Preoperative Dose-dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab in Operable Breast Cancer

• Sponsor: Ian E. Krop, MD, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00546156
• Collaborator: Genentech, Inc. (Industry), Massachusetts General Hospital (Other), Brigham and Women's Hospital (Other), New Hampshire Oncology-Hematology PA (Other)
• Enrollment: 104
• Locations: 4
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 26
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Dose dense chemotherapy, which is the term for Adriamycin and Cyclophosphamide (AC) followed by Taxol chemotherapy given every two weeks, is the standard chemotherapy for the treatment of ER+ or PR+ breast cancer. In this trial, the standard chemotherapy is being combined with bevacizumab. Bevacizumab is an antibody which works differently from the way other chemotherapy drugs work. Bevacizumab slows or stops cell growth in cancerous tumors by decreasing the blood supply to the tumors by binding to a substance found on cancer cells called VEGF (vascular endothelial growth factor). Bevacizumab is approved by the FDA for the treatment of colorectal cancer and lung cancer. However, it is not approved for the treatment of breast cancer. Another goal of this research is to determine whether we can develop a way to identify tumors that will respond well to this study treatment.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Drug: Bevacizumab	Phase 2

Detailed Description

• To prepare for the surgery that will occur at the end of the study treatment, a small "clip" will be placed into the tumor area so that the surgeon can locate the site of the tumor at the time of surgery. This is a standard procedure for breast cancer.

• During the clip placement, a needle will be inserted into the tumor to measure interstitial fluid pressure (IFP measurement). IFP is done for research purposes to help understand how the tumor responds to the study treatment.

• Study treatment will begin with one dose of bevacizumab alone, followed two weeks later by chemotherapy and bevacizumab in eight two-week cycles. The study treatment will be given intravenously in the clinic.

• After the first dose of bevacizumab and prior to starting chemotherapy, a needle biopsy of the breast tumor will be performed for research purposes. A second measurement of IFP will also be done at this time.

• During the treatment period, tests and procedures will be performed at specified intervals and include the following: research MRI, physical exams, blood tests, urine tests, EKG, and MUGA or ECHO.

• Surgery to remove the tumor will occur no less than four weeks after the last dose of Paclitaxel.

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Preoperative Dose-dense (dd) Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel (T) With Bevacizumab in ER+ and/or PR+, HER2-negative Operable Breast Cancer
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: HR+, HER2- Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.	Drug: Doxorubicin; Standard chemotherapy regimen; Other Names: Adriamycin ; Drug: Cyclophosphamide; Standard chemotherapy regimen; Other Names: Cytoxan ; Drug: Paclitaxel; Standard chemotherapy regimen; Other Names: Taxol ; Drug: Bevacizumab; One intravenous dose given followed 2 weeks later with standard chemotherapy drugs and bevacizumab given intravenously in 8 two-week cycles.; Other Names: Avastin
Active Comparator: Triple Negative Breast Cancer Cohort Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.	Drug: Doxorubicin; Standard chemotherapy regimen; Other Names: Adriamycin ; Drug: Cyclophosphamide; Standard chemotherapy regimen; Other Names: Cytoxan ; Drug: Paclitaxel; Standard chemotherapy regimen; Other Names: Taxol ; Drug: Bevacizumab; One intravenous dose given followed 2 weeks later with standard chemotherapy drugs and bevacizumab given intravenously in 8 two-week cycles.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response Rate After Preoperative Therapy in This Patient Population. [3 Years]

   Pathological Complete response is defined as complete disappearance of invasive tumor in the breast at the time of surgery

Secondary Outcome Measures

1. Decrease in Interstitial Fluid Pressure. [3 years]

   To determine if bevacizumab monotherapy results in a decrease in interstitial fluid pressure

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Documented primary invasive breast cancer by histologic assessment

• Tumors must express estrogen (ER) and/or progesterone receptors (PR) by standard immunohistochemical methods. Tumors must be negative for HER2. There must be sufficient sample for further protocol-specified immunohistochemical analysis

• Patients must have high risk ER+ or PR+ breast cancer as defined by criteria listed in protocol

• 18 year of age or older

• Performance status of 0 or 1 by ECOG criteria

• Use of an effective means of contraception in subjects of childbearing potential

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to starting therapy.

• Patients taking exogenous sex-steroid hormone treatments for any reason at the time of diagnosis must discontinue all hormonal treatments at least 2 weeks prior to enrollment

• Patients must have preoperative treatment within 60 days of initial diagnosis of breast cancer

• No other malignancy that requires on-going treatment

• Normal organ function as outlined in the protocol

Exclusion Criteria:

• Prior cytotoxic chemotherapy or radiation for the current breast cancer

• Patients with inflammatory breast cancer

• HER2 positive disease defined as HER2-amplified by FISH or IHC 3+. HER2 2+ must be negative by FISH

• Known metastatic (Stage IV) disease

• Other investigational agents within 4 weeks prior to the start of study treatment

• Life expectancy of less than 6 months

• Peripheral neuropathy greater than or equal to grade 2

• Inadequately controlled hypertension

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• NYHA grade II or greater congestive heart failure

• History of prior myocardial infarction

• History of unstable angina within 12 months prior to study enrollment

• Any history of stroke or transient ischemic attack at any time

• Known CNS disease

• Significant vascular disease

• Symptomatic peripheral vascular disease

• Evidence of significant bleeding within 6 months of study; any serious non-healing wound, skin ulcers, or bone fracture; any abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the past 6 months; any major surgical procedure within 28 days prior to randomization or anticipation of need for major surgery during course of study.

• Known HIV positive

• Unwilling to undergo pretreatment biopsy and consent to acquisition of archival tissue

• Pregnant of lactating

• Known hypersensitivity to any component of bevacizumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Dana-Farber at Faulkner Hospital	Boston	Massachusetts	United States	02130
4	New Hampshire Oncology-Hematology PA	Hooksett	New Hampshire	United States	03106

Sponsors and Collaborators

• Ian E. Krop, MD, PhD
• Genentech, Inc.
• Massachusetts General Hospital
• Brigham and Women's Hospital
• New Hampshire Oncology-Hematology PA

Investigators

• Principal Investigator: Ian Krop, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ian E. Krop, MD, PhD, Medical Oncologist, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00546156
• Other Study ID Numbers: 07-130
• First Posted: Oct 18, 2007
• Last Update Posted: May 18, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Ian E. Krop, MD, PhD, Medical Oncologist, Dana-Farber Cancer Institute: ER positive; PR positive
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Cyclophosphamide; Bevacizumab; Doxorubicin

Study Results

Participant Flow

Recruitment Details	Study was activated on 10/17/2007 and Closed to accrual on 7/1/2011.

Arm/Group Title	HR+, HER2-	Triple Negative Breast Cancer Cohort
Arm/Group Description	Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.	Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
Period Title: Overall Study
STARTED	84	20
COMPLETED	70	19
NOT COMPLETED	14	1

Baseline Characteristics

Arm/Group Title	HR+, HER2-	Triple Negative Breast Cancer Cohort	Total
Arm/Group Description	Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.	Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.	Total of all reporting groups
Overall Participants	84	20	104
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47.5	47.5	47.5
Sex: Female, Male (Count of Participants)
Female	84 100%	20 100%	104 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	84 100%	20 100%	104 100%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response Rate After Preoperative Therapy in This Patient Population.
Description	Pathological Complete response is defined as complete disappearance of invasive tumor in the breast at the time of surgery
Time Frame	3 Years

Outcome Measure Data

Analysis Population Description

Participants who met all study eligibility criteria and signed informed consent.

Arm/Group Title	HR+, HER2-	Triple Negative Breast Cancer Cohort
Arm/Group Description	Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.	Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
Measure Participants	84	20
Number [percentage of participants]	8 9.5%	44 220%

2. Secondary Outcome

Title	Decrease in Interstitial Fluid Pressure.
Description	To determine if bevacizumab monotherapy results in a decrease in interstitial fluid pressure
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

This represents the number of patients with paired IFP measurements from day 0 and day 14

Arm/Group Title	HR+, HER2-	Triple Negative Breast Cancer Cohort
Arm/Group Description	Patients with Hormone Receptor Positive, HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.	Hormone receptor negative, HER2 negative Cohort. Receive same drug protocol as Arm A.
Measure Participants	52	13
Median (Inter-Quartile Range) [mm Hg]	0.70	1.04

Adverse Events

Time Frame	4 years
Arm/Group Title	All Study Participants
Arm/Group Description	Patients with HER2 negative Breast Cancer. A single dose of Bevacizumab 10mg/kg, followed two weeks later by Adriamycin60 mg/m2 and Cyclophosphamide 600 mg/m2 with Bevacizumab 10mg/kg every 2 weeks x4, followed by Taxol 175 mg/m2 with Bevacizumab 10 mg/kg every 2 weeks x3, followed by Taxol 175 mg/m2 x1.
All Cause Mortality
	All Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	4/104 (3.8%)
Blood and lymphatic system disorders
Neutropenia	1/104 (1%)	1
Leukopenia	2/104 (1.9%)	2
General disorders
paranasal sinus reaction	1/104 (1%)	1
Skin and subcutaneous tissue disorders
cellulitis	1/104 (1%)	1
Other (Not Including Serious) Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	104/104 (100%)
Blood and lymphatic system disorders
febrile neutropenia	6/104 (5.8%)	10
Hematologic-other	38/104 (36.5%)	194
Hemoglobin	86/104 (82.7%)	387
Leukocytes	24/104 (23.1%)	39
Lymphopenia	56/104 (53.8%)	182
Nose-hemorrhage	33/104 (31.7%)	68
Platelets	30/104 (28.8%)	54
Endocrine disorders
Hot flashes	15/104 (14.4%)	29
Hyperglycemia	79/104 (76%)	304
Eye disorders
Neutrophils	20/104 (19.2%)	32
Gastrointestinal disorders
Abdomen-pain	10/104 (9.6%)	16
Anorexia	20/104 (19.2%)	40
constipation	47/104 (45.2%)	89
Diarrhea	34/104 (32.7%)	65
Dyspepsia	21/104 (20.2%)	45
GI-other	20/104 (19.2%)	34
Hemorrhoids	12/104 (11.5%)	29
Nausea	76/104 (73.1%)	197
Vomiting	25/104 (24%)	29
General disorders
Constitutional-other	6/104 (5.8%)	7
Fatigue	91/104 (87.5%)	367
fever w/o neutropenia	22/104 (21.2%)	35
Insomnia	19/104 (18.3%)	35
Oral cavity-pain	6/104 (5.8%)	8
Pain-other	27/104 (26%)	41
Taste disturbance	6/104 (5.8%)	7
Voice changes/dysarthria	15/104 (14.4%)	32
Weight loss	7/104 (6.7%)	17
Hepatobiliary disorders
ALT-SGPT	48/104 (46.2%)	84
AST-SGOT	48/104 (46.2%)	120
Immune system disorders
Allergic Reaction	10/104 (9.6%)	10
Infections and infestations
Infection-other	7/104 (6.7%)	8
Muco/stomatitis (symptom) oral cavity	23/104 (22.1%)	49
Muco/stomatitis by exam-oral cavity	18/104 (17.3%)	28
Investigations
Alkaline Phosphatase	36/104 (34.6%)	87
Metabolism and nutrition disorders
Bicarbonate	19/104 (18.3%)	41
Hypoalbuminemia	7/104 (6.7%)	18
Hypocalcemia	13/104 (12.5%)	24
Hypoglycemia	7/104 (6.7%)	8
Hyponatremia	11/104 (10.6%)	18
Metabolic/laboratory-other	37/104 (35.6%)	123
Musculoskeletal and connective tissue disorders
Back-pain	22/104 (21.2%)	27
Bone-pain	16/104 (15.4%)	27
Extremity-limb-pain	13/104 (12.5%)	18
Joint-pain	31/104 (29.8%)	60
Muscle-pain	53/104 (51%)	96
Rigors/chills	6/104 (5.8%)	7
Throat/pharynx/larynx-pain	30/104 (28.8%)	44
Nervous system disorders
Dizziness	9/104 (8.7%)	11
Headache	57/104 (54.8%)	129
Neuropathy-motor	9/104 (8.7%)	11
Psychiatric disorders
Anxiety	18/104 (17.3%)	32
Depression	6/104 (5.8%)	9
Renal and urinary disorders
Creatinine	34/104 (32.7%)	115
Proteinuria	30/104 (28.8%)	53
Respiratory, thoracic and mediastinal disorders
Cough	26/104 (25%)	59
Dyspnea	21/104 (20.2%)	47
Infection Gr0-2 neut-upper airway	10/104 (9.6%)	15
Pulmonary-Upper Respiratory-other	19/104 (18.3%)	36
Skin and subcutaneous tissue disorders
Alopecia	39/104 (37.5%)	179
Dry Skin	9/104 (8.7%)	13
erythema multiforme	7/104 (6.7%)	8
Flushing	8/104 (7.7%)	13
Hand-foot reaction	6/104 (5.8%)	12
Nail changes	9/104 (8.7%)	19
Neuropathy-sensory	64/104 (61.5%)	150
Rash/desquamation	25/104 (24%)	36
Sweating	6/104 (5.8%)	9
Vascular disorders
Hypertension	27/104 (26%)	59
Skin-other	8/104 (7.7%)	13

Limitations/Caveats

[Not Specified]

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.