| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent clear cell carcinoma of the ovary or endometrium |
| Uusiutuva munasarjan tai kohdun limakalvon kirkassolusyöpä |
|
| E.1.1.1 | Medical condition in easily understood language |
| ovarian or endometrial clear cell cancer that has come back or started to grow again |
| Uusiutuva munasarjan tai kohdun limakalvon kirkassolusyöpä |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009252 |
| E.1.2 | Term | Clear cell endometrial carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this research is to estimate progression-free survival (PFS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib, and to compare this with PFS in women treated with chemotherapy. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this research are to estimate or assess the following and compare them between women receiving chemotherapy and women receiving Nintedanib:
-Estimate overall survival, response rate, disease control rate.
-Assess toxicity, quality of life,Q-TWIST (quality-adjusted time without symptoms of disease or toxicity of treatment)in women with clear cell carcinoma of the ovary, -Q-TWIST in women with clear cell carcinoma of the endometrium
-Estimate progression-free survival, overall survival, response rate, disease control rate and to record treatment received post-progression. |
|
| 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 |
Sample collection study is to establish a collection of tumour, circulating tumour DNA (ctDNA, circulating endothelial cells (CECs), and plasma samples from patients with relapsed ovarian and endometrial CCC that will allow investigation of prognostic and predictive markers and further the understanding of the biology of CCC. In Finland the site will not participate to DNA study. Only tissue blocks from original primary surgery and blood samples for circulating endothelial celss will be taken to be used to further investigational research of this type of cancer.
Initial investigations will focus on the effect of Nintedanib on markers of angiogenesis; markers of activation of the IL6-STAT3-HIF signalling; the frequency of ARID1A and PIK3CA mutations in primary tumours of patients with relapsed disease; and correlation of these factors with clinical outcome measures. In addition the feasibility of collecting ctDNA, its prognostic value and the spectrum of mutations identified in ctDNA at relapse compared with those in original tissue will be assessed.Circulating endothelial cells (CECs) are found in increased numbers in cancer patients as a result of vascular damage and angiogenesis.No studies on the clinical relevance of CEC counts in ovarian cancer have been published so far. This trial allows us to study the prognostic value of CECs in CCC for the first time. |
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| E.3 | Principal inclusion criteria |
1.Progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by RECIST 1.1.
2.Failure after ≥1 prior platinum containing regimen which may have been given in the adjuvant setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6 months of their last platinum dose.
3.ECOG Performance status of ≤2.
4.Life expectancy of >3 months.
5.Adequate hepatic, bone marrow coagulation and renal function
a.Hepatic function: total bilirubin within normal limits; ALT and AST < 2.5 x ULN
b.Coagulation parameters: INR <2 x ULN and prothrombin time and activated partial thromboplastin time < 1.5 x ULN in the absence of therapeutic anticoagulation
c.absolute neutrophil count (ANC) ≥ 1.5 x 109/L
d.platelets ≥ 100 x 109L
e.haemoglobin ≥ 9.0 g/dL
f.proteinuria < grade 2 CTCAE (version 4)
g.Glomerular Filtration Rate ≥40ml/min. (calculated using Cockroft & Gault equation or measured by EDTA clearance)
6.Female and > 18 years of age.
7.Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and local legislation.
8.Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.
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|
| E.4 | Principal exclusion criteria |
1.Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted..
2.Treatment within the last 4 weeks with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease.
3.Previous treatment with the chemotherapy regimen selected as the control arm by the investigator. (Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving weekly paclitaxel).
4.Other malignancy diagnosed within 5 years of enrolment except for:
a.non-melanomatous skin cancer (if adequately treated)
b.cervical carcinoma in situ (if adequately treated)
c.carcinoma in situ of the breast (if adequately treated)
d.For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met:
•disease stage FIGO Stage 1a (tumour invades less than one half of myometrium)
•Grade 1 or 2
5.Patients with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality.
6.Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption.
7.Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection.
8.Symptomatic CNS metastasis or leptomeningealcarcinomatosis.
9.Known, uncontrolled hypersensitivity to the investigational drugs or their excipients.
10.Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to enrolment, congestive heart failure > NYHA III, severe peripheral vascular disease, clinically significant pericardial effusion.
11.History of major thromboembolic event defined as:
•pulmonary embolism (PE) within six months prior to enrolment
•recurrent pulmonary embolism (history of at least 2 events)
•history of at least 2 unprovoked (=without a transient reversible risk factor) events of proximal deep venous thrombosis
•history of a provoked (=with transient or reversible risk factor, such as surgery) thrombosis of proximal deep veins or visceral vessels within 6 months prior to enrolment if not on stable therapeutic anticoagulation.
12.Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation, Prothrombin G20210A mutation).
13.Known inherited predisposition to bleeding or thrombosis.
14.History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months.
15.History of clinically significant haemorrhage in the past 6 months.
16.Major injuries or surgery within the past 28 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
17.Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment.
18.Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
19.Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels.
20.Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure is to estimate the progression free survival (PFS)as defined by RECIST 1.1 criteria, in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to PFS in women treated with chemotherapy. PFS is defined as the duration of time from date of randomisation to date of progression or death, which ever occurs earlier. CA125 progression alone will not be considered as progressive disease.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease evaluation will be performed based on tumour imaging. All patients will undergo baseline evaluation tumour assessment with a CT scan or MRI of abdomen and pelvis plus a thoracic CT or CXR imaging within 28 days prior to starting study treatment. The same modality should be used for the duration of the study. From date of randomisation until wk 48 or until progressive disease occurs, patients will undergo imaging every 8 weeks. Patients who have not progressed by wk 48 will have a further scan at wk 72. In patients who do not progress by wk 72, subsequent imaging will be performed only as clinically indicated. Patients that come off treatment for reasons other than progression continue to have imaging scans at the specified time points. |
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| E.5.2 | Secondary end point(s) |
To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to OS in women treated with chemotherapy.
To estimate response rate (RR) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to RR in women treated with chemotherapy.
To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to DCRS in women treated with chemotherapy.
To assess toxicity in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.
To assess quality of life in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.
To assess Q-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and and compare this with those treated with chemotherapy.
To assess Q-TWiST in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate progression free survival (PFS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate response rate (RR) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To record treatment received post progression.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Toxicity: day 1 of each cycle of treatment (NCI CTC AE version 4.0).
-Q-TWiST: This is assessed by combining toxicity and progression data.Progression is assessed using the imaging data (see 23-1).
-RR and DCR: Assessed from imaging data (see 23-1).
-Quality of life (QoL): QoL questionnaires will be completed at screening, and day 1 of cycle 2, 4 and 6. For patients on chemotherapy QoL assessments will be performed at the end of treatment visit and every 8 weeks subsequently and for patients on Nintedanib, day 1 of every cycle from cycle 7 onwards. QoL assessments will continue 2 monthly post progression as long as the PI considers it appropriate and the patient continues to consent
-Patients will be followed up for survival after progression (every 2 months). |
|
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | No |
| 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
|
For the purpose of the Clinical Trial Authorisation the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of Nintedanib.
For the purposes of the main REC approval, the study end date is deemed to be the date of last data capture. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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