor in relapse after a platinum-based chemotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Patients diagnosed with a rare tumor (ovarian sex-cord stromal tumor) in relapse after a platinum-based chemotherapy. |
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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 | 17.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the clinical benefit of combining bevacizumab long-term treatment to weekly paclitaxel measured by the non-progression rate after 6 months of treatment |
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E.2.2 | Secondary objectives of the trial |
•The Progression-Free survival
•The Overall Survival
•The Objective Response Rate measured with the number of radiological responses defined as PR or CR
•The duration of response
•To describe the safety profile of the association paclitaxel + bevacizumab and of bevacizumab long-term maintenance monotherapy. The safety profiles will be defined by the number of patients with adverse events (AE) any type and any grade using the NCI-CTC AE scale version 4.0
•In arm A, to evaluate progression-free survival after introduction of bevacizumab at progression during the surveillance period.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
•To identify predictive biomarkers of treatment response via:
•Analysis of the circulating levels of VEGF, soluble VEGFR1, PIGF, PDGF-β, b-FGF, HGF, sVCAM-1, sICAM1, IL-6, IL-8, by ELISA at inclusion, after 2, 4, 6, 8, 12, and 16 weeks of treatment (i.e. C1D1, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1) and at time of disease progression.
•Analysis of the number of circulating endothelial cells (CEC, CD45-, CD31, CD46+) and circulating endothelial progenitors (CEP) will be quantified using flow cytometry analysis at inclusion, after 2, 4, 6, 8, 12, and 16 weeks of treatment (i.e. C1D1, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1) and at time of disease progression.
•To analyse the expression pattern of AKT, mTOR, S6rp, 4EBP1, PTEN and their related phospho-proteins (p-AKT Ser473 and Thr308, p-mTOR Ser2448, p-S6rp Ser 235/236, 4EBP1Thr37/46, PTEN Ser380) by immunohistochemistry on archival tumor samples.
•To determine mutation status of PI3K, AKT, mTOR, PTEN and Forkhead transcription factor (FOX2) genes from archival tumor samples.
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E.3 | Principal inclusion criteria |
I1.Female aged >= 18 years at inclusion
I2.Histologically confirmed diagnosis of ovarian SCST including the following cell types: granulosa cell tumors (adults and juveniles types), granulosa cell theca cell tumor, Sertoli-Leydig cell tumors, malignant steroïd cell tumors, gynandroblastoma, unclassified SCST and mixed tumors
I3.Documented relapse of SCST defined by progression of disease (radiologic, clinic or biological progression)
I4.At least one measurable site of disease as defined by RECIST 1.1
-Tumors within a previously irradiated field will be designated as “non-target” lesions unless progression is documented or a biopsy is obtained to confirm persistence > 90 days following completion of radiotherapy.
I5.Patients must have been pre-treated with at least 1 prior line of platinum based chemotherapy
I6.Adequate bone marrow, liver and renal functions including the following:
•Absolute neutrophil count ≥ 1.5 G/L, platelet count ≥ 100 G/L, and hemoglobin ≥ 9 g/dL. Prior transfusion is authorized to keep haemoglobin level to ≥9g/dL
•AST/ALT ≤ 3 x upper limit of normal (ULN) (or ≤ 5.0 ULN if liver metastasis) and total bilirubin ≤ 1.5 ULN
•Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥ 50 mL/min according to Cockcroft formula (or to MDRD formula for patients older than 65 years-old).
I7.Adequate coagulation panel:
•PT ≤ 1.2 ULN
•aPTT ≤ 1.5 ULN
•INR ≤ 1.5 ULN
I8.Adequate neurologic function: only neuropathy (sensory and motor) grade ≤ 1 (CTCAE v4.0) are allowed
I9.ECOG Performance status of 0, 1, or 2
I10.Life expectancy ≥ 4 months
I11.Satisfactory cardiac function.
Normal left ventricular ejection fraction (FEVG ≥ 50%)
I12.Ability to understand and sign informed consent and willingness to comply with the study procedures before study entry
I13.Women of childbearing potential* are required to have a negative serum pregnancy test within 7 days prior to study treatment initiation (i.e. Cycle 1 Day 1)
*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
•≥ 50 years old and naturally amenorrheic for ≥ 1 year
•Permanent premature ovarian failure confirmed by a specialist gynaecologist
•Previous bilateral salpingo- oopherectomy or hysterectomyoophrectomy
•XY genotype, Turner’s syndrome, or uterine agenesis
•Female patient who do not meet at least of the above criteria are defined as women of childbearing potential
I14.Willingness to use adequate contraceptive method during the whole study period and for up to 6 months after the last treatment intake
I15.Covered by a medical insurance (in country where applicable)
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E.4 | Principal exclusion criteria |
E1.Prior systemic therapy with bevacizumab
E2.Active peripheral neuropathy ≥ grade 2 (NCI-CTCAE v4.0)
E3.Prior history of other malignancies other than ovarian SCST (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the subjects has been free of the disease for at least 3 years or 5 years for breast cancer
E4.No resolution of specific toxicities related to any prior anti-cancer therapy to grade ≤1, excluding alopecia, according to the NCI-CTCAE v.4.0
E5.History or evidence of thrombotic or hemorrhagic disorders, including cerebro-vascular accident/stroke or transient ischemic attack or sub-arachnoids’ haemorrhage within 6 months prior to first dose of study drugs.
E6.Uncontrolled arterial hypertension (systolic ≥ 150 mmHg or diastolic ≥ 100 mmHg) despite optimal antihypertensive therapy or clinically significant cardiovascular disease including one of the following:
•Myocardial infarction or instable angina within 6 months prior to first dose of study drugs
•NYHA grade ≥ II congestive heart failure
•Serious cardiac arrhythmia requiring medication
•Peripheral vascular disease ≥ grade 3
E7.History of bowel obstruction, including sub-occlusive syndrome and history of abdominal fistula, gastro-intestinal perforation or intra-abdominal abscess during the year prior to inclusion
E8.Prior treatments:
•Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study inclusion or anticipation of need for major surgical procedure during the course of the study
•Current or recent treatment with another investigational drug within 30 days of first study treatment dosing or within 6 weeks in case of prior nitrozo-urea and or mitomycin C treatment. In case of hormonotherapy , patients will be eligible if hormonotherapy is discontinued within at least 1 week before treatment initiation
•Current or recent (within 10 days prior to randomization) chronic use of aspirin
•> 325 mg/dayf or use of any other inhibitor of platelet aggregation
•Chronic treatment (i.e. > 15 days) with non steroids anti-inflammatory agents unless a washout period of 15 days was observed before the inclusion.
• Intake of granulocyte growth factor within 3 weeks before study entry
E9. Treatment during the study :
Debulking surgery prior to disease progression is not foreseen
Concurrent radiotherapy during the study treatment
E10.Presence of hematuria and proteinuria ≥ 2+ (urine dipstick). Patients with ≥ 2+ proteinuria on dipstick at screening should undergo a 24-hour urine collection and will be eligible only if 24-h proteinuria ≤ 1 g
E11.Untreated evolutive brain metastases
E12.Active bacteria or fungal infection (grade ≥2, CTC AE V4.0)
E13.Known HIV1, HIV2 or chronic hepatitis B or C infection
E14.Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies
E15.Any contraindications to paclitaxel treatment: for example severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil) or to any of the excipients (Ethanol Citric acid) (refer to Taxol® SPC for further details)
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E.5 End points |
E.5.1 | Primary end point(s) |
The 6-month non progression rate will be summarized by treatment arm by a proportion together with its 95% confidence interval. It will be compared between the two arms using a Fisher exact test. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 months of chemotherapy +/- bevacizumab |
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E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) will be measured from the date of randomization to the date of event defined as the first documented progression or death due to any cause. Patients with no event at the time of the analysis will be censored at the date of the last adequate tumour assessment. PFS will be estimated using the Kaplan-Meier method. patients with adverse events (AE) any type and any grade using the NCI-CTC AE scale version 4.0
Overall survival (OS) will be measured from the date of randomization to the date of death or the date of last contact (censored data) and will be estimated using the Kaplan-Meier method.
Median OS will be presented in each treatment arm with its 95% confidence interval. Survival curves will be compared using the log-rank test.
The objective response rate (complete or partial response) will be presented in each treatment arm by a proportion together with its 95% confidence interval and will be compared between the two arms using a Fisher exact test.
Duration of response will apply only to patients with an objective tumour response. It will be measured from the date of documented objective response to the date of event defined as the first documented progression or death due to underlying disease. Patients with no event at the time of the analysis will be censored at the date of last adequate tumour assessment. Duration of response will be described in each treatment arm and compared between the two arms using a non parametric Wilcoxon test.
Safety analyses will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTC-V3) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to bevacizumab. Adverse events will be coded according to the MedDRA®.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In each treatment arm, PFS rate will be evaluated at 6 months,
OS evaluation after 54 months |
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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 | 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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Paclitaxel as standard of care given in the 2 arms |
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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 | 50 |
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 |
Australia |
Belgium |
Denmark |
Finland |
France |
Germany |
Italy |
Japan |
Netherlands |
Norway |
Spain |
Sweden |
United Kingdom |
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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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The study period will include a first treatment period of chemotherapy for 6 months followed by a second period of surveillance (Arm A) or bevacizumab maintenance therapy (Arm B) for a maximum of 1 year. Follow-up will be performed for a maximum of 36 months after maintenance treatment.
The end of the trial is the last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |