| 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 |
| Histologically proven recurrent advanced ovarian, fallopian tube or primary peritoneal carcinomas. |
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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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| 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 |
| In women with multiple relapsed advanced ovarian cancer, does nintedanib in combination with low dose chemotherapy (cyclophosphamide) improve overall survival. |
|
| E.2.2 | Secondary objectives of the trial |
Does nintedanib improve survival if given with low dose chemotherapy (cyclophosphamide) on a daily basis?
Are there any additional toxicities associated with the combination of treatment?
What are the effects on quality of life, compared with standard treatment?
Does the daily metronomic treatment affect the pattern of relapse for advanced patients?
Can outcome be predicted using diffusional weighted and perfusion MRI? (a sub-study to be carried out at one-two study sites). This will be further developed at a later stage.
|
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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 |
| A sub-study will be carried out at 1-2 sites investigating whether survival outcome can be predicted using diffusional weighted and perfusion MRI. This will be developed at a later stage. |
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| E.3 | Principal inclusion criteria |
- Female subjects, >18 years, histologically proven recurrent advanced epithelial ovarian, fallopian tube or primary peritoneal carcinomas
- Have either undergone a hysterectomy or bilateral oophorectomy/salpingectomy and/or have been postmenopausal for 24 consecutive months (i.e. who have not had menses at any time in the preceding 24 consecutive months without an alternative medical cause).
- Performance status 0-2
- Adequate organ function
- Life expectancy > 6 weeks
- Has received 2 or more lines of chemotherapy for ovarian cancer and patient is platinum resistant or platinum intolerant or not suitable for any further standard intravenous chemotherapy
- No previous oral cyclophosphamide, nintedanib, or other tyrosine kinase inhibitors such as cediranib but patients can have received anti-VEGF therapies such as bevacizumab as they will be stratified for this.
- Measurable lesions according to RECIST 1.1 criteria or serum CA125 levels for evaluation by GCIG CA125 criteria are welcomed but not a prerequisite for inclusion as response will only be assessed for those with evaluable disease.
- Able to give written informed consent and to complete QoL
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|
| E.4 | Principal exclusion criteria |
- Carcinosarcoma or malignant tumour of non-epithelial origin (e.g. germ cell tumour, sex cord-stromal tumour) of the ovary, fallopian tube or peritoneum
- Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture
- Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other GI disorders or abnormalities that would interfere with drug absorption or inability to take oral medication
- Active brain metastases (i.e. symptoms deteriorating, changing condition in < 4 weeks) or leptomeningeal disease. Trial entry is allowed if the brain metastases are stable (asymptomatic or condition stable for > 4 weeks). Dexamethasone for brain metastases is allowed if administered as stable dose for > 4 weeks before randomisation (if < 4 weeks the patient is not eligible)
- Clinically relevant therapy-related toxicity from previous chemotherapy and radiotherapy
- History of major thromboembolic event within last 6 months, such as pulmonary embolism or proximal deep vein thrombosis, unless on stable therapeutic anticoagulation (>3 months if on warfarin, PT / INR needs to be monitored regularly)
- Known inherited or acquired bleeding disorder
- Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within the past 6 months, congestive heart failure > NYHA II, severe peripheral vascular disease, significantly relevant pericardial effusion
- History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 6 months
- radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels.
Laboratory values at baseline indicating an increased risk for adverse events:
a. calculated GFR < 45 ml/min. Sites can use any calculation method according to local practice.
b. absolute neutrophil count (ANC) <1.5 x 109/L
c. platelets <100 x 109/L
d. haemoglobin < 90 g/L
e. proteinuria CTCAE 2 or greater
f. total bilirubin higher than twice ULN
g. ALT and/or AST > 1.5 x ULN unless liver metastases present when ALT / AST > 2.5 ULN
h. International normalized ratio (INR)>2, prothrombin time (PT) and activated partial thromboplastin time (APPT) > 1.5 x ULN in the absence of therapeutic anticoagulation
- Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal or antiviral therapy), including active or chronic hepatitis B and/or C infection, HIV- infection
- Poorly controlled diabetes mellitus
- Previous breast cancer patients are permitted only if diagnosis and any chemotherapy treatment for this was > 5 years previously and there is no evidence of metastatic breast cancer at trial entry (Please contact UCL CTC / CI if patient still on hormone treatment for breast cancer).
- Other malignancy diagnosed within the past 5 years. In exception to this rule, the following malignancies may be included:
(a) non-melanoma skin cancer (if adequately treated)
(b) cervical carcinoma in situ (if adequately treated)
(c) prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: G1 or G2, no LVSI and FIGO (2010) stage IA only
- Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease or a laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study
- Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
- Any contraindications for therapy with cyclophosphamide, e.g. a history of severe hypersensitivity reactions to listed excipients for cyclophosphamide treatment with other investigational drugs
- Patients should not commence trial treatment within 6 weeks of any major surgical procedure
- Participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial
- Chemotherapy, including immunotherapy or monoclonal antibody treatment (VEGF) within 4 weeks of starting study start.
- Hormone treatment for ovarian cancer within 2 weeks of starting study start (ongoing HRT is allowed).
- Any previous tyrosine kinase inhibitor treatment that has predominantly anti-angiogenic action (please discuss with CTC / CI)
- Radiotherapy within 3 months not allowed except when given for symptom control >28d previously. All patients receiving any radiotherapy will require evidence of recurrent ovarian cancer outside the irradiated field either on imaging or via rising CA125
- Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients of nintedanib
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is overall survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival (OS) will be measured from the date of randomisation until the date of death from any cause. Patients who do not die will be censored at the date last seen alive. |
|
| E.5.2 | Secondary end point(s) |
The secondary outcome measures are:
Progression Free Survival based on RECIST 1.1 and CA-125
Safety and tolerability based on toxicity data
Quality of Life (EORTC QLQ-C£0, EORTC QLQ OV28 and MOST recent symptoms)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression free survival (PFS) will be measured from the date of randomisation until the date of first progression or death, whichever comes first. Patients who do not die or progress will be censored at the date last seen alive.
Safety and Tolerability
Adverse events will be recorded and the highest CTCAE grade will be obtained for each type of adverse event, for each patient. Focus will be on those with grade 3 or 4 events. Safety will be assessed at each patient visit i.e. baseline,every 3 weeks for the first 6 weeks and then 6 weekly thereafter and 30 days after the end of treatment. The first 12 patients will be assessed on a 3 weekly basis for 12 weeks.
Quality of life will be collected at baseline, during treatment and at 6 weekly clinic visits. |
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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 | 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 | Yes |
| 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 | 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 | 16 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 formal end of the trial is defined as when 100 deaths have occurred or 12 months after the last patient has been recruited, whichever is the soonest (with confirmation by the IDMC). At this point the trial results should be available, and a 'declaration of end of trial' form will be submitted to participating regulatory authorities and ethical committees, as required. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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