A Randomised Phase II Study of Nintedanib (BIBF1120) Compared to Chemotherapy in Patients with Recurrent Clear Cell Carcinoma of the Ovary or Endometrium

Patients will be eligible for the study if the following criteria
are met:
1. Progressive or recurrent ovarian peritoneal or fallopian tube 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 calendar
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< ULN; 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)
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g. Glomerular Filtration Rate >=40ml/min. (calculated using
the Wright, 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.

Patients will be excluded from the study in the following
circumstances:
1. Prior treatment with Nintedanib or other angiogenesis
inhibitor/VEGF targeted therapy, except for prior
treatment with bevacizumab which is permitted.
2. Treatment within 28 days prior to randomisation 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. Prior
treatment with weekly paclitaxel is permitted where this
has been used as part of first line therapy and it is greater
than 6 months since the last dose of weekly paclitaxel.
Prior weekly paclitaxel for relapsed disease is not
permitted).
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
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antibiotic (antimicrobial, antifungal) or antiviral therapy,
including known hepatitis B and/or C infection and HIVinfection.
8. Symptomatic CNS metastasis or leptomeningeal
carcinomatosis
9. Known, uncontrolled hypersensitivity to the investigational
drugs or their excipients.
10.Hypersensitivity to Nintedanib, peanut or soya, or to any
of the excipients of Nintedanib.
11.Significant cardiovascular diseases, including uncontrolled
hypertension, clinically relevant cardiac arrhythmia,
unstable angina or myocardial infarction within 6 months
prior to randomisation, congestive heart failure > NYHA
III, severe peripheral vascular disease or clinically
significant pericardial effusion.
12.History of major thromboembolic event, such as
pulmonary embolism or proximal deep vein thrombosis,
unless on stable therapeutic anticoagulation
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 treatmentor planned surgery during the ontreatment
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 (see
section 5.7) for the duration of the trial and for 6 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.
21. Patients who have already received maximal lifetime dose
of anthracycline or have experienced cardiac toxicity from
an anthracycline should not receive doxorubicin or PLD.