Breast Cancer
Conditions
Brief summary
Pilot, phase II, parallel-group, open-label, noncomparative, prospective, multicenter study designed to evaluate the progression-free survival of docetaxel and bevacizumab ± trastuzumab for the first-line treatment of participants with metastatic breast cancer. Participants were stratified according to human epidermal growth factor receptor-2 (HER2) status at the time of enrollment. HER2 negative participants were assigned to receive docetaxel and bevacizumab (DB). HER2 positive participants were assigned to receive docetaxel, bevacizumab, and trastuzumab (DBT). All participants (except one) were off study treatment on 30 June 2011. All efficacy analysis and safety analysis was performed using the cut-off date of June 2011. One participant continued treatment till 11 March 2012. For this participant, adverse events were collected upto 19 April 2012 and included in the safety analysis.
Detailed description
The study included: * Study registration on Day 1: Treatment Cycle 1 was initiated within 14 days of signing informed consent * Treatment was administered in 3 week treatment cycles until the participant developed unacceptable toxicity, had disease progression, withdrew consent, or died * If participants experienced a complete response (CR), partial response (PR), or stable disease (SD) at Cycle 8 or beyond or had unacceptable toxicity due to docetaxel, they could continue on bevacizumab and/or trastuzumab until they developed unacceptable toxicity, had disease progression, or withdrew consent * Participants had follow-up assessments within 30 days after discontinuation of treatment with the last of the study drugs for any reason other than death
Interventions
DRUGBevacizumab
Bevacizumab (Avastin) 15 mg/kg will be administered prior to chemotherapy on * On Day 1 of the 1st cycle over 120 minutes * On Day 1 of the 2nd cycle over 90 minutes, if no reaction on the first dose * On Day 1 of 3rd cycle over 60 minutes, if no reaction on previous doses * On Day 1 of subsequent cycles over 30 minutes, if no reaction on previous doses
DRUGDocetaxel
Docetaxel 75 mg/m\^2 IV infused over 60 minutes after completion of Bevacizumab infusion q3w
DRUGTrastuzumab
* A loading dose of 8 mg/kg Trastuzumab (Herceptin) IV will be infused over 90 minutes on Day 2 of Cycle 1. * For all subsequent cycles 6 mg/kg trastuzumab will be administered on Day 1 one hour following completion of docetaxel infusion
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The following information on clinical trials is provided for information purposes only to allow participants and physicians to have an initial discussion about the trial. This information is not intended to be complete information about the trial, to contain all considerations that may be relevant to potential participation in the trial, or to replace the advice of a personal physician or health professional. INCLUSION CRITERIA: 1. Histologically or cytologically proven adenocarcinoma of the breast at first diagnosis 2. Stage IV disease with at least one measurable lesion according to the RECIST criteria 3. HER2/neu positive as determined by 3+ immunohistochemistry (IHC) staining or fluorescence in situ hybridization (FISH) positivity or negative tumors 4. Life expectancy of \>/= 24 weeks 5. No prior chemotherapy for metastatic breast cancer. (Prior endocrine therapy is permitted). 6. Prior neoadjuvant or adjuvant chemotherapy is permitted, or at least 12 months must have elapsed since the neoadjuvant or adjuvant therapy. Subjects may have received prior adjuvant anthracyclines (maximum cumulative dose, 360 mg/m\^2 doxorubicin or 750 mg/m\^2 epirubicin) 7. At least 4 weeks since prior surgery, radiotherapy, endocrine therapy, or experimental drug therapy with complete recovery from the effects of these interventions 8. It is recommended that all baseline staging should be completed within 35 days prior to study entry. All subjects will have the following workup as applicable; CT scan of brain, CT scan or MRI of chest and abdomen, and bone scan or PET scan. In cases of positive bone or PET scans, bone X-ray evaluation and/or MRI is required to confirm or exclude metastatic bone disease. Subjects with metastatic disease limited to bone are ineligible unless at least one lytic lesion is measurable and can be followed by RECIST criteria. Other tests may be performed as clinically indicated 9. Normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF) of \>/= 50% or shortening fraction (multiple-gated acquisition \[MUGA\] scan or echocardiography respectively). The result must be greater than the lower limit of normal (LLN) for the institution. 10. Subjects receiving bisphosphonate therapy; however, if bisphosphonates were started within \<2 months prior to treatment the bone lesions will not be evaluated for response, and the subjects must have another site of metastatic disease that is either measurable or evaluable for response
Exclusion criteria
1. Prior chemotherapy for metastatic breast cancer 2. Prior treatment with bevacizumab or other anti-VEGF therapy 3. Concurrent treatment with any other non-protocol anticancer therapy with the exception of radiation therapy as long as all target lesions being followed are not in the radiation field and if HER2/neu positive, HER2/neu-directed therapy 4. Current or prior history of brain or leptomeningeal metastases 5. Presence of neuropathy \>/= 2 6. Presence of any non-healing wound, fracture, or ulcer, or the presence of clinically significant (\>/= Grade 2) peripheral vascular disease 7. History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma in-situ of the cervix 8. Clinically significant cardiovascular disease 9. Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal condition increasing the risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning therapy 10. History of bleeding diathesis or coagulopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Rate: Percentage of Participants With PFS | Up to 6 months and 12 months after treatment initiation | PFS was the time from registration to first documentation of * progressive disease (PD) based on Response Evaluation Criteria in Solid Tumors (RECIST) - criteria pre-defining changes in lesion size or appearance * symptomatic deterioration * death due to any cause (in absence of PD). The Percentage of participants with PFS is reported. For the analysis, participants were censored * on the last available tumor assessment date on study treatment if they * had no PFS event * were on anticancer therapy not related to study treatment * on the registration date if they * did not receive study drug * had no post baseline tumor assessment |
| Time to Progression-free Survival (PFS) | From treatment initiation to PFS event (up to June 2011) | Time to PFS was the interval from the date of registration to the earliest of the following documented dates: * PD as defined by RECIST (criteria pre-defining changes in lesion size or appearance) * symptomatic deterioration * death. Time to PFS was estimated from Kaplan-Meier Plots. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DR) | From treatment initiation to June 2011 | DR was the interval from date of initial documented confirmed response (CR or PR) to the first documented confirmed date of disease progression (PD) or death from any cause in the absence of previous documentation of objective tumor progression. Participants who were alive and without any record of PD at the time of discontinuation were censored at the last available tumor assessment date; participants with non-study anti-cancer therapy during the study were censored at the last available tumor assessment date prior to the anti-cancer therapy. DR was estimated from Kaplan-Meier Plots. |
| Confirmed Overall Response (OR) Based on RECIST Criteria | From treatment initiation to June 2011 | Confirmed OR was confirmed Complete Response (CR) + confirmed Partial Response (PR). According to RECIST * CR was the disappearance of all tumor lesions * PR was a pre-defined decrease in the size of tumor lesions. To determine a response, radiologic tumors assessments were performed using computed tomography (CT) and/or magnetic resonance imaging (MRI) of the chest, and the abdomen, bone scan or positron emission tomography (PET) scan, and other imaging techniques as clinically indicated. To confirm a response, 2 assessments separated by 28 days or more were required. |
| Number of Participants With Adverse Events (AE) | From treatment initiation to 30 days after the last dose of study treatment | An adverse event (AE) was any unfavorable and unintended sign, symptom, syndrome, or illness that developed or worsened during the clinical study. AEs occurring on or after first dose of study medication inclusive to 30 days post-last dose were the treatment emergent adverse events (TEAEs). An serious adverse event was an AE that at any dose (including overdose) resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly, and/or was medically important. |
| Overall Survival (OS) Time | From treatment initiation to June 2011 | OS was the interval between the date of study entry and the date of death from any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. OS time was estimated from Kaplan-Meier Plots. |
| Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | From treatment initiation to June 2011 | Clinical Benefit (CB) was achieved in participants with a response (CR + PR) or a stable disease (SD). According to RECIST * CR was the disappearance of all tumor lesions * PR was a pre-defined decrease in the size of tumor lesions * SD was neither sufficient decrease in tumor size to qualify for PR or sufficient increase to qualify for PD. Confirmation of a response needed 2 responses scored, separated by 28 days or more (for CR and PR), and by 26 weeks or more (for SD). |
Countries
United States
Participant flow
Pre-assignment details
103 participants signed the informed consent for this study. Of these, 73 were determined to be eligible for inclusion. One participant did not receive any study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel and Bevacizumab Stratum 1: HER2 Negative participants with metastatic breast cancer treated with DB (docetaxel and bevacizumab) intravenously (IV) every 3 weeks (q3w) until treatment discontinuation criteria (unacceptable toxicity, disease progression or death) are met | 52 |
| Docetaxel, Bevacizumab and Trastuzumab Stratum 2: HER2 Positive participants with metastatic breast cancer treated with DBT (docetaxel, bevacizumab, and trastuzumab) IV q3w until treatment discontinuation criteria (unacceptable toxicity, disease progression or death) are met | 21 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 4 |
| Overall Study | Did not receive study medication | 0 | 1 |
| Overall Study | Disease Progression | 38 | 8 |
| Overall Study | Found Ineligible | 1 | 0 |
| Overall Study | Investigator decision | 2 | 2 |
| Overall Study | Participant's Request | 3 | 4 |
| Overall Study | Presumed CR on Study | 0 | 1 |
| Overall Study | Receiving Liver Ablation | 0 | 1 |
Baseline characteristics
| Characteristic | Docetaxel and Bevacizumab | Docetaxel, Bevacizumab and Trastuzumab | Total |
|---|---|---|---|
| Age Continuous | 56.2 years STANDARD_DEVIATION 10.78 | 52.8 years STANDARD_DEVIATION 12.65 | 55.2 years STANDARD_DEVIATION 11.37 |
| Age, Customized <=65 years | 41 participants | 17 participants | 58 participants |
| Age, Customized >=75 years | 3 participants | 1 participants | 4 participants |
| Age, Customized Between 65 and 75 years | 8 participants | 3 participants | 11 participants |
| Eastern Cooperative Oncology ECOG Performance Score is 0 | 28 participants | 16 participants | 44 participants |
| Eastern Cooperative Oncology ECOG Performance Score is 1 | 24 participants | 5 participants | 29 participants |
| Sex: Female, Male Female | 52 Participants | 21 Participants | 73 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 | — / — | — / — |
| other Total, other adverse events | 52 / 52 | 20 / 20 |
| serious Total, serious adverse events | 14 / 52 | 4 / 20 |
Outcome results
Primary
Progression-free Survival (PFS) Rate: Percentage of Participants With PFS
PFS was the time from registration to first documentation of * progressive disease (PD) based on Response Evaluation Criteria in Solid Tumors (RECIST) - criteria pre-defining changes in lesion size or appearance * symptomatic deterioration * death due to any cause (in absence of PD). The Percentage of participants with PFS is reported. For the analysis, participants were censored * on the last available tumor assessment date on study treatment if they * had no PFS event * were on anticancer therapy not related to study treatment * on the registration date if they * did not receive study drug * had no post baseline tumor assessment
Time frame: Up to 6 months and 12 months after treatment initiation
Population: Intent to treat population: all registered participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel and Bevacizumab | Progression-free Survival (PFS) Rate: Percentage of Participants With PFS | PFS rate at 6 months | 59.6 percentage of participants |
| Docetaxel and Bevacizumab | Progression-free Survival (PFS) Rate: Percentage of Participants With PFS | PFS rate at 12 months | 30.8 percentage of participants |
| Docetaxel, Bevacizumab and Trastuzumab | Progression-free Survival (PFS) Rate: Percentage of Participants With PFS | PFS rate at 6 months | 90.5 percentage of participants |
| Docetaxel, Bevacizumab and Trastuzumab | Progression-free Survival (PFS) Rate: Percentage of Participants With PFS | PFS rate at 12 months | 81.0 percentage of participants |
Primary
Time to Progression-free Survival (PFS)
Time to PFS was the interval from the date of registration to the earliest of the following documented dates: * PD as defined by RECIST (criteria pre-defining changes in lesion size or appearance) * symptomatic deterioration * death. Time to PFS was estimated from Kaplan-Meier Plots.
Time frame: From treatment initiation to PFS event (up to June 2011)
Population: Intent-to-treat population: all registered participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Bevacizumab | Time to Progression-free Survival (PFS) | 255 days |
| Docetaxel, Bevacizumab and Trastuzumab | Time to Progression-free Survival (PFS) | 403 days |
Secondary
Confirmed Overall Response (OR) Based on RECIST Criteria
Confirmed OR was confirmed Complete Response (CR) + confirmed Partial Response (PR). According to RECIST * CR was the disappearance of all tumor lesions * PR was a pre-defined decrease in the size of tumor lesions. To determine a response, radiologic tumors assessments were performed using computed tomography (CT) and/or magnetic resonance imaging (MRI) of the chest, and the abdomen, bone scan or positron emission tomography (PET) scan, and other imaging techniques as clinically indicated. To confirm a response, 2 assessments separated by 28 days or more were required.
Time frame: From treatment initiation to June 2011
Population: Intent-to-treat population: all registered participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel and Bevacizumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed overall response | 30 participants |
| Docetaxel and Bevacizumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed complete response | 3 participants |
| Docetaxel and Bevacizumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed partial response | 27 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed overall response | 17 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed complete response | 4 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Confirmed Overall Response (OR) Based on RECIST Criteria | Confirmed partial response | 13 participants |
Secondary
Duration of Response (DR)
DR was the interval from date of initial documented confirmed response (CR or PR) to the first documented confirmed date of disease progression (PD) or death from any cause in the absence of previous documentation of objective tumor progression. Participants who were alive and without any record of PD at the time of discontinuation were censored at the last available tumor assessment date; participants with non-study anti-cancer therapy during the study were censored at the last available tumor assessment date prior to the anti-cancer therapy. DR was estimated from Kaplan-Meier Plots.
Time frame: From treatment initiation to June 2011
Population: Participants with a documented response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Bevacizumab | Duration of Response (DR) | 232 days |
| Docetaxel, Bevacizumab and Trastuzumab | Duration of Response (DR) | 366 days |
Secondary
Number of Participants With Adverse Events (AE)
An adverse event (AE) was any unfavorable and unintended sign, symptom, syndrome, or illness that developed or worsened during the clinical study. AEs occurring on or after first dose of study medication inclusive to 30 days post-last dose were the treatment emergent adverse events (TEAEs). An serious adverse event was an AE that at any dose (including overdose) resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly, and/or was medically important.
Time frame: From treatment initiation to 30 days after the last dose of study treatment
Population: Safety population: all participants who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel and Bevacizumab | Number of Participants With Adverse Events (AE) | with treatment emergent adverse events (TEAEs) | 52 participants |
| Docetaxel and Bevacizumab | Number of Participants With Adverse Events (AE) | with serious adverse events | 14 participants |
| Docetaxel and Bevacizumab | Number of Participants With Adverse Events (AE) | with TEAEs resulting in death | 3 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Adverse Events (AE) | with treatment emergent adverse events (TEAEs) | 20 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Adverse Events (AE) | with serious adverse events | 4 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Adverse Events (AE) | with TEAEs resulting in death | 0 participants |
Secondary
Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria
Clinical Benefit (CB) was achieved in participants with a response (CR + PR) or a stable disease (SD). According to RECIST * CR was the disappearance of all tumor lesions * PR was a pre-defined decrease in the size of tumor lesions * SD was neither sufficient decrease in tumor size to qualify for PR or sufficient increase to qualify for PD. Confirmation of a response needed 2 responses scored, separated by 28 days or more (for CR and PR), and by 26 weeks or more (for SD).
Time frame: From treatment initiation to June 2011
Population: Intent-to-treat: all registered participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel and Bevacizumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed Clinical Benefit (CR+PR+SD) | 35 participants |
| Docetaxel and Bevacizumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed CR | 3 participants |
| Docetaxel and Bevacizumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed PR | 27 participants |
| Docetaxel and Bevacizumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed SD | 14 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed SD | 1 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed Clinical Benefit (CR+PR+SD) | 17 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed PR | 13 participants |
| Docetaxel, Bevacizumab and Trastuzumab | Number of Participants With Confirmed Clinical Benefit Based on RECIST Criteria | with confirmed CR | 4 participants |
Secondary
Overall Survival (OS) Time
OS was the interval between the date of study entry and the date of death from any cause. In the absence of confirmation of death, survival time was censored at the last date the participant was known to be alive. OS time was estimated from Kaplan-Meier Plots.
Time frame: From treatment initiation to June 2011
Population: Intent-to-treat population: all registered participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel and Bevacizumab | Overall Survival (OS) Time | 750 days |
| Docetaxel, Bevacizumab and Trastuzumab | Overall Survival (OS) Time | 986 days |