Breast Cancer
Conditions
Brief summary
This is a phase IIb, randomized, parallel-group, noncomparative, multicenter, pilot study designed to evaluate the safety and efficacy of bevacizumab with or without (+/-) trastuzumab administered with three different docetaxel-based combination regimens for the adjuvant treatment of participants with node positive or high-risk node negative breast cancer.
Detailed description
In this study, participants were stratified according to HER2 status at the time of enrollment. HER2-negative participants were randomized in a 1:1 ratio to either stratum 1 (AC-\>T sequential + bevacizumab) or stratum 2 (TAC + bevacizumab). All HER2-positive participants were assigned to stratum 3 (TCH + bevacizumab). The study included a treatment period of 1 year, followed by a 2 year posttreatment survival follow-up period.
Interventions
DRUGDoxorubicin and cyclophosphamide (AC) + bevacizumab
For every 3-week cycle * bevacizumab 15 mg/kg infused intravenously (IV) on Day 1 followed by * doxorubicin 60 mg/m\^2 IV push or infusion followed by cyclophosphamide 600 mg/m\^2 IV push or infusion * Prophylactic G-CSF was administered within 24 hours following each cycle of chemotherapy but no greater than 72 hours after chemotherapy
DRUGDocetaxel (T) + bevacizumab
For every 3-week cycle * bevacizumab 15 mg/kg infused intravenously (IV) on Day 1 followed by * docetaxel 100 mg/m\^2 IV * Prophylactic G-CSF was administered within 24 hours following each cycle of chemotherapy but no greater than 72 hours after chemotherapy Note: The starting dose of docetaxel was reduced to 75 mg/m\^2 if toxicity occurred that met the criteria for doxorubicin dose reduction
DRUGDocetaxel, doxorubicin, cyclophosphamide (TAC) + bevacizumab
For every 3-week cycle * bevacizumab 15 mg/kg infused intravenously (IV) on Day 1 followed by * doxorubicin 50 mg/m\^2 IV push or infusion followed by cyclophosphamide 500 mg/m\^2 IV push or infusion followed by docetaxel 75 mg/m\^2 * Prophylactic G-CSF was administered within 24 hours following each cycle of chemotherapy but no greater than 72 hours after chemotherapy
DRUGDocetaxel, carboplatin, trastuzumab (TCH) + bevacizumab
For every 3-week cycle * bevacizumab 15 mg/kg infused intravenously (IV) on Day 1 followed by * docetaxel in 75 mg/m\^2 IV followed by carboplatin AUC 6 mg/mL/min IV followed by * trastuzumab 6 mg/kg by IV infusion (For the first cycle 1 only a loading dose of trastuzumab 8 mg/kg IV was infused on Day 2) * Prophylactic G-CSF was administered within 24 hours following each cycle of chemotherapy but no greater than 72 hours after chemotherapy
DRUGBevacizumab and trastuzumab maintenance therapy
* bevacizumab 15 mg/kg was infused IV followed by * trastuzumab 6 mg/kg IV Treatment was every 3 weeks for 52 weeks from the date of the first administration regardless of the number of doses received or missed.
DRUGBevacizumab maintenance therapy
\- bevacizumab 15 mg/kg was infused IV Treatment was every 3 weeks for 52 weeks from the date of the first administration regardless of the number of doses received or missed.
Sponsors
Sanofi
Study design
Allocation
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: * Women \>/= 18 years of age. * Histologically proven breast cancer with an interval between definitive breast surgery that includes axillary lymph node (LN) dissection or axillary nodal evaluation and study registration of \< 60 days. (Note: Cycle 1 of chemotherapy treatment may NOT be infused until \> 28 days after the date of definitive breast surgery and the participant must be recovered from any clinically significant toxicity thereof.) * Definitive surgical treatment must be either mastectomy, or breast conserving surgery with axillary lymph node dissection (axillary lymph node evaluation can be either full axillary node dissection or sentinel LN evaluation followed by dissection if sentinel LN is positive) for operable breast cancer (pT1-4 \[including inflammatory\], pNO-3, and MO). Margins of resected specimen from definitive surgery must be histologically free of invasive adenocarcinoma and ductal carcinoma in-situ (DCIS). Lobular carcinoma in-situ does not count as a positive margin. * Subjects must be either lymph node-positive (pN1-3) or lymph node-negative (pN0) with high-risk features as determined by Investigator. * High-risk, lymph node-negative participants, (pN0) will be defined as subjects having invasive adenocarcinoma with either a negative sentinel node biopsy (pN0\[sn\]) OR negative lymph node dissection (pN0) disease AND tumor size \> 2 cm or tumor size \>/= 1 cm with at least one of the following factors: * negative estrogen receptor (ER) and negative progesterone receptor (PR) status * histologic and/or nuclear Grade 2-3; or * age \< 35 years * HER2/neu positive or negative tumors are eligible. HER2 positivity must be documented by fluorescence in situ hybridization (FISH). * Estrogen and progesterone receptor status must be performed on the primary tumor prior to study entry. Results must be pending or known at the time of study entry. * Normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF) 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. * Hematology evaluation within 2 weeks prior to study entry: * Absolute neutrophil count (ANC) \>/= 1,500/μL * Platelets \>/= 100,000/μL * Hemoglobin \>/= 9 g/dL * Hepatic function evaluation within 2 weeks prior to study entry: * Total bilirubin \</= ULN for the institution * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be in the acceptable range. * Complete staging work-up as follows: All subjects must have an appropriate radiographic evaluation, e.g., computed tomography (CT), positron emission tomography (PET)/CT, and/or (magnetic resonance imaging) MRI of the brain, chest, abdomen and pelvis, and imaging of bone by either a bone scan or PET scan. In cases of positive bone imaging, a bone X-ray or MRI evaluation is mandatory to rule out the possibility of metastatic bone scan disease. Other tests may be performed as clinically indicated. It is recommended that all baseline staging should be completed within 35 days prior to study entry.
Exclusion criteria
* Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy). * Prior anthracycline therapy, taxoids or platinum salts for any malignancy. * Prior radiation therapy for breast cancer or any radiotherapy to the chest wall for any other malignancy. * Bilateral invasive breast cancer. * Pregnant or lactating subjects * Cardiac disease or risk for same as judged by Investigator * Other serious illness or medical conditions such as (partial list- review with Investigator) history of significant neurologic or psychiatric disorders that would prohibit the understanding and giving of informed consent, active uncontrolled infection, active peptic ulcer, unstable diabetes mellitus or subjects with symptomatic, intrinsic lung disease resulting in dyspnea at rest * Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention of breast cancer. Subjects must have discontinued these agents prior to study entry. * Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must be stopped prior to study entry. * Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational non-marketed drug within 30 days prior to study entry. * Concurrent treatment with any other anti-cancer therapy. * Male subjects, as no clinical efficacy or safety data are available from phase I-II studies. * Chemotherapy and/or bevacizumab may not be given until \> 7 days following a minor surgical procedure. Chemotherapy may be given without bevacizumab in circumstances in which the participant has recovered sufficiently to receive chemotherapy but has not yet reached a 28 day time point at which bevacizumab could be administered.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Safety - Number of Participants With Grade 3-4 Clinical Congestive Heart Failure (CHF) | from the first dose of study medication up to the end of follow-up (up to 3 yrs) | Participants were evaluated for clinical CHF every 3 weeks during chemotherapy, every 3 months while on maintenance therapy, and every 3 months during the 2-year follow-up period. Left ventricular ejection fraction (LVEF) of CHF was assessed by multi-gated acquisition (MUGA) or echocardiogram (ECHO) performed midway through completion of chemotherapy according to a treatment-specific schedule, every 12 weeks during maintenance therapy, and at 6 and 24 months after completion of maintenance therapy. Grade 3-4 CHF were identified through a clinical review of all study collected investigator verbatim and the Medical Dictionary for Regulatory Activities (MedDRA). The preferred terms (PT) cardiac failure congestive, cardiomyopathy, and ejection fraction decreased were associated with CHF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Number of Participants With Adverse Events (AE) | from the administration of the first dose of study medication up to 30 days after the last dose of study medication; events ongoing at the time of discontinuation were monitored in the follow-up period until resolution. | An adverse event was any untoward medical occurrence in a participant of the clinical investigation, regardless of the relationship to study treatment. A serious adverse event (SAE) was an AE that at any dose (including overdose) resulted in death, was life-threatening, required inpatient hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly/birth defect, and/or was medically important. Treatment-emergent adverse events (TEAE) were defined as AEs that developed or worsened in severity during the on-treatment period. |
| Disease-free Survival (DFS) Rate | from the administration of the first-dose of study medication up to 12 months, 18 months and 24 months | DFS was defined as the time from the administration of the first-dose of study medication until recurrence of tumor or death from any cause in the absence of previous documentation of tumor recurrence. DFS rate was the probability of being disease free and alive at a particular time. DFS rates were estimated using Kaplan-Meier Method, and 95% confidence intervals were computed using the method of Kalbfleisch and Prentice. For participants who did have objective recurrence of tumor and who were still on study at the time of an analysis, or who were given antitumor treatment other than the study treatment, or who were removed from study follow-up prior to documentation of the tumor recurrence, DFS was censored at the last date the participant was known to be disease-free. |
Countries
United States
Participant flow
Recruitment details
239 participants were screened in this study. 214 were considered eligible for enrollment and 25 were screen failures. Of the 214 eligible participants, 155 were HER2-negative and 59 were HER2-positive.
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1 (AC->T + Bevacizumab) HER2-negative participants administered
* doxorubicin and cyclophosphamide (AC) + bevacizumab for 4 cycles followed by
* docetaxel (T) + bevacizumab for 4 cycles followed by
* bevacizumab maintenance therapy for total of 52 weeks from date of first dose regardless of number of doses received or missed | 78 |
| Stratum 2 (TAC + Bevacizumab) HER2-negative participants administered
* docetaxel, doxorubicin, cyclophosphamide (TAC) + bevacizumab for 6 cycles followed by
* bevacizumab maintenance therapy for total of 52 weeks from date of first dose regardless of number of doses received or missed | 75 |
| Stratum 3 (TCH + Bevacizumab).) All HER2-positive participants administered
* docetaxel, carboplatin, trastuzumab (TCH) + bevacizumab for 6 cycles followed by
* bevacizumab and trastuzumab maintenance therapy for total of 52 weeks from date of first dose regardless of number of doses received or missed | 59 |
| Total | 212 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 6 | 3 |
| Overall Study | Death | 1 | 3 | 0 |
| Overall Study | Disease progression/relapse | 9 | 6 | 7 |
| Overall Study | Lost to Follow-up | 3 | 3 | 3 |
| Overall Study | Moved | 2 | 0 | 0 |
| Overall Study | New cancer | 1 | 0 | 0 |
| Overall Study | Patient/physician decision | 0 | 0 | 1 |
| Overall Study | Poor compliance to protocol | 0 | 1 | 0 |
| Overall Study | Randomized but not treated | 0 | 2 | 0 |
| Overall Study | Second malignancy | 0 | 1 | 0 |
| Overall Study | Subject's request | 11 | 13 | 1 |
| Overall Study | Withdrew consent | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Stratum 1 (AC->T + Bevacizumab) | Stratum 2 (TAC + Bevacizumab) | Stratum 3 (TCH + Bevacizumab).) | Total |
|---|---|---|---|---|
| Age Continuous | 53.0 years STANDARD_DEVIATION 10.45 | 55.1 years STANDARD_DEVIATION 9.89 | 50.8 years STANDARD_DEVIATION 9.61 | 53.1 years STANDARD_DEVIATION 10.12 |
| Eastern Cooperative Oncology Group Score (ECOG) ECOG Score = 0 | 73 participants | 67 participants | 55 participants | 195 participants |
| Eastern Cooperative Oncology Group Score (ECOG) ECOG Score = 1 | 5 participants | 8 participants | 4 participants | 17 participants |
| Electrocardiogram (ECG) Abnormal | 22 participants | 19 participants | 19 participants | 60 participants |
| Electrocardiogram (ECG) Normal | 45 participants | 53 participants | 36 participants | 134 participants |
| Electrocardiogram (ECG) Not done/missing | 11 participants | 3 participants | 4 participants | 18 participants |
| Sex: Female, Male Female | 78 Participants | 75 Participants | 59 Participants | 212 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 78 / 78 | 75 / 75 | 59 / 59 |
| serious Total, serious adverse events | 23 / 78 | 24 / 75 | 12 / 59 |
Outcome results
Primary
Cardiac Safety - Number of Participants With Grade 3-4 Clinical Congestive Heart Failure (CHF)
Participants were evaluated for clinical CHF every 3 weeks during chemotherapy, every 3 months while on maintenance therapy, and every 3 months during the 2-year follow-up period. Left ventricular ejection fraction (LVEF) of CHF was assessed by multi-gated acquisition (MUGA) or echocardiogram (ECHO) performed midway through completion of chemotherapy according to a treatment-specific schedule, every 12 weeks during maintenance therapy, and at 6 and 24 months after completion of maintenance therapy. Grade 3-4 CHF were identified through a clinical review of all study collected investigator verbatim and the Medical Dictionary for Regulatory Activities (MedDRA). The preferred terms (PT) cardiac failure congestive, cardiomyopathy, and ejection fraction decreased were associated with CHF.
Time frame: from the first dose of study medication up to the end of follow-up (up to 3 yrs)
Population: Safety population - participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 (AC->T + Bevacizumab) | Cardiac Safety - Number of Participants With Grade 3-4 Clinical Congestive Heart Failure (CHF) | 1 participants |
| Stratum 2 (TAC + Bevacizumab) | Cardiac Safety - Number of Participants With Grade 3-4 Clinical Congestive Heart Failure (CHF) | 3 participants |
| Stratum 3 (TCH + Bevacizumab).) | Cardiac Safety - Number of Participants With Grade 3-4 Clinical Congestive Heart Failure (CHF) | 1 participants |
Secondary
Disease-free Survival (DFS) Rate
DFS was defined as the time from the administration of the first-dose of study medication until recurrence of tumor or death from any cause in the absence of previous documentation of tumor recurrence. DFS rate was the probability of being disease free and alive at a particular time. DFS rates were estimated using Kaplan-Meier Method, and 95% confidence intervals were computed using the method of Kalbfleisch and Prentice. For participants who did have objective recurrence of tumor and who were still on study at the time of an analysis, or who were given antitumor treatment other than the study treatment, or who were removed from study follow-up prior to documentation of the tumor recurrence, DFS was censored at the last date the participant was known to be disease-free.
Time frame: from the administration of the first-dose of study medication up to 12 months, 18 months and 24 months
Population: Intent-to-treat population - All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 (AC->T + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 36 months | 85.5 percentage of participants |
| Stratum 1 (AC->T + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 24 months | 87.1 percentage of participants |
| Stratum 1 (AC->T + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 12 months | 93.6 percentage of participants |
| Stratum 2 (TAC + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 24 months | 94.1 percentage of participants |
| Stratum 2 (TAC + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 12 months | 95.9 percentage of participants |
| Stratum 2 (TAC + Bevacizumab) | Disease-free Survival (DFS) Rate | DFS rate at 36 months | 90.4 percentage of participants |
| Stratum 3 (TCH + Bevacizumab).) | Disease-free Survival (DFS) Rate | DFS rate at 12 months | 98.2 percentage of participants |
| Stratum 3 (TCH + Bevacizumab).) | Disease-free Survival (DFS) Rate | DFS rate at 36 months | 90.4 percentage of participants |
| Stratum 3 (TCH + Bevacizumab).) | Disease-free Survival (DFS) Rate | DFS rate at 24 months | 96.3 percentage of participants |
Secondary
Safety - Number of Participants With Adverse Events (AE)
An adverse event was any untoward medical occurrence in a participant of the clinical investigation, regardless of the relationship to study treatment. A serious adverse event (SAE) was an AE that at any dose (including overdose) resulted in death, was life-threatening, required inpatient hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly/birth defect, and/or was medically important. Treatment-emergent adverse events (TEAE) were defined as AEs that developed or worsened in severity during the on-treatment period.
Time frame: from the administration of the first dose of study medication up to 30 days after the last dose of study medication; events ongoing at the time of discontinuation were monitored in the follow-up period until resolution.
Population: Safety population - participants who received at least one dose of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 (AC->T + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with serious TEAE | 23 participants |
| Stratum 1 (AC->T + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to treatment discontinuation | 21 participants |
| Stratum 1 (AC->T + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with TEAE | 78 participants |
| Stratum 1 (AC->T + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to death | 0 participants |
| Stratum 1 (AC->T + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any Grade 3-4 Serious TEAE | 23 participants |
| Stratum 2 (TAC + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to death | 2 participants |
| Stratum 2 (TAC + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to treatment discontinuation | 24 participants |
| Stratum 2 (TAC + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with any Grade 3-4 Serious TEAE | 24 participants |
| Stratum 2 (TAC + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with serious TEAE | 24 participants |
| Stratum 2 (TAC + Bevacizumab) | Safety - Number of Participants With Adverse Events (AE) | with TEAE | 75 participants |
| Stratum 3 (TCH + Bevacizumab).) | Safety - Number of Participants With Adverse Events (AE) | with any Grade 3-4 Serious TEAE | 9 participants |
| Stratum 3 (TCH + Bevacizumab).) | Safety - Number of Participants With Adverse Events (AE) | with TEAE | 59 participants |
| Stratum 3 (TCH + Bevacizumab).) | Safety - Number of Participants With Adverse Events (AE) | with serious TEAE | 12 participants |
| Stratum 3 (TCH + Bevacizumab).) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to death | 0 participants |
| Stratum 3 (TCH + Bevacizumab).) | Safety - Number of Participants With Adverse Events (AE) | with any TEAE leading to treatment discontinuation | 16 participants |