Study Of Nintedanib Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium

NCT ID: NCT02866370

Last Updated: 2016-08-15

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

120 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-04-30

Study Completion Date

2021-03-31

Brief Summary

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The trial will recruit up to 120 patients; 90 with ovarian clear cell carcinoma and up to 30 with endometrial clear cell carcinoma. Patients will be randomised between chemotherapy and Nintedanib 200mg twice daily oral administration (PO) continuously. 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

Detailed Description

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Clear cell carcinoma (CCC) is an uncommon histotype of ovarian and a rare histotype of endometrial cancer. The prognosis for recurrent disease is poor with response rates to standard chemotherapy of \<10% so there is an urgent need for novel therapies. Ovarian CCC (OCCC) is biologically different from other ovarian cancer histotypes but shares features with renal CCC, including upregulation of angiogenesis pathways. Hence inhibition of angiogenesis, which has been a successful strategy in renal CCC, may also be of benefit in OCCC and endometrial CCC (ECCC).

Nintedanib is a well-tolerated, potent, orally-available, kinase inhibitor targeting Vascular Endothelial Growth Factor (VEGFR) 1-3, Platelet Derived Growth Factor Receptor (PDGFR)α/β, and Firbroblas Gworth Factor Receptors (FGFR) 1-3. It is licensed in Europe in combination with docetaxel after first line chemotherapy for Non-Small Cell Lung Cancer (NSCLC). Importantly it also has significant activity as a single agent in renal CCC with an Overall Response Rate (ORR) of 20.3%, disease control rate of 76.% and 43% 9 month progression free survival.

Response rates (RR) of ovarian CCC to standard chemotherapy with or without platinum are poor whatever line of treatment. A number of different agents are used in recurrent CCC and, although isolated instances of response to a variety of agents have been reported, no regimen seems to offer a particular advantage. As a result the investigators do not expect to see significant differences in response rates within the chemotherapy arms of the study. Hence it is feasible to allow physicians a choice of chemotherapy from a pre-specified selection and to include patients with multiple previous relapses. Since overall and progression free survival may be shorter with successive lines of treatment, the number of previous lines of treatment will be a stratification factor. These measures should maximise recruitment of this rare tumour sub-type across different countries.

Conditions

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Ovarian Clear Cell Carcinoma Endometrial Clear Cell Carcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Nintedanib

Nintedanib (BIBF1120) 200mg twice daily PO, continuously

Group Type EXPERIMENTAL

Nintedanib

Intervention Type DRUG

Nintedanib (BIBF1120) 200mg twice daily PO, continuously, until progression or withdrawal from the treatment.

Chemotherapy

Ovarian Cancer Patients:

Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days Topotecan (4mg/m2) IV Day 1, 8, 15 every 28 days

Endometrial Cancer Patients:

Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days Doxorubicin IV (60mg/m2) every 21 days

Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity. The maximal lifetime cumulative dose of doxorubicin or pegylated liposomal doxorubicin allowed is 450 mg/m2.

Group Type ACTIVE_COMPARATOR

Paclitaxel

Intervention Type DRUG

Ovarian Cancer Patients Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days\* Endometrial Cancer Patients Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Pegylated Liposomal Doxorubicin (PLD)

Intervention Type DRUG

Ovarian Cancer Patients Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity. The maximal lifetime cumulative dose of doxorubicin or pegylated liposomal doxorubicin allowed is 450 mg/m2.

Topotecan

Intervention Type DRUG

Ovarian Cancer Patients Topotecan 4mg/m2 IV Day 1, 8, 15 every 28 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Carboplatin

Intervention Type DRUG

Endometrial Cancer Patients Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Doxorubicin

Intervention Type DRUG

Endometrial Cancer Patients Doxorubicin IV 60mg/m2 every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity. The maximal lifetime cumulative dose of doxorubicin or pegylated liposomal doxorubicin allowed is 450 mg/m2.

Interventions

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Nintedanib

Nintedanib (BIBF1120) 200mg twice daily PO, continuously, until progression or withdrawal from the treatment.

Intervention Type DRUG

Paclitaxel

Ovarian Cancer Patients Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days\* Endometrial Cancer Patients Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Intervention Type DRUG

Pegylated Liposomal Doxorubicin (PLD)

Ovarian Cancer Patients Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity. The maximal lifetime cumulative dose of doxorubicin or pegylated liposomal doxorubicin allowed is 450 mg/m2.

Intervention Type DRUG

Topotecan

Ovarian Cancer Patients Topotecan 4mg/m2 IV Day 1, 8, 15 every 28 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Intervention Type DRUG

Carboplatin

Endometrial Cancer Patients Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity.

Intervention Type DRUG

Doxorubicin

Endometrial Cancer Patients Doxorubicin IV 60mg/m2 every 21 days\*

\* Patients will usually receive up to 6 cycles of chemotherapy. If in the opinion of the Investigator, a patient would benefit from continuing with chemotherapy beyond 6 cycles, it is acceptable to continue until progression or unacceptable toxicity. The maximal lifetime cumulative dose of doxorubicin or pegylated liposomal doxorubicin allowed is 450 mg/m2.

Intervention Type DRUG

Other Intervention Names

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BIBF 1120 Vargatef Caelyx Hycamtin

Eligibility Criteria

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Inclusion Criteria

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 Response Evaluation Criteria in Solid Tumours (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 (Eastern Cooperative Oncology Group) Performance status of ≤2.
4. Life expectancy of \>3 months.
5. Adequate hepatic, bone marrow coagulation and renal function

1. Hepatic function: total bilirubin \< Upper Limit of Normal (ULN); ALT and AST \< 2.5 x ULN
2. Coagulation parameters: INR (International Normalised Ratio) \<2 x ULN and prothrombin time and activated partial thromboplastin time \< 1.5 x ULN in the absence of therapeutic anticoagulation
3. absolute neutrophil count (ANC) ≥ 1.5 x 109/L
4. platelets ≥ 100 x 109L
5. haemoglobin ≥ 9.0 g/dL
6. proteinuria \< grade 2 CTCAE (version 4)
7. 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 International Conference on Harmonization on Good Clinical Practice (ICH-GCP) guidelines and local legislation.
8. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.

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 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:

1. non-melanomatous skin cancer (if adequately treated)
2. cervical carcinoma in situ (if adequately treated)
3. carcinoma in situ of the breast (if adequately treated)
4. 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 (International Federation of Gynecology and Obstetrics) 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 central nervous system (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 (New York Heart Association) III, severe peripheral vascular disease, 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 treatment 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 (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 Paclitaxel Liposomal Doxorubicin (PLD).
Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Boehringer Ingelheim

INDUSTRY

Sponsor Role collaborator

Cancer Research UK

OTHER

Sponsor Role collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role collaborator

Nordic Society of Gynaecological Oncology - Clinical Trials Unit

OTHER

Sponsor Role collaborator

ARCAGY/ GINECO GROUP

OTHER

Sponsor Role collaborator

NHS Greater Glasgow and Clyde

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Rosalind Glasspool

Role: PRINCIPAL_INVESTIGATOR

NHS Greater Glasgow and Clyde

Locations

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Beatson West of Scotland Cancer Centre

Glasgow, Lanarkshire, United Kingdom

Site Status RECRUITING

Ninewells Hospital

Dundee, Tayside, United Kingdom

Site Status RECRUITING

Clatterbridge Cancer Centre

Liverpool, Wirral, United Kingdom

Site Status RECRUITING

Belfast City Hospital (Northern Ireland Cancer Centre)

Belfast, , United Kingdom

Site Status RECRUITING

Bristol Heamatology and Cancer Centre

Bristol, , United Kingdom

Site Status RECRUITING

Velindre Hospital

Cardiff, , United Kingdom

Site Status RECRUITING

Kent & Canterbury Hospital

Kent, , United Kingdom

Site Status RECRUITING

Queen Elizabeth Queen Mother Hospital

Kent, , United Kingdom

Site Status RECRUITING

William Harvey Hospital

Kent, , United Kingdom

Site Status RECRUITING

St James Hospital

Leeds, , United Kingdom

Site Status RECRUITING

Guy's Hosital

London, , United Kingdom

Site Status RECRUITING

Royal Marsden Hospital

London, , United Kingdom

Site Status RECRUITING

St Bartholomew's Hospital

London, , United Kingdom

Site Status NOT_YET_RECRUITING

University College London Hospital

London, , United Kingdom

Site Status NOT_YET_RECRUITING

The Christie Hospital

Manchester, , United Kingdom

Site Status RECRUITING

Great Western Hospital

Swindon, , United Kingdom

Site Status RECRUITING

Musgrove Park Hospital

Taunton, , United Kingdom

Site Status RECRUITING

Countries

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United Kingdom

Central Contacts

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Claire A Lawless

Role: CONTACT

Facility Contacts

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Ros Glasspool

Role: primary

References

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Gaitskell K, Rogozinska E, Platt S, Chen Y, Abd El Aziz M, Tattersall A, Morrison J. Angiogenesis inhibitors for the treatment of epithelial ovarian cancer. Cochrane Database Syst Rev. 2023 Apr 18;4(4):CD007930. doi: 10.1002/14651858.CD007930.pub3.

Reference Type DERIVED
PMID: 37185961 (View on PubMed)

Other Identifiers

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2013-002109-73

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ISRCTN50772895

Identifier Type: REGISTRY

Identifier Source: secondary_id

ENGOT-GYN1

Identifier Type: OTHER

Identifier Source: secondary_id

EORTC1212

Identifier Type: OTHER

Identifier Source: secondary_id

GN12ON259 (NiCCC2013)

Identifier Type: -

Identifier Source: org_study_id

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