Pilot Study of Docetaxel & Bevacizumab +/- Trastuzumab in First-Line Treatment of Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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

Official Title
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A Pilot, Phase II, Multicenter, Open-Label, Prospective Evaluation of Docetaxel and Bevacizumab ± Trastuzumab in the First-Line Treatment of Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Docetaxel
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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: Histologically or cytologically proven adenocarcinoma of the breast at first diagnosis Stage IV disease with at least one measurable lesion according to the RECIST criteria HER2/neu positive as determined by 3+ immunohistochemistry (IHC) staining or fluorescence in situ hybridization (FISH) positivity or negative tumors Life expectancy of >/= 24 weeks No prior chemotherapy for metastatic breast cancer. (Prior endocrine therapy is permitted). 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) At least 4 weeks since prior surgery, radiotherapy, endocrine therapy, or experimental drug therapy with complete recovery from the effects of these interventions 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 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. 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: Prior chemotherapy for metastatic breast cancer Prior treatment with bevacizumab or other anti-VEGF therapy 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 Current or prior history of brain or leptomeningeal metastases Presence of neuropathy >/= 2 Presence of any non-healing wound, fracture, or ulcer, or the presence of clinically significant (>/= Grade 2) peripheral vascular disease 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 Clinically significant cardiovascular disease 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 History of bleeding diathesis or coagulopathy

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel and Bevacizumab<br>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 | Drug: Bevacizumab<br>* 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<br>* Other names: Avastin;Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 IV infused over 60 minutes after completion of Bevacizumab infusion q3w<br>|
| Experimental: Docetaxel, Bevacizumab and Trastuzumab<br>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 | Drug: Bevacizumab<br>* 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<br>* Other names: Avastin;Drug: Docetaxel<br>* Docetaxel 75 mg/m^2 IV infused over 60 minutes after completion of Bevacizumab infusion q3w<br>Drug: Trastuzumab<br>* 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<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 6 months and 12 months after treatment initiation | 
| 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. | From treatment initiation to PFS event (up to June 2011) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From treatment initiation to June 2011 | 
| 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). | From treatment initiation to June 2011 | 
| 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. | From treatment initiation to June 2011 | 
| 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. | From treatment initiation to June 2011 | 
| 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. | From treatment initiation to 30 days after the last dose of study treatment |