Breast Cancer, Metastases
Conditions
Brief summary
In metastatic breast cancer (MBC) patients who have already received anthracyclines, taxanes, antimetabolites and vinca-alkaloids and have developed drug resistance to these drugs, therapeutic options are very limited. Alkylating agents showed a modest activity in pretreated metastatic breast cancer. This phase III trial will compare the effectiveness and the safety profile of vinflunine to an alkylating agent of physician choice in MBC patients who have exhausted anthracyclines, taxanes, antimetabolites and vinca-alkaloids.
Detailed description
Breast cancer is the most frequently diagnosed cancer in women worldwide and the second leading cause of cancer-related deaths in women. Patients with metastatic breast cancer (MBC) remains incurable, and current goals of therapy are to ameliorate symptoms, delay disease progression, improve or at least maintain quality of life (QoL), and prolong overall survival (OS).There are a number of agents with established single-agent activity, with the anthracyclines and taxanes considered generally the most active. In addition, several drugs with different mechanisms of action such as antimetabolites and vinca-alkaloids have also demonstrated substantial activity in the metastatic setting as single-agents or in combination. In patients who progress after having received anthracyclines, taxanes, antimetabolites and vinca- alkaloids, therapeutic options are scarce. In this heavily pretreated population for whom overall survival is not expected to exceed 6 to 7 months, there is a clear need for novel therapies. Vinflunine (VFL) is a microtubule inhibitor obtained by semi-synthesis, interacts with tubulin at the vinca-binding domain and inhibits tubulin assembly by perturbing microtubule dynamics and mitotic spindles without affecting assembled microtubules. VFL antitumour activity was fully demonstrated against a large and varied panel of murine and xenograft models. The main haematological toxicity reported was the neutropenia Grade 3-4 (40-50%). The incidence of its complications (febrile neutropenia and neutropenic infection) was less than 8%. The main non-haematological toxicity Grade 3-4 (with an incidence more than 10%) reported were constipation and fatigue. This was a prospective multicentre, open-label, randomised (1:1), phase III study comparing OS in patients treated with vinflunine versus those treated with an alkylating agent of physician's choice as third line treatment or more for patients with locally recurrent and/or metastatic breast cancer previously treated with and no longer candidate to anthracyclines, antimetabolites, taxanes and vinca- alkaloids.. The primary endpoint for the trial was OS. Patients were assessed for toxicity, tumour response and progression and status (alive-dead) at regular intervals during the study treatment and the follow-up period. Patients were treated until disease progression, unacceptable toxicity, patient or investigator's decision. After the study treatment discontinuation, patients were followed until death. The VFL dose of 280 mg/m² was the selected dose for this phase III study in patients with heavily pre- treated MBC. Indeed, VFL dose was reduced from 320 to 280 mg/m² in advanced transitional cell carcinoma of urothelial tract patients with performance status (PS) of 1 or with PS of 0 and having received prior pelvic irradiation. This dose was more regularly tolerable in patients with advanced disease stage who were heavily pre-treated.
Interventions
DRUGvinflunine
280 mg/m2 on day 1 of each cycle every 3 weeks
DRUGAlkylating agent of physician choice registered in cancer
cyclophosphamide or melphalan or mitomycin C or thiotepa or cisplatin or carboplatin
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
(main conditions) * Female patients 18 to 75 years of age with metastatic breast cancer histologically/cytologically confirmed not amenable to curative surgery or radiotherapy and who have received at least two prior chemotherapy regimens including anthracyclines,taxanes,antimetabolite and vinca-alkaloid and are no longer candidate for these drugs, * Karnofsky performance score of at least 70 %, adequate haematological, hepatic and renal functions and ECG without clinically relevant abnormality.
Exclusion criteria
* Concurrent serious uncontrolled medical disorder, * known or clinical evidence of brain metastases or leptomeningeal involvement, * pulmonary lymphangitis or symptomatic pleural effusion or symptomatic ascites, * history of second primary malignancy, * HIV infection, preexisting neuropathy, * pregnancy or breast feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From baseline up to 3 years 1 month | The main endpoint of this study is overall survival defined as the time from randomisation to the date of death or last follow-up. For patients who have not died, survival duration will be censored at the date of last contact or last follow-up or the date of last news. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | From baseline up to 3 years 1 month | DCR was defined as the proportion of patients with Complete Response (CR), Partial Response (PR) and stable disease (SD), relative to the total number of patients in the analysed population. |
| Progression Free Survival (PFS) | From baseline to cut-off date(27 August 2012), up to 3 years | PFS was defined as the time from randomisation to the first tumour progression or death due to any cause in the absence of previous documentation of objective tumour progression. PFS was performed in the ITT and eligible populations every 6 weeks based on RECIST version 1.1. For patients lost of follow up, or without a known record of progression or death, PFS was censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression which ever occured last. |
Countries
Argentina, Austria, Belarus, Belgium, France, Germany, Italy, Portugal, Russia, South Africa, Spain, Taiwan, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Vinflunine Patients randomised in the test arm (arm A) received VFL at the dose of 280 mg/m² on day 1 of each cycle every 3 weeks, over a 20-minute intravenous (IV) infusion. Cycles were repeated every 3 weeks.
vinflunine: 280 mg/m2 on day 1 of each cycle every 3 weeks | 298 |
| Arm B: Alkylating Agent of Physician Choice Patients randomised in the control arm (arm B) received an alkylating agent used as a single agent which was available in the investigational center and was approved for the treatment of cancer in the country.
Alkylating agent of physician choice registered in cancer: cyclophosphamide or melphalan or mitomycin C or thiotepa or cisplatin or carboplatin | 296 |
| Total | 594 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 24 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician, patient's decision, other | 27 | 37 |
| Overall Study | Progressive disease | 250 | 234 |
Baseline characteristics
| Characteristic | Arm A: Vinflunine | Arm B: Alkylating Agent of Physician Choice | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 62 Participants | 69 Participants | 131 Participants |
| Age, Categorical Between 18 and 65 years | 236 Participants | 227 Participants | 463 Participants |
| Sex: Female, Male Female | 298 Participants | 296 Participants | 594 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 | 276 / 298 | 274 / 296 |
| other Total, other adverse events | 197 / 297 | 262 / 290 |
| serious Total, serious adverse events | 82 / 297 | 66 / 290 |
Outcome results
Primary
Overall Survival
The main endpoint of this study is overall survival defined as the time from randomisation to the date of death or last follow-up. For patients who have not died, survival duration will be censored at the date of last contact or last follow-up or the date of last news.
Time frame: From baseline up to 3 years 1 month
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine | Overall Survival | 9.1 Months |
| Alkylating Agent | Overall Survival | 9.3 Months |
Comparison: Kaplan-Meier curves and life tables by treatment arm were provided. Confidence intervals on the median were calculated using the Brookmeyer and Crowley method. Hazard ratio and 95% confidence intervals were reported. A stratified Cox proportional model was performed to compare the two treatment arms taking into account the stratification factors (except centre) used at the time of randomisation.p-value: 0.67395% CI: [0.86, 1.25]Cochran-Mantel-Haenszel
Secondary
Disease Control Rate (DCR)
DCR was defined as the proportion of patients with Complete Response (CR), Partial Response (PR) and stable disease (SD), relative to the total number of patients in the analysed population.
Time frame: From baseline up to 3 years 1 month
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vinflunine | Disease Control Rate (DCR) | 43.6 Percentage of participants |
| Alkylating Agent | Disease Control Rate (DCR) | 35.5 Percentage of participants |
Comparison: The disease control rate (DCR) were compared in the ITT population and in the population evaluable for response between the 2 arms with a cochran Mantel Haenszel, stratified on WHO performance status at baseline, number of prior chemotherapy lines for the treatment of disease and disease measurability at Baseline.p-value: 0.0424Log Rank
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from randomisation to the first tumour progression or death due to any cause in the absence of previous documentation of objective tumour progression. PFS was performed in the ITT and eligible populations every 6 weeks based on RECIST version 1.1. For patients lost of follow up, or without a known record of progression or death, PFS was censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression which ever occured last.
Time frame: From baseline to cut-off date(27 August 2012), up to 3 years
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vinflunine | Progression Free Survival (PFS) | 2.5 Months |
| Alkylating Agent | Progression Free Survival (PFS) | 1.9 Months |
Comparison: PFS was compared between the 2 treatment arms by the log-rank test procedure with the 5 % significant level, stratified on the stratification factors (except study site) as specified at the time of randomisation. Os was analysed using Kaplan-Meir method and summarized with median and 95% CI of the medianp-value: 0.492795% CI: [0.8, 1.12]Log Rank