A study of Nintedanib compared to chemotherapy in patients with recurrent Clear Cell Carcinoma of the ovary or endometrium

INTERVENTION: Patients are randomised on a 1:1 basis to either: Nintedanib (BIBF1120) 200mg PO twice daily, continuously until disease progression or chemotherapy. The chemotherapy regime will be chosen by the Investigator from the following: Ovarian Cancer Patients Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days, x6 cycles Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days, x6 cycles Topotecan 4mg/m2 IV Day 1, 8, 15 every 28 days, x6 cycles Endometrial Cancer Patients Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days, x6 cycles Doxorubicin IV 60mg/m2 every 21 days x6 cycles For the first 24 weeks of the study patients will be seen formally on a 4 weekly basis in clinic. Radiological assessments (CT or MRI scan of chest, abdomen and pelvis plus a thoracic CT or CXR imaging) will occur at 8 weekly intervals until disease progression or week 48. From week 24 onwards all patients will be seen on a 8 weekly basis until disease progression. CONDITION: Relapsed or progressive clear cell carcinoma of the ovary or endometrium ; Cancer ; Malignant neoplasm of ovary PRIMARY OUTCOME: Progression Free Survival (PFS); The primary endpoint for efficacy is progression free survival as defined by RECIST 1.1 criteria. Progression free survival (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. ; Disease evaluation will be performed according to RECIST 1.1 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 imaging modality should be used for the duration of the study. Then from date of randomisation until week 48 or until progressive disease occurs, patients will undergo imaging every 8 weeks. Patients who have not progressed by week 48 will have a further scan at week 72. In patients who do not progress by week 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. The schedule for imaging scans is to be maintained even if delays occur in treatment. Imaging may occur within 1 week prior and 1 week after the planned date. SECONDARY OUTCOME: 1. Overall Survival (OS); 2. Overall Response Rate (ORR): Assessed from imaging data; 3. Disease Control Rate (DCR) (CR+PR+SD) at 12 weeks, assessed from imaging data; 4. Toxicity: day 1 of each cycle of treatment using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.; 5. Quality of Life (QoL): questionnaires will be completed at screening, 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.; 6. Quality Adjusted Time Without Symptoms of Disease or Toxicity of Treatment (Q‐TWIST) ‐ This is assessed on the basis by combining toxicity and progression data. Progression is assessed using the imaging data .; 7. Treatment post progression; ; Patients be followed up for survival after progression (follow‐up forms will be required every 2 months). Information on subsequent anti‐cancer therapy will continue to be collected after progression. 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 Response Evaluation Criteria In Solid Tumors (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. Eastern Cooperative Oncology Group (ECOG) Performance status of =2 4. Life expectancy of >3 months 5. Adequate hepatic, bone marrow coagulation and renal function 5.1. Hepatic function: total bilirubin within normal limits; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x