Trial of Eribulin Followed by Doxorubicin & Cyclophosphamide for Her2-negative, Locally Advanced Breast Cancer

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01498588
• Collaborator: Eisai Inc. (Industry)
• Enrollment: 7
• Locations: 4
• Arm: 1
• Duration (Months): 43
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Previous studies have shown that chemotherapy has the same effect on treating breast cancer whether you receive it before or after surgery. Receiving chemotherapy before surgery, rather than after surgery, may allow the patient to have less extensive surgery. The purpose of this study is to identify new treatment regimens with better response rates and to find out if the combination of eribulin followed by doxorubicin and cyclophosphamide can shrink the size of the patient's breast tumor and allow you to preserve your breast. Additionally, by receiving chemotherapy before surgery, the investigators will be able to determine if your cancer is responsive to chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms; Breast Cancer; Breast Tumors; Cancer of the Breast; Neoplasms, Breast; Tumors, Breast	Drug: Eribulin; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Pegfilgrastim	Phase 2

Detailed Description

This is a phase 2, single-arm, open label study. Patients with Her2-negative, locally advanced breast cancer will be enrolled on the study prior to receiving neoadjuvant chemotherapy. Patients will receive 4 cycles of neoadjuvant eribulin followed by 4 cycles of dose-dense doxorubicin and cyclophosphamide (AC).

All patients will have a baseline biopsy prior to study entry to determine eligibility. Patients will undergo repeat breast imaging and optional biopsy after completing 4 cycles of eribulin. Patients will then receive 4 cycles of dose-dense AC. Patients will undergo repeat breast imaging followed by surgical resection within 30 days of completing last cycle of chemotherapy. Patients who are not surgical candidates after completion of chemotherapy will be asked to undergo optional repeat biopsy prior to receiving additional treatment at the discretion of the investigator. Patients will continue to be followed per standard practice guideline after surgery

Clinical response will be determined by clinical breast examination prior to each cycle of chemotherapy and by breast imaging performed at baseline, after completion of eribulin, and prior to surgery. Pathologic complete response (pCR) will be determined at the time of surgical resection. Correlative biomarker studies will be performed on tumor samples at the completion of the clinical trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Neoadjuvant Trial of Eribulin Followed by Dose Dense Doxorubicin and Cyclophosphamide for Her2-negative, Locally Advanced Breast Cancer
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Eribulin+Doxorubicin+Cyclophosphamide Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy at the discretion of the investigator.

Drug: Eribulin; Patients will receive 4 cycles of neoadjuvant eribulin followed by 4 cycles of dose-dense doxorubicin and cyclophosphamide (AC).; Other Names: Halaven ; Drug: Doxorubicin; Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide; Other Names: Adriamycin ; Drug: Cyclophosphamide; Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide; Other Names: Cytoxan ; Drug: Pegfilgrastim; Growth factor support (pegfilgrastim) can be given at the discretion of the investigator. Administration of pegfilgrastim is required 24 to 48 hours following administration of dose-dense doxorubicin and cyclophosphamide.; Other Names: Neulasta

Outcome Measures

Primary Outcome Measures

1. Pathologic Complete Response Rate at the Time of Surgery [Average of 24 weeks]

   Patients will receive treatment for 20 weeks with primary outcome measured at the time of surgery. Surgery is typically 4-6 weeks after completion of chemotherapy, so patients will be on study for 24 weeks on average. Response was measured by pathologist's standard of care assessment of extent of residual disease. If the patient had no evidence of invasive or in situ residual disease present in the breast and lymph node (i.e. ypT0N0), then this was defined as a pathologic complete response (pCR). Reported is the number of participants showing pCR.

Secondary Outcome Measures

1. Toxicity of Chemotherapy Regimen (Number of Participants With Any Adverse Events) [Through 20 weeks of chemotherapy]

   Toxicity of chemotherapy at each physician visit using Common Toxicity Criteria for Adverse Effects (CTCAE) criteria.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast carcinoma.

• Locally advanced breast cancer (Stage IIIA to IIIC).

• Invasive breast cancer must be Her2-negative. If breast cancer is Her2 2+ by immunohistochemistry (IHC), then fluorescence in situ hybridization (FISH) must be negative for Her2 gene amplification.

• No evidence of disease outside the breast or chest wall, except ipsilateral axillary lymph nodes on staging scans (CT chest/abdomen/pelvis and bone scan or positron emission tomography [PET] scan).

• Patients must have measurable disease as defined by palpable lesion with both diameters ≥ 1 cm measurable with caliper and/or a positive mammogram or ultrasound with at least one dimension ≥ 1 cm. Bilateral mammogram and clip placement is required for study entry. Baseline measurements of the indicator lesions must be recorded on the Patient Registration Form. To be valid for baseline, the measurements must have been made within the 14 days if palpable. If not palpable, a mammogram or MRI must be done within 14 days. If palpable, a mammogram or MRI must be done within 2 months prior to study entry. If clinically indicated, xrays and scans must be done within 28 days of study entry.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 within 14 days of study entry.

• Normal (greater than 50%) left ventricular ejection fraction (LVEF) by multigated acquisition (MUGA) scan or echocardiography.

• Signed informed consent.

• Adequate organ function within 2 weeks of study entry:

• Absolute neutrophil count ≥ 1500/mm³, Hgb ≥ 9.0 g/dl and platelet count ≥ 100,000/mm³.

• Total bilirubin ≤ upper limit of normal.

• Creatinine ≤ 1.5 mg/dL or calculated creatinine clearance rate (CrCL) ≥ 50 mL/min using the Cockroft Gault equation.

• Serum glutamate oxaloacetate transaminase (SGOT)/(AST) or serum glutamate pyruvate transaminase (SGPT)/(ALT) and alkaline phosphatase (alk phos) must be within the range allowing for eligibility.

• Patients must be over 18 years old.

• International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate.

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.

• Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation.

• Patient must have signed informed consent prior to registration on this study.

Exclusion Criteria:

• Prior chemotherapy, hormonal therapy, biologic therapy, investigational agent, targeted therapy or radiation therapy for current breast cancer. Patients with history of breast cancer greater than 5 years from initial diagnosis are eligible for the study. Patients may not have received anthracycline-based chemotherapy in the past. Patients with history of ductal carcinoma in situ (DCIS) are eligible if there were treated with surgery alone.

• Medical, psychological or surgical condition which the investigator feels might compromise study participation.

• History of previous or current malignancy at other sites with the exception of adequately treated carcinoma in-situ of the cervix or basal or squamous cell carcinoma of the skin. Patients with a history of other malignancies, who remain disease free for greater than five years are eligible.

• Evidence of sensory and/or peripheral neuropathy > grade 1.

• Serious, uncontrolled, concurrent infection(s).

• Major surgery within 4 weeks of the start of study treatment, without complete recovery.

• Pregnant or lactating women are not eligible. Women of childbearing potential must have a negative serum or urine pregnancy test completed within 7 days of study treatment. Women or men of childbearing potential not using a reliable and appropriate contraceptive method are not eligible. (Postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential).

• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.

• Active clinically serious infection > CTCAE Grade 2.

• Thromboembolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

• Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.

• Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug.

• Cardiac disease: congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.

• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.

• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Grady Memorial Hospital	Atlanta	Georgia	United States	30303
2	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
3	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
4	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Emory University
• Eisai Inc.

Investigators

• Principal Investigator: Keerthi Gogineni, MD, MSHP, Emory University Winship Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Keerthi Gogineni, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT01498588
• Other Study ID Numbers: IRB00050068; WCI1937-10
• First Posted: Dec 23, 2011
• Last Update Posted: Oct 3, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Keerthi Gogineni, Principal Investigator, Emory University: Breast Neoplasms; Breast Cancer; Breast Tumors; Cancer of the Breast; Neoplasms, Breast; Tumors, Breast
• Additional relevant MeSH terms: Breast Neoplasms; Neoplasms; Cyclophosphamide; Doxorubicin

Study Results

Participant Flow

Recruitment Details	This study was open to accrual from October 2011 to June 2015. Enrolled participants were from Winship Cancer Institute of Emory University and Emory University Hospital Midtown.

Arm/Group Title	Eribulin+Doxorubicin+Cyclophosphamide
Arm/Group Description	Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eribulin+Doxorubicin+Cyclophosphamide
Arm/Group Description	Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	7 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	6 85.7%
Unknown or Not Reported	1 14.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 14.3%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 42.9%
White	2 28.6%
More than one race	0 0%
Unknown or Not Reported	1 14.3%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response Rate at the Time of Surgery
Description	Patients will receive treatment for 20 weeks with primary outcome measured at the time of surgery. Surgery is typically 4-6 weeks after completion of chemotherapy, so patients will be on study for 24 weeks on average. Response was measured by pathologist's standard of care assessment of extent of residual disease. If the patient had no evidence of invasive or in situ residual disease present in the breast and lymph node (i.e. ypT0N0), then this was defined as a pathologic complete response (pCR). Reported is the number of participants showing pCR.
Time Frame	Average of 24 weeks

Outcome Measure Data

Analysis Population Description

Pathology information at the time of definitive resection was available for six of seven patients. One patient was ultimately lost to follow-up.

Arm/Group Title	Eribulin+Doxorubicin+Cyclophosphamide
Arm/Group Description	Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy
Measure Participants	7
Pathologic Complete Response (pCR)	1 14.3%
No pCR	5 71.4%
Unknown	1 14.3%

2. Secondary Outcome

Title	Toxicity of Chemotherapy Regimen (Number of Participants With Any Adverse Events)
Description	Toxicity of chemotherapy at each physician visit using Common Toxicity Criteria for Adverse Effects (CTCAE) criteria.
Time Frame	Through 20 weeks of chemotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eribulin+Doxorubicin+Cyclophosphamide
Arm/Group Description	Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy
Measure Participants	7
Number [participants]	2 28.6%

Adverse Events

Arm/Group Title	Eribulin+Doxorubicin+Cyclophosphamide
Arm/Group Description	Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide Eribulin Day 1 and Day 8 of a 21 day cycle x 4 cycles: Day 1: Eribulin 1.4mg/m² IV Day 8: Eribulin 1.4mg/m² IV Dose-dense doxorubicin and cyclophosphamide every 14 days x 4 cycles: Day 1: Doxorubicin 60mg/m² IV Day 1: Cyclophosphamide 600mg/m² IV Day 2: Pegfilgrastim support 6mg sc at least 24 hours after chemotherapy
All Cause Mortality
	Eribulin+Doxorubicin+Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eribulin+Doxorubicin+Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Eribulin+Doxorubicin+Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)
Blood and lymphatic system disorders
Hemorrhage	1/7 (14.3%)
Gastrointestinal disorders
Anorexia	1/7 (14.3%)
General disorders
Fatigue	1/7 (14.3%)
Insomnia	1/7 (14.3%)
Metabolism and nutrition disorders
Hypoalbuminemia	1/7 (14.3%)
Elevated ALT	1/7 (14.3%)
Elevated AST	1/7 (14.3%)
Hypercalcemia	1/7 (14.3%)
Hyperglycemia	1/7 (14.3%)
Hyponatremia	1/7 (14.3%)
Nervous system disorders
Neuropathy	2/7 (28.6%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Rash	1/7 (14.3%)

Limitations/Caveats

Study accrual was low at 7 patients.

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.