A Study of Vinflunine Plus Gemcitabine Versus Paclitaxel Plus Gemcitabine in Patients With Advanced Breast Cancer

Study Overview
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Brief Summary
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The combination of vinflunine and gemcitabine in advanced breast cancer in comparison to paclitaxel and gemcitabine is based on the following points: the significant antitumour activity of vinflunine in metastatic breast cancer (MBC) as single agent after anthracycline-taxane exposure and recent phase I study results of the vinflunine plus gemcitabine is at least additive and both drugs have a distinct mechanism of action; since taxanes have been approved in the adjuvant setting and are widely used in the treatment of early breast cancer it is worthwhile to assess new combination chemotherapy regimens as first line therapy for metastatic breast cancer.

Detailed Description
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This is a randomised, multicentre, open-label phase III study comparing antitumour efficacy of vinflunine plus gemcitabine versus paclitaxel plus gemcitabine, as first line treatment for patients with unresectable, locally recurrent or metastatic breast cancer after prior anthracycline-based adjuvant chemotherapy. Patients with metastatic breast cancer are incurable using conventional therapy with antitumoural hormonal drugs or cytostatic agents. The median survival from diagnosis of metastatic disease to death is reported to be approximately 3 years. While newer chemotherapeutic agents have been able to achieve tumour shrinkage, no significant increases in overall survival have been demonstrated so far. One reason for this result may be that breast cancer has a longer disease time span than NSCLC, allowing for administration of multiple therapies with different modalities. These therapies confound overall survival regardless of whether the treatment is a first-line or a subsequent treatment. The combination of gemcitabine plus paclitaxel has demonstrated improvement in overall survival over paclitaxel alone as first line therapy in patients with locally recurrent or metastatic breast cancer, however, this study compared single agent versus combination chemotherapy. Using overall survival as a primary endpoint in a trial Using overall survival as a primary endpoint in a trial comparing 2 different cytostatic combinations in the treatment of metastatic breast cancer requires a large phase III study to detect a clinically significant difference. The advantages with such an endpoint are that it is technically easy to monitor and it is not dependent on monitoring tumour status. However, since patients with breast cancer typically receive 3 or more lines of chemotherapy, it becomes difficult to assess the impact of a first-line therapy on overall survival (as proposed herein) due to the potential for confounding effects from later treatments. A more specific instrument -if closely monitored- is progression-free survival. This endpoint reflects the impact of a specific treatment modality on the disease at a given time period and is probably confounded neither by prior treatments nor by subsequent therapies. Progression-free survival also represents an important clinical achievement for patients with metastatic breast cancer.

Official Title
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Phase III Study of Vinflunine Plus Gemcitabine Versus Paclitaxel Plus Gemcitabine in Patients With Unresectable, Locally Recurrent or Metastatic Breast Cancer After Prior Anthracycline-based Adjuvant Chemotherapy

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: Vinflunine+Gemcitabine
* Drug: Paclitaxel+Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female patients 18 years or older but less than 75 years old histologically/cytologically confirmed breast cancer documented locally recurrent or metastatic breast cancer HER-2 negative or unknown prior neo- and/or adjuvant anthracycline-based chemotherapy measurable or non-measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 adequate haematological, hepatic and renal functions ECG without any clinically relevant abnormality Exclusion Criteria: known or clinical evidence of brain metastases or leptomeningeal involvement history of second primary malignancy patients having as sole tumour lesion: malignant effusion, lymphangitis, cystic lesion, bone lesion, and any other lesion not assessed by imaging techniques or colour photography pre-existing motor/sensory grade > 1 peripheral neuropathy prior therapy with vinca alkaloids and/or gemcitabine history of severe hypersensitivity to vinca alkaloids and/or gemcitabine or contraindication to any of these drugs pregnancy or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: vinflunine plus gemcitabine<br>vinflunine 320 mg/m² D1 plus gemcitabine 1000 mg/m2 D1 and D8 every 3 weeks | Drug: Vinflunine+Gemcitabine<br>* Vinflunine 320 mg/m² IV on day 1 and.Gemcitabine 1000 mg/m² on days 1 and 8 of each cycle repeated every 3 weeks<br>* Other names: L0070 IN;|
| Active Comparator: paclitaxel plus gemcitabine<br>paclitaxel 175 mg/m² D1 followed by Gemcitabine 1250 mg/m² D1 and D8 every 3 weeks | Drug: Paclitaxel+Gemcitabine<br>* paclitaxel 175 mg/m² on day 1 plus gemcitabine 1250 mg/m² on days 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | The primary efficacy parameter was Progression-free survival (PFS) analysed in the Intent-to-treat (ITT) population. PFS was defined as the time elapsed from randomisation date until the date of progression or death due to any cause (whichever came first).Tumor response was evaluated using the RECIST version 1.0 every 6 weeks until progression was recorded. | PFS was calculated from the registration date until the date of progression or death due to any cause if no progression was recorded first (median duration of follow-up: 14.1 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The secondary efficacy parameter was Overall Survival (OS) analysed in the Intent-to-treat (ITT) population. OS was defined as the time elapsed from the date of randomisation up to death or last follow-up. | OS was evaluated from the date of registration to the date of death due to any cause (median duration of follow-up: 14.1 months) | 
| Overall Response Rate & Disease Control Rate | Disease control rate (DCR) is defined as the sum of Complete Response (CR) and Partial Response (PR) and Stable Disease (SD) ≥ 6 months rate. Objective response rate (ORR) is defined as the sum of Complete Response (CR) and Partial Response (PR) rate (using the best confirmed response recorded from the date of randomisation to the end of treatment). DCR and ORR, assessed by Independent Review Committee using RECIST 1.0, were calculated in the ITT population. | ORR and DCR were calculated from the date of randomisation of first patient until the database cut-off (30 June 2011), assessed up to 5 years |