Phase II Study of Docetaxel +/- Nintedanib in Breast Cancer

Study Overview
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Brief Summary
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National, randomized, unblinded, phase IIb trial with 2 strata: First-line chemotherapy / Second-line chemotherapy for locally recurrent or metastatic breast cancer.

Detailed Description
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Patients will be stratified at randomization according to first-line chemotherapy / Second-line chemotherapy for metastatic or locally recurrent breast cancer Treatment until progression or unacceptable toxicity Visits are planned every 3 weeks during treatment and every 3 months after end of treatment or patient's withdrawal

Official Title
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A Phase II Randomized Study of Docetaxel With or Without NINTEDANIB (BIBF-1120) in Patient Receiving a First or Second-line of Chemotherapy for HER Negative Metastatic or Locally Recurrent Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Nintedanib
* Drug: Docetaxel: increase of the dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old Histologically or cytologically confirmed adenocarcinoma of the breast Locally recurrent or metastatic disease HER 2 negative status Requiring a first or a second-line chemotherapy for locally recurrent or metastatic disease. Prior first line chemotherapy not containing Docetaxel Measurable or evaluable disease according to RECIST 1.1 criteria Allowed prior chemotherapy as follows : Docetaxel in the neoadjuvant or adjuvant setting is allowed provided that relapse has been observed more than 12 months after the end of docetaxel treatment Bevacizumab in 1st line is allowed with a wash-out of 4 weeks, with recovery to NCI-CTCAE v3.0 toxicity ECOG performance status 0-1 Adequate bone marrow, hepatic and renal functions as evidence by the following: Hemoglobin ≥ 10 G/100 mL Neutrophils count ≥ 1500 /mm3 Platelets ≥ 100 000 /mm3 Total bilirubin ≤ ULN (ULN:Upper Limit of Normal) SGOT/SGPT ≤ 1.5 x ULN (≤ 2.5 x ULN in case of hepatic metastasis) Serum alkaline phosphatase ≤ 2.5 x ULN Creatinin clearance ≥ 45 ml/min or creatinin ≤ 1.5 x ULN Proteinuria < CTCAE grade 2 Coagulation parameters: International normalised ratio (INR) ≤ 2, prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 50% of deviation of institutional ULN Effective contraception for patients (male and female) with reproductive potential during their entire participation in the study and during 3 months after the last administration of Nintedanib or Docetaxel Negative pregnancy test (serum beta-HCG) performed within 1 week prior to start of study treatment in females with reproductive potential Patient covered by government health insurance Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and to the local legislation Exclusion Criteria: Concomitant hormone therapy for metastatic breast cancer Patients with dysphagia, or inability to swallow the tablets Other serious illness or medical conditions: Cardiac disease Unstable diabetes Uncontrolled hypercalcemia Pregnancy or breast feeding woman Unable for medical follow-up (geographic, social or mental reasons) Prior treatment with Nintedanib or any other VEGFR inhibitor Known hypersensitivity to the trial drugs , to their excipients, to peanut, to soya or to contrast media Contra indication to the use of the backbone treatment and to the comparator Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomisation) Leptomeningeal disease Radiographic evidence of cavitary or necrotic tumors Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels History of clinically significant haemorrhagic or thromboembolic event in the past 6 months Known inherited predisposition to bleeding or thrombosis Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion) Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy Active or chronic hepatitis C and/or B infection Active alcohol or drug abuse Significant weight loss (> 10% of BW) within past 6 months prior to inclusion into the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Docetaxel + Nintedanib | Drug: Docetaxel<br>* 75 mg/m2 IV Day 1 / 3 weeks<br>* Other names: Taxotere;Drug: Nintedanib<br>* 200 mg x 2 per os daily from D2* *No Nintedanib on days when docetaxel is administered<br>* Other names: OFEV;|
| Active Comparator: Arm B<br>Docetaxel + increase of the dose | Drug: Docetaxel<br>* 75 mg/m2 IV Day 1 / 3 weeks<br>* Other names: Taxotere;Drug: Docetaxel: increase of the dose<br>* Dose can be increased to 100 mg/m² secondarily at cycle 2 on the initiative of the investigator<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) in patients receiving Docetaxel + Nintedanib treatment (Arm A) compared to Docetaxel alone (Arm B) | 6-months progression free disease | baseline, every 9 weeks (or 3 cycles), up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response rate | according to RECIST 1.1 | baseline, every 9 weeks (or 3 cycles), up to 6 months | 
| overall survival | time from the date of randomization to the date of death from any cause | up to 2 years | 
| quality of life by QLQ-C30 and additionnel module BR23 | questionnaire : EORTC QLQ C30 (Additional module BR23) | baseline, every 9 weeks (or 3 cycles), up to 6 months | 
| biological markers levels in tumors and endothelial cells | biological analysis of cells RT-qPCR analysis, including endothelial cells using a specific reference gene | baseline, every 9 weeks (or 3 cycles), up to 6 months | 
| biological markers in patient serum | biological analysis in patient's serum Dosage of VEGF-A, -C, FGF-1, -2, PDGF-AA, -AB, -BB in patient's serum | baseline, every 9 weeks (or 3 cycles), up to 6 months | 
| safety profile of Nintedanib | according to NCI CTCAE v3.0 | before each cycle, 3 weeks after the last dose or at the end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally recurrent or metastatic breast cancer, Docetaxel, Nintedanib