Carboplatin, Paclitaxel, and Bevacizumab in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

• Sponsor: Loyola University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00654836
• Collaborator: Genentech, Inc. (Industry), Celgene Corporation (Industry)
• Enrollment: 32
• Locations: 6
• Arm: 1
• Duration (Months): 95
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving carboplatin and paclitaxel together with bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving carboplatin and paclitaxel together with bevacizumab works in treating patients with locally recurrent or metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: bevacizumab; Drug: Carboplatin; Drug: ABI-007	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the progression-free survival of patients with locally recurrent or metastatic breast cancer treated with carboplatin, paclitaxel albumin-stabilized nanoparticle formulation, and bevacizumab as first-line therapy.

Secondary

• To determine the response rate in these patients.

• To determine the overall survival of these patients.

• To evaluate the toxicity profile of this regimen in these patients.

OUTLINE: Patients receive carboplatin IV over 1 hour and bevacizumab IV on days 1, 22 and 43. Patients also receive paclitaxel albumin-bound nanoparticle formulation IV over 30 minutes on days 1, 8 ,15, 22, 29, 36, 43, and 50. Treatment continues in the absence of disease progression or unacceptable toxicity.

Formalin-fixed paraffin-embedded archived tumor tissue samples are assessed by immunohistochemistry (IHC) for various biomarkers. Levels of Notch-1, Notch-4, cyclin A, cyclin B, Jagged-1, and DLL4 in tumor-associated endothelial cells are correlated with response in both estrogen- and progesterone-positive and negative tumors, and independently of p53 status.

After completion of study treatment, patients are followed for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Carboplatin, Nanoparticle Albumin-Bound Paclitaxel (ABI-007) and Avastin as the First Line Therapy in Metastatic Breast Cancer.
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carboplatin, ABI-007 and Bevacizumab Participants will receive combination carboplatin, nanoparticle albumin-bound paclitaxel (ABI-007-Abraxane), and bevacizumab (Avastin)

Biological: bevacizumab; Participants will receive bevacizumab 15 mg/kg on days 1,22, and 43.; Other Names: Avastin ; Drug: Carboplatin; Participants will receive a standard carboplatin dose according to their area under the plasma drug concentration-time curve (AUC-6) on days 1, 22, and 43.; Other Names: Paraplatin ; Drug: ABI-007; Participants will receive ABI-007 (Abraxane) 100mg/m2 on days 1,8, 15, 22, 29, 36,43,and 50.; Other Names: Abraxane

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [30 Months]

   Progression-free survival was measured from treatment initiation to 30 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Response Rate at End of Treatment [30 Months]

   Response to treatment was recorded 30 months following treatment initiation. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions .

2. Overall Survival [80 Months]

   Overall survival was measured from treatment initiation to 80 months

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed primary adenocarcinoma of the breast

• Locally recurrent or metastatic disease

• Must have HER-2-negative breast cancer or, if HER-2-positive, must be unable to receive trastuzumab (Herceptin®) or have previously received trastuzumab in the past

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by conventional techniques or as > 10 mm by spiral CT scan.

• No known CNS disease

• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Postmenopausal status not specified

• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%

• Life expectancy > 12 weeks

• WBC ≥ 3,000/mcL

• Absolute neutrophil count ≥ 1,500/mcL

• Platelet count ≥ 100,000/mcL

• Total bilirubin normal

• AST and ALT ≤ 2.5 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 2.5 times ULN (unless bone metastasis is present in the absence of liver metastasis)

• Creatinine ≤ 1.5 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other concurrent malignancies within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

Exclusion criteria:

• Pre-existing neuropathy ≥ grade 1

• Uncontrolled intercurrent illness including, but not limited to, any of the following:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Serious, non-healing wound, ulcer, or bone fracture

• Psychiatric illness/social situations that would limit compliance with study requirements

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications)

• History of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association class II-IV congestive heart failure

• History of myocardial infarction or unstable angina within the past 6 months

• History of stroke or transient ischemic attack within the past 6 months

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Significant traumatic injury within the past 28 days

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• Proteinuria, as demonstrated by either urine protein:creatinine ratio ≥ 1.0 OR urine dipstick for proteinuria ≥ 2+

• Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline must demonstrate 24-hour urine protein ≤ 1g

• History of allergy or hypersensitivity to paclitaxel albumin-stabilized nanoparticle formulation, paclitaxel, bevacizumab, carboplatin, albumin, drug product excipients, or chemically similar agents

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from all prior therapy

• No prior chemotherapy for locally recurrent or metastatic disease

• Prior neoadjuvant or adjuvant chemotherapy allowed

• More than 1 week since prior core biopsy or other minor surgical procedure, excluding placement of a vascular access device

• More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy

• More than 4 weeks since prior radiotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)

• At least 1 year since prior taxane regimen

• No other concurrent investigational agents

• Concurrent anticoagulation allowed, provided the following criteria are met:

• Stable dose of warfarin or low molecular weight heparin

• INR within desired range (2-3)

• No evidence of active bleeding or coagulopathy

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent radiotherapy, chemotherapy, immunotherapy, or antitumor hormonal therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Good Samaritan Cancer Care Center at Advocate Good Samaritan Hospital	Downers Grove	Illinois	United States	60515-1500
2	Delnor Community Hospital - Geneva	Geneva	Illinois	United States	60134-4200
3	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois	United States	60153
4	Edward Hospital Cancer Center	Naperville	Illinois	United States	60540
5	Swedish-American Regional Cancer Center	Rockford	Illinois	United States	61104-2315
6	Central Dupage Cancer Center	Winfield	Illinois	United States	60190-1295

Sponsors and Collaborators

• Loyola University
• Genentech, Inc.
• Celgene Corporation

Investigators

• Principal Investigator: Shelly Lo, MD, Loyola University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shelly Lo, Associate Professor, Loyola University
• ClinicalTrials.gov Identifier: NCT00654836
• Other Study ID Numbers: 200027
• First Posted: Apr 9, 2008
• Last Update Posted: Sep 14, 2017
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Shelly Lo, Associate Professor, Loyola University: recurrent breast cancer; stage III breast cancer; stage IV breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Bevacizumab; Carboplatin; Albumin-Bound Paclitaxel

Study Results

Participant Flow

Recruitment Details	Participants with metastatic breast cancer were recruited from medical clinics between October 15, 2007 and February 15, 2012
Pre-assignment Detail	No enrolled participant was excluded from therapy

Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
Period Title: Overall Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
Overall Participants	32
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	58.38
Sex: Female, Male (Count of Participants)
Female	32 100%
Male	0 0%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
ECOG 0	22 68.8%
ECOG 1	7 21.9%
ECOG 2	1 3.1%
Undetermined	2 6.3%
Site of Metastatic Disease was Bone (participants) [Number]
Yes	20 62.5%
No	12 37.5%
Site of Metastatic Disease was Liver (participants) [Number]
Yes	14 43.8%
No	18 56.3%
Site of Metastatic Disease was Loco-regional (participants) [Number]
Yes	12 37.5%
No	20 62.5%
Site of Metastatic Disease was Lung (participants) [Number]
Yes	9 28.1%
No	23 71.9%
Site of Metastatic Disease was Distant Lymph Nodes (participants) [Number]
Yes	7 21.9%
No	25 78.1%
Prior adjuvant therapy was chemotherapy (participants) [Number]
Yes	17 53.1%
No	15 46.9%
Prior adjuvant therapy was endocrine therapy (participants) [Number]
Yes	18 56.3%
No	14 43.8%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival was measured from treatment initiation to 30 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	30 Months

Outcome Measure Data

Analysis Population Description

All enrolled participants are included in this analysis

Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
Measure Participants	32
Median (95% Confidence Interval) [Months]	16

2. Secondary Outcome

Title	Response Rate at End of Treatment
Description	Response to treatment was recorded 30 months following treatment initiation. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions .
Time Frame	30 Months

Outcome Measure Data

Analysis Population Description

Of the 32 enrolled participants, two participants did not return to the clinic at 30 months for final evaluation of their response to treatment.

Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
Measure Participants	32
Complete Response (CR)	2 6.3%
Partial Response (PR)	24 75%
Stable Disease (SD)	3 9.4%
Progressive Disease (PD)	1 3.1%
Undetermined	2 6.3%

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival was measured from treatment initiation to 80 months
Time Frame	80 Months

Outcome Measure Data

Analysis Population Description

All enrolled participants are included in this analysis

Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
Measure Participants	32
Median (95% Confidence Interval) [Months]	21

Adverse Events

Time Frame	Adverse event information was collected from all 32 enrolled participants between February 28, 2008 and April 26, 2013
Arm/Group Title	Carboplatin, ABI-007 and Bevacizumab
Arm/Group Description	Participants received combination carboplatin, ABI-007 (i.e., a nanoparticle albumin-bound paclitaxel also called Abraxane), and bevacizumab (Avastin). Bevacizumab was administered as 15 mg/kg on days 1, 22, and 43 for patients without hematologic toxicity. For those with hematologic toxicity, bevacizumab was administered as 10mg/kg on day 1 and 15. Similarly, for patients without hematologic toxicity, a standard carboplatin dose according to the participant's area under the plasma drug concentration-time curve (AUC-6) was administered on days 1, 22, and 43. For patients with a hematologic toxicity, carboplatin was only given on day 1. Finally, for those without hematologic toxicity, ABI-007 (Abraxane) 100mg/m2 was administered on days 1,8, 15, 22, 29, 36,43,and 50. Conversely, for patients with hematologic toxicity, Abraxane was administered as 100mg/m2 only on days 1, 8, and 15.
All Cause Mortality
	Carboplatin, ABI-007 and Bevacizumab
	Affected / at Risk (%)	# Events
Total	24/32 (75%)
Serious Adverse Events
	Carboplatin, ABI-007 and Bevacizumab
	Affected / at Risk (%)	# Events
Total	24/32 (75%)
General disorders
Disease Progression	24/32 (75%)	24
Other (Not Including Serious) Adverse Events
	Carboplatin, ABI-007 and Bevacizumab
	Affected / at Risk (%)	# Events
Total	31/32 (96.9%)
Blood and lymphatic system disorders
Abnormal hemoglobin	15/32 (46.9%)	15
Abnormal Leukocytes	17/32 (53.1%)	17
Gastrointestinal disorders
Nausea	5/32 (15.6%)	5
Vomiting	3/32 (9.4%)	3
General disorders
Cough	2/32 (6.3%)	2
Dyspnea	4/32 (12.5%)	4
Chest Pain	4/32 (12.5%)	4
Joint Pain	2/32 (6.3%)	2
Proteinuria	2/32 (6.3%)	2
Thrombosis	2/32 (6.3%)	2
Hepatobiliary disorders
Abnormal Liver Test (AST)	2/32 (6.3%)	5
Immune system disorders
Allergic reaction	2/32 (6.3%)	2
Metabolism and nutrition disorders
Constipation	3/32 (9.4%)	3
Psychiatric disorders
Anorexia	4/32 (12.5%)	4
Vascular disorders
Hemorrhage of the Nose	8/32 (25%)	8

Limitations/Caveats

There are no limitations or caveats to disclose.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.