Advanced Breast Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGVinflunine+Gemcitabine
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
DRUGPaclitaxel+Gemcitabine
paclitaxel 175 mg/m² on day 1 plus gemcitabine 1250 mg/m² on days 1
Sponsors
Pierre Fabre Medicament
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 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) | 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. |
| Overall Response Rate & Disease Control Rate | 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 | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vinflunine Plus Gemcitabine vinflunine 320 mg/m² D1 plus gemcitabine 1000 mg/m2 D1 and D8 every 3 weeks
Vinflunine
vinflunine plus gemcitabine: 320 mg/m² IV on day 1 plus gemcitabine 1000 mg/m² on days 1 and 8 of each cycle repeated every 3 weeks | 503 |
| Paclitaxel Plus Gemcitabine paclitaxel 175 mg/m² D1 followed by Gemcitabine 1250 mg/m² D1 and D8 every 3 weeks
paclitaxel plus gemcitabine: paclitaxel 175 mg/m² on day 1 plus gemcitabine 1250 mg/m² on days 1 | 501 |
| Total | 1,004 |
Baseline characteristics
| Characteristic | Vinflunine Plus Gemcitabine | Paclitaxel Plus Gemcitabine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 75 Participants | 63 Participants | 138 Participants |
| Age, Categorical Between 18 and 65 years | 428 Participants | 438 Participants | 866 Participants |
| Age, Continuous | 53.2 years | 54.4 years | 53.6 years |
| Sex: Female, Male Female | 503 Participants | 501 Participants | 1004 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 406 / 495 | 394 / 496 |
| other Total, other adverse events | 494 / 495 | 494 / 496 |
| serious Total, serious adverse events | 215 / 495 | 128 / 496 |
Outcome results
Primary
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.
Time frame: 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)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Gemcitabine | Progression Free Survival | 8.0 Months |
| Paclitaxel Plus Gemcitabine | Progression Free Survival | 8.4 Months |
Comparison: Kaplan-Meier curves and life tables by treatment arm to describe time-dependent parameters. Stratified Cox proportional model was used to compare the 2 treatment arms. A stratified Cox proportional hazards model and logistic regression were applied to the progression-free survival and to the tumour response, respectively.p-value: 0.5495% CI: [0.91, 1.2]Log Rank
Secondary
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.
Time frame: 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
Population: ITT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vinflunine Plus Gemcitabine | Overall Response Rate & Disease Control Rate | Overall Response Rate | 11.3 percentage of patients |
| Vinflunine Plus Gemcitabine | Overall Response Rate & Disease Control Rate | Disease Control Rate | 39.8 percentage of patients |
| Paclitaxel Plus Gemcitabine | Overall Response Rate & Disease Control Rate | Overall Response Rate | 14.6 percentage of patients |
| Paclitaxel Plus Gemcitabine | Overall Response Rate & Disease Control Rate | Disease Control Rate | 44.9 percentage of patients |
p-value: 0.195% CI: [8.7, 14.4]Log Rank
Secondary
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.
Time frame: 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)
Population: ITT population - Cut-off date: 30 June 2011
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine Plus Gemcitabine | Overall Survival | 18.9 Months |
| Paclitaxel Plus Gemcitabine | Overall Survival | 19.1 Months |
p-value: 0.8695% CI: [0.87, 1.19]Log Rank