Doxorubicin Hydrochloride, Cyclophosphamide, and Filgrastim Followed By Paclitaxel Albumin-Stabilized Nanoparticle Formulation With or Without Trastuzumab in Treating Patients With Breast Cancer Previously Treated With Surgery

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00407888
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 60
• Location: 1
• Arm: 1
• Duration (Months): 74
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, 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. Colony-stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Monoclonal antibodies, such as trastuzumab, 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 tumor-killing substances to them. Giving combination chemotherapy and filgrastim together with trastuzumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving doxorubicin hydrochloride, cyclophosphamide, and filgrastim together followed by paclitaxel albumin-stabilized nanoparticle formulation and trastuzumab works in treating patients with breast cancer previously treated with surgery

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor-positive Breast Cancer; HER2-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer	Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Biological: filgrastim; Drug: paclitaxel albumin-stabilized nanoparticle formulation; Biological: trastuzumab; Other: laboratory biomarker analysis; Procedure: quality-of-life assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess disease-free survival following a dose-intensive weekly regimen of Adriamycin + oral cyclophosphamide augmented with G-CSF support followed by Abraxane and Herceptin if appropriate for adjuvant treatment of high risk breast cancer patients.

SECONDARY OBJECTIVES:

1. To assess the toxicity associated with this regimen. II. To assess the delivered dose intensity of the regimen. III. To assess time to treatment failure and overall survival of the regimen. IV. To assess the incidence and severity of delayed nausea and vomiting with this regimen.

OUTLINE:

Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adjuvant Therapy for High-Risk Localized Breast Cancer Using Weekly Adriamycin + Daily Oral Cytoxan With Continuous G-CSF Support for 12 Weeks Followed by Weekly Abraxane™ for 12 Weeks With Concurrent Herceptin for Subjects With HER-2/Neu Positive Disease, Phase II
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity.

Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: cyclophosphamide; Given orally; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Biological: filgrastim; Given SC; Other Names: G-CSF Neupogen ; Drug: paclitaxel albumin-stabilized nanoparticle formulation; Given IV; Other Names: ABI-007 nab paclitaxel nab-paclitaxel nanoparticle albumin-bound paclitaxel ; Biological: trastuzumab; Given IV; Other Names: anti-c-erB-2 Herceptin MOAB HER2 ; Other: laboratory biomarker analysis; Correlative studies; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment

Outcome Measures

Primary Outcome Measures

1. Disease-free Survival Following a Dose-intensive Weekly Regimen of Adriamycin + Oral Cyclophosphamide Augmented With G-CSF Support Followed by Abraxane and Herceptin [2 years]

Secondary Outcome Measures

1. Delivered Dose Intensity of the Regimen [After at least one course of Adriamycin, up to 12 weeks.]

2. Toxicity Associated With This Regimen [After at least one course of Adriamycin, up to 12 weeks.]

3. Time to Treatment Failure [Up to 6 years]

   Median time from date of start of therapy to date of removal from therapy for reason other than completion, date of first observation of recurrent disease or date of death due to any cause whichever comes first.

4. Overall Survival [Up to 6 years.]

   Count of surviving patients at two years and six years

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Have a histologically confirmed diagnosis of primary breast carcinoma that has been surgically resected; (this regimen is not intended for neoadjuvant treatment)

• 4 + nodes

• OR if 1-3 + nodes, either ER OR HER-2/neu+

• OR have high-risk node negative disease that is HER-2/neu positive OR >= 2.0 cm tumor size

• HER-2/new + definition: patient has known tumor HER-2/new expression = 3+ by IHC or, if 2+ by IHC confirmed to be FISH positive

• Patients with clinically apparent cardiac disease, or history of same, are not eligible; patients who are >= 60 years of age or who have a history of hypertension must have an echocardiogram or MUGA prior to enrollment; patients with breast cancer that is HER-2/neu positive and a treatment plan that includes Herceptin must have an echocardiogram or MUGA scan prior to enrollment; the LVEF must be within the institutional normal range; if LVEF is > 75%, the investigator should consider having the LVEF reviewed or repeating the MUGA prior to registration

• WBC >= 4,000

• ANC >= 1,500

• Platelet count >= 100,000

• Serum creatinine =< 1.5 x IULN

• Bilirubin =< 2.0

• SGOT/SGPT/alkaline phosphatase =< 2 x IULN

• Elevations greater than these require metastatic work up

• Be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study specific screening procedures

Exclusion Criteria:

• Except for the following, no other malignancy is allowed: synchronous ipsilateral breast cancer of the same subtype (ER/PR, HER-2/neu), adequately treated basal cell or squamous cell skin cancer, in situcervical cancer or other stage I or II cancer from which the patient has been disease free for at least 5 years

• Patients with cardiac disease that would preclude the use of Adriamycin, Taxol or

Herceptin are not eligible; this includes:

• Angina pectoris that requires the use of antianginal medication

• Cardiac arrhythmia requiring medication

• Severe conduction abnormality

• Clinically significant valvular disease

• Cardiomegaly on chest x-ray

• Ventricular hypertrophy on EKG

• Uncontrolled hypertension, (diastolic greater than 100 mm/Hg or systolic > 200 mm/hg)

• Current use of digitalis or beta blockers for CHF

• Clinically significant pericardial effusion

• Myocardial infarction documented as a clinical diagnosis or by EKG or any other test

• Documented congestive heart failure

• Documented cardiomyopathy

• Documented arrhythmia or cardiac valvular disease that requires medication or is medically significant

• Patients who have received prior chemotherapy or radiotherapy are not eligible

• Patients who are pregnant or breastfeeding are not eligible; women of child bearing potential must agree to practice adequate contraception

• Patients with active infection are not eligible

• Patients who are known to be infected with HIV, hepatitis B or hepatitis C are not eligible; testing is not required unless there is a high index of clinical suspicion

• Patients suffering from psychiatric impairment are not eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vijayakrishna K Gadi, MDPHD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vijayakrishna Gadi, Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00407888
• Other Study ID Numbers: 6141; NCI-2010-02117
• First Posted: Dec 5, 2006
• Last Update Posted: Aug 31, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Period Title: Overall Study
STARTED	60
COMPLETED	60
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Overall Participants	60
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	60 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 6.7%
Not Hispanic or Latino	55 91.7%
Unknown or Not Reported	1 1.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 3.3%
Asian	4 6.7%
Native Hawaiian or Other Pacific Islander	1 1.7%
Black or African American	2 3.3%
White	51 85%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival Following a Dose-intensive Weekly Regimen of Adriamycin + Oral Cyclophosphamide Augmented With G-CSF Support Followed by Abraxane and Herceptin
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Measure Participants	60
Count of Participants [Participants]	56 93.3%

2. Secondary Outcome

Title	Delivered Dose Intensity of the Regimen
Time Frame	After at least one course of Adriamycin, up to 12 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Measure Participants	60
Doxorubicin	92.6
Cyclophosphamide	92.1
nP (intent-to-treat)	88.0

3. Secondary Outcome

Title	Toxicity Associated With This Regimen
Time Frame	After at least one course of Adriamycin, up to 12 weeks.

Outcome Measure Data

Analysis Population Description

Some results reported are only considered amongst patients receiving Trastuzumab (n = 15).

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Measure Participants	60
Filgrastim used	37 61.7%
Dose holds/reductions	43 71.7%
Hospitalization/ER evaluation	5 8.3%
Trastuzumab patients with decease in LVEF to <50%	2 3.3%
Trastuzumab patients with decease in LVEF to <10%	3 5%

4. Secondary Outcome

Title	Time to Treatment Failure
Description	Median time from date of start of therapy to date of removal from therapy for reason other than completion, date of first observation of recurrent disease or date of death due to any cause whichever comes first.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Outcome measure reported only for those that had an event (death, recurrent disease or removal).

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Measure Participants	11
Median (Full Range) [years]	2.7

5. Secondary Outcome

Title	Overall Survival
Description	Count of surviving patients at two years and six years
Time Frame	Up to 6 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
Measure Participants	60
Two years	59 98.3%
Six years	53 88.3%

Adverse Events

Arm/Group Title	Arm I
Arm/Group Description	Patients receive dose-intensive chemotherapy comprising doxorubicin hydrochloride IV over 10-15 minutes on day 1, oral cyclophosphamide once daily on days 1-7, and filgrastim subcutaneously on days 2-7. Courses repeat every 7 days for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Beginning 1 week later, patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes once a week for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients with HER-2/neu positive disease also receive trastuzumab IV over 30-90 minutes once a week for 1 year in the absence of disease progression or unacceptable toxicity. doxorubicin hydrochloride: Given IV cyclophosphamide: Given orally filgrastim: Given SC paclitaxel albumin-stabilized nanoparticle formulation: Given IV trastuzumab: Given IV laboratory biomarker analysis: Correlative studies quality-of-life assessment: Ancillary studies
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	5/60 (8.3%)
Blood and lymphatic system disorders
Febrile Neutopenia	1/60 (1.7%)
Gastrointestinal disorders
Hemorrhoidal Hemorrhage	1/60 (1.7%)
Mucositis	1/60 (1.7%)
General disorders
Fever	1/60 (1.7%)
Infections and infestations
Possible Pneumoncystis Pneumonia	1/60 (1.7%)
Metabolism and nutrition disorders
Dehydration	1/60 (1.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax due to MVA	1/60 (1.7%)
Shortness of Breath	1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	33/60 (55%)
Gastrointestinal disorders
Nausea	3/60 (5%)
Mucositis	6/60 (10%)
Investigations
Neutropenia	33/60 (55%)
Leukopenia	3/60 (5%)
Nervous system disorders
Neuropathy	4/60 (6.7%)
Renal and urinary disorders
Low Hemoglobin	3/60 (5%)
Skin and subcutaneous tissue disorders
Hand Foot Syndrome	5/60 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.