Ixabepilone and Cyclophosphamide as Neoadjuvant Therapy in HER-2 Negative Breast Cancer
Study Details
Study Description
Brief Summary
We propose to evaluate ixabepilone in combination with cyclophosphamide for the neoadjuvant treatment of locally advanced breast cancer. In this regimen, ixabepilone is substituted for docetaxel, since preclinical and clinical
studies suggest that ixabepilone is more active than either docetaxel or paclitaxel. The combination of ixabepilone and cyclophosphamide could further improve the efficacy of non-anthracycline neoadjuvant therapy.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Detailed Description
In this study, patients with early stage, HER2-negative breast cancer will receive neoadjuvant treatment with ixabepilone and cyclophosphamide given every three weeks for a total of six cycles. Following surgery patients with hormone receptor-positive tumors will receive anti-estrogen treatment. Patients may receive local regional radiation therapy after surgery per institutional guidelines at the investigator's discretion. Baseline tumor tissue and tumor tissue removed at the time of surgery will be tested by Oncotype Detailed Description (DX) assay to determine whether it is predictive of response to this neoadjuvant treatment regimen. This study will be one of the first investigations of the combination of ixabepilone and cyclophosphamide as neoadjuvant treatment for HER2-negative breast cancer. It will examine this treatment regimen for potential advantages gained from substitution of ixabepilone for a taxane and use of non-anthracycline agents.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Ixabepilone/Cyclophosphamide Systemic Therapy followed by surgery and possible radiation therapy |
Drug: Ixabepilone
40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles
Other Names:
Drug: Cyclophosphamide
600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Pathologic Complete Response Rate (pCR) [6 months]
Pathologic complete response (pCR) rate will be determined by the pathologic evaluation of breast and lymph node samples collected at the time of surgery. pCR is defined as no residual disease in breast or lymph nodes in resected tissue samples.
Secondary Outcome Measures
- Absence of Grade-4 Non-hematologic Toxicity Excluding, Alopecia, Nausea, Vomiting and Bone Pain [3 months]
Non hematologic treatment-related grade 4 toxicities measured according to CTCAE 3.0
- Overall Survival [36 months]
Overall survival (OS) determined as the time between day 1 cycle 1 to the date of death from any cause. The percentage of patients who were alive at 3 years, estimated by Kaplan Meier method as the probability of being event free at 3 years is reported here.
- Disease Free Survival [36 Months]
Defined as the time between Day 1 Cycle 1, and date of first documented recurrence, initiation of additional chemotherapy, or death.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Female patients, age ≥18 years.
-
Histologically confirmed invasive adenocarcinoma of the breast.
-
Primary palpable disease confined to a breast and axilla on
physical examination. For patients without clinically suspicious
axillary adenopathy, the primary tumor must be larger than 2 cm
in diameter by physical exam or imaging studies (clinical T2-T3,
N0-N1, M0). For patients with clinically suspicious axillary
adenopathy, the primary breast tumor can be any size (clinical
T1-3, N1-2, M0). (T1N0M0 lesions are excluded.)
- Patients without clearly defined palpable breast mass or axillary
lymph nodes but radiographically measurable tumor masses are
acceptable. Accepted procedures for measuring breast disease
are mammography, MRI, and breast ultrasound. This will need to
be re-evaluated after 3 cycles and prior to surgery.
- Eastern Cooperative Oncology Group performance status (ECOG
PS) 0-2.
- No metastatic disease, as documented by complete staging workup
- 6 weeks prior to initiation of study treatment.
-
No previous treatment for breast cancer.
-
HER2-negative tumor status. HER2-negative is defined as:
-
Immunohistochemical (IHC) 0, IHC 1+ OR
-
IHC 2+ or IHC 3+ must be confirmed as FISH (fluorescence in situ
hybridization) negative (defined by ratio <2.2).
- Adequate hematologic function with:
-
Absolute neutrophil count (ANC) >1500/μL.
-
Platelets ≥100,000/μL.
-
Hemoglobin ≥10 g/dL.
- Adequate hepatic function with:
-
Serum bilirubin ≤ the institutional upper limit of normal (ULN).
-
Aspartate aminotransferase (AST) ≤2.5 x institutional ULN.
-
Alanine aminotransferase (ALT) ≤2.5 x institutional ULN.
-
Adequate renal function with serum creatinine ≤1.5 x ULN.
-
Estrogen and progesterone receptor status in the primary tumor
known or pending at the time of study registration.
- Knowledge of the investigational nature of the study and ability to
provide consent for study participation.
- For patients who had, or will have sentinel lymph node and/or
axillary dissection prior to initiation of study treatment, completion
at least 4 weeks prior to starting study treatment and well-healed
wound
- Bilateral, synchronous breast cancer is allowed if one primary
tumor meets the inclusion criteria.
- Sufficient archived breast tumor specimen available at baseline
for the Oncotype DX assay.
-
Exclusion Criteria:
-
Inflammatory breast cancer.
-
Peripheral neuropathy (motor or sensory) ≥ grade 1 by the
Common Terminology Criteria for Adverse Events version 3.0
(CTCAE v 3.0).
- Prior radiation that included ≥30% of major bone marrow containing
areas (pelvis, lumbar, spine).
- Chronic use of cytochrome P450 (CYP) 3A4 inhibitors and use of
the following strong CYP3A4 inhibitors: ketoconazole,
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir,
telithromycin, ritonavir, amprenavir, indinavir, nelfinavir,
delavirdine, and voriconazole. Use of these agents should be
discontinued at least 72 hours prior to initiation of study treatment.
- Chemotherapy within 5 years of starting study treatment except
for low doses of agents used for anti-inflammatory indications
such as rheumatoid arthritis, psoriasis, and connective tissue
disorders. Although such doses and schedules cannot result in
myelosuppression, patients must discontinue this therapy while
they are receiving study treatment.
- Known or suspected hypersensitivity to Cremophor®EL
(polyoxyethylated castor oil) or a drug formulated in
Cremophor®EL such as paclitaxel, or any other agent given in the
course of this study.
- Pregnancy or breast-feeding. A negative serum pregnancy test
within 7 days prior to first study treatment (Day 1, Cycle 1) for all
women of childbearing potential is required. Patients of
childbearing potential must agree to use a birth control method
that is approved by their study physician while receiving study
treatment and for 3 weeks after their last dose of study treatment.
Patients must agree to not breast-feed while receiving study
treatment.
- Concurrent treatment with an ovarian hormonal replacement
therapy or with hormonal agents such as raloxifene, tamoxifen or
other selective estrogen receptor modulator (SERM). Patients
must have discontinued use of such agents prior to beginning
study treatment.
- History of malignancy treated with curative intent within the
previous 5 years with the exception of skin cancer, cervical
carcinoma in situ, or follicular thyroid cancer. Patients with
previous invasive cancers (including breast cancer) are eligible if
the treatment was completed more than 5 years prior to initiating
current study treatment, and there is no evidence of recurrent
disease.
- Uncontrolled intercurrent illness including (but not limited to)
ongoing or active infection.
- Chronic treatment with corticosteroid unless treatment was begun
6 months prior to study treatment and is at a low dose (≤20 mg
methylprednisolone or equivalent).
- Use of any investigational agent within 30 days of administration
of the first dose of study drug.
- Requirement for radiation therapy concurrent with neoadjuvant
study chemotherapy.
- Concurrent treatment with any anti-cancer therapy other than
those agents used in this study.
- Inability or unwillingness to comply with study procedures
including follow-up visits.
- Mental condition or psychiatric disorder that would prevent patient
comprehension of the nature, scope, and possible consequences
of the study or that would limit compliance with study
requirements.
- Any other disease(s), metabolic dysfunction, or findings from a
physical examination or clinical laboratory test result that would
cause reasonable suspicion of a disease or condition that
contraindicates the use of study drugs, that may affect the
interpretation of the results, or that renders the patient at high risk
from treatment complications
-
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Aventura Medical Center | Aventura | Florida | United States | 33180 |
2 | Florida Cancer Specialists | Fort Myers | Florida | United States | 33901 |
3 | Watson Clinic Center for Cancer Care and Research | Lakeland | Florida | United States | 33805 |
4 | Medical Oncology Associates of Augusta | Augusta | Georgia | United States | 30901 |
5 | Northeast Georgia Medical Center | Gainesville | Georgia | United States | 30501 |
6 | Providence Medical Group | Terre Haute | Indiana | United States | 47802 |
7 | Mercy Hospital | Portland | Maine | United States | 04101 |
8 | Center for Cancer and Blood Disorders | Bethesda | Maryland | United States | 20817 |
9 | National Capital Clinical Research Consortium | Bethesda | Maryland | United States | 20817 |
10 | St. Louis Cancer Care | Chesterfield | Missouri | United States | 63017 |
11 | Methodist Cancer Center | Omaha | Nebraska | United States | 68114 |
12 | Hematology Oncology Associates of Northern NJ | Morristown | New Jersey | United States | 07960 |
13 | Oncology Hematology Care | Cincinnati | Ohio | United States | 45242 |
14 | Cancer Centers of Southwest Oklahoma | Lawton | Oklahoma | United States | 73505 |
15 | South Carolina Oncology Associates, PA | Columbia | South Carolina | United States | 29210 |
16 | Chattanooga Oncology Hematology Associates | Chattanooga | Tennessee | United States | 37404 |
17 | Family Cancer Center | Collierville | Tennessee | United States | 38017 |
18 | Tennessee Oncology | Nashville | Tennessee | United States | 37203 |
19 | South Texas Oncology and Hematology | San Antonio | Texas | United States | 78258 |
20 | Virginia Cancer Institute | Richmond | Virginia | United States | 23235 |
Sponsors and Collaborators
- SCRI Development Innovations, LLC
- Bristol-Myers Squibb
Investigators
- Study Chair: Denise A Yardley, M.D., SCRI Development Innovations, LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SCRI BRE 133
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Ixabepilone/Cyclophosphamide |
---|---|
Arm/Group Description | Ixabepilone: 40 mg/m2 via intraveous (IV) infusion over 3 hours Cyclophosphamide: 600 mg/m2 via IV infusion per institutional guidelines |
Period Title: Overall Study | |
STARTED | 168 |
COMPLETED | 135 |
NOT COMPLETED | 33 |
Baseline Characteristics
Arm/Group Title | Arm/Group 1 |
---|---|
Arm/Group Description | All patients who received at least one dose of treatment. |
Overall Participants | 168 |
Age (Years) [Median (Full Range) ] | |
Median (Full Range) [Years] |
53
|
Sex: Female, Male (Count of Participants) | |
Female |
168
100%
|
Male |
0
0%
|
Region of Enrollment (participants) [Number] | |
United States |
168
100%
|
Outcome Measures
Title | Pathologic Complete Response Rate (pCR) |
---|---|
Description | Pathologic complete response (pCR) rate will be determined by the pathologic evaluation of breast and lymph node samples collected at the time of surgery. pCR is defined as no residual disease in breast or lymph nodes in resected tissue samples. |
Time Frame | 6 months |
Outcome Measure Data
Analysis Population Description |
---|
To be evaluable, patients had to undergo surgery after neoadjuvant therapy. Out of 168 patients, only 161 patients underwent surgery after neoadjuvant therapy and were included in this analysis. |
Arm/Group Title | Ixabepilone/Cyclophosphamide |
---|---|
Arm/Group Description | Systemic Therapy followed by surgery and possible radiation therapy |
Measure Participants | 161 |
Number [participants] |
27
16.1%
|
Title | Absence of Grade-4 Non-hematologic Toxicity Excluding, Alopecia, Nausea, Vomiting and Bone Pain |
---|---|
Description | Non hematologic treatment-related grade 4 toxicities measured according to CTCAE 3.0 |
Time Frame | 3 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ixabepilone/Cyclophosphamide |
---|---|
Arm/Group Description | Systemic Therapy followed by surgery and possible radiation therapy |
Measure Participants | 168 |
Fatigue |
1
0.6%
|
Peripheral neuropathy |
1
0.6%
|
Arthralgia/myalgia |
1
0.6%
|
Title | Overall Survival |
---|---|
Description | Overall survival (OS) determined as the time between day 1 cycle 1 to the date of death from any cause. The percentage of patients who were alive at 3 years, estimated by Kaplan Meier method as the probability of being event free at 3 years is reported here. |
Time Frame | 36 months |
Outcome Measure Data
Analysis Population Description |
---|
All patients who received a dose of study treatment. |
Arm/Group Title | Ixabepilone/Cyclophosphamide |
---|---|
Arm/Group Description | Systemic Therapy followed by surgery and possible radiation therapy Ixabepilone: 40 mg/m2 IV infusion over 3 hours on day 1 of a 21 day cycle for 6 cycles Cyclophosphamide: 600 mg/m2 IV infusion per institutional guidelines on day 1 of a 21 day cycle for 6 cycles |
Measure Participants | 168 |
Number [percentage of participants] |
90
53.6%
|
Title | Disease Free Survival |
---|---|
Description | Defined as the time between Day 1 Cycle 1, and date of first documented recurrence, initiation of additional chemotherapy, or death. |
Time Frame | 36 Months |
Outcome Measure Data
Analysis Population Description |
---|
All patients who received a dose of study treatment. |
Arm/Group Title | Ixabepilone/Cyclophosphamide |
---|---|
Arm/Group Description | Ixabepilone: 40 mg/m2 via intraveous (IV) infusion over 3 hours Cyclophosphamide: 600 mg/m2 via IV infusion per institutional guidelines |
Measure Participants | 168 |
Median (95% Confidence Interval) [months] |
NA
|
Adverse Events
Time Frame | ||
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Ixabepilone/Cyclophosphamide | |
Arm/Group Description | All patients who received a dose of study treatment | |
All Cause Mortality |
||
Ixabepilone/Cyclophosphamide | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Ixabepilone/Cyclophosphamide | ||
Affected / at Risk (%) | # Events | |
Total | 6/168 (3.6%) | |
Blood and lymphatic system disorders | ||
FEBRILE NEUTROPENIA | 3/168 (1.8%) | 3 |
Gastrointestinal disorders | ||
ENTERITIS | 1/168 (0.6%) | 1 |
Nervous system disorders | ||
PERIPHERAL NEUROPATHY | 2/168 (1.2%) | 2 |
Psychiatric disorders | ||
DEPRESSION | 1/168 (0.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||
Ixabepilone/Cyclophosphamide | ||
Affected / at Risk (%) | # Events | |
Total | 167/168 (99.4%) | |
Blood and lymphatic system disorders | ||
ANEMIA | 118/168 (70.2%) | 430 |
FEBRILE NEUTROPENIA | 12/168 (7.1%) | 15 |
LEUKOPENIA | 128/168 (76.2%) | 457 |
NEUTROPENIA | 127/168 (75.6%) | 457 |
THROMBOCYTOPENIA | 56/168 (33.3%) | 136 |
Gastrointestinal disorders | ||
ABDOMINAL PAIN | 14/168 (8.3%) | 29 |
CONSTIPATION | 60/168 (35.7%) | 175 |
DIARRHEA | 60/168 (35.7%) | 127 |
DYSPEPSIA | 32/168 (19%) | 88 |
MUCOSITIS | 17/168 (10.1%) | 31 |
NAUSEA | 102/168 (60.7%) | 297 |
VOMITING | 32/168 (19%) | 54 |
General disorders | ||
CHEST PAIN | 9/168 (5.4%) | 16 |
EDEMA | 14/168 (8.3%) | 32 |
FATIGUE | 136/168 (81%) | 547 |
FEVER | 16/168 (9.5%) | 18 |
PAIN | 13/168 (7.7%) | 23 |
Pain | 21/168 (12.5%) | 37 |
Immune system disorders | ||
ALLERGIC REACTION | 10/168 (6%) | 10 |
Infections and infestations | ||
INFECTION | 13/168 (7.7%) | 18 |
Investigations | ||
WEIGHT LOSS | 11/168 (6.5%) | 22 |
Metabolism and nutrition disorders | ||
ANOREXIA | 41/168 (24.4%) | 92 |
DEHYDRATION | 10/168 (6%) | 12 |
HYPERGLYCEMIA | 14/168 (8.3%) | 31 |
Musculoskeletal and connective tissue disorders | ||
ARTHRALGIA | 87/168 (51.8%) | 290 |
ASTHENIA | 17/168 (10.1%) | 30 |
BACK PAIN | 18/168 (10.7%) | 34 |
BONE PAIN | 16/168 (9.5%) | 26 |
MYALGIA | 55/168 (32.7%) | 168 |
PAIN IN EXTREMITY | 40/168 (23.8%) | 96 |
Nervous system disorders | ||
DIZZINESS | 23/168 (13.7%) | 41 |
HEADACHE | 38/168 (22.6%) | 95 |
PARESTHESIA | 13/168 (7.7%) | 34 |
PERIPHERAL NEUROPATHY | 117/168 (69.6%) | 399 |
TASTE ALTERATION | 35/168 (20.8%) | 122 |
Psychiatric disorders | ||
ANXIETY | 25/168 (14.9%) | 79 |
DEPRESSION | 17/168 (10.1%) | 40 |
INSOMNIA | 48/168 (28.6%) | 145 |
Reproductive system and breast disorders | ||
BREAST PAIN | 15/168 (8.9%) | 34 |
Respiratory, thoracic and mediastinal disorders | ||
ALLERGIC RHINITIS | 15/168 (8.9%) | 38 |
COUGH | 35/168 (20.8%) | 58 |
DYSPNEA | 26/168 (15.5%) | 39 |
SORE THROAT | 10/168 (6%) | 11 |
UPPER RESPIRATORY INFECTION | 11/168 (6.5%) | 16 |
Skin and subcutaneous tissue disorders | ||
ALOPECIA | 100/168 (59.5%) | 390 |
NAIL CHANGES | 12/168 (7.1%) | 27 |
PRURITUS | 11/168 (6.5%) | 22 |
RASH | 29/168 (17.3%) | 53 |
Vascular disorders | ||
HOT FLASHES | 30/168 (17.9%) | 79 |
HYPERTENSION | 13/168 (7.7%) | 28 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from the date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish results until 18 mos. after the trial has been completed at all sites.
Results Point of Contact
Name/Title | John D. Hainsworth, MD |
---|---|
Organization | Sarah Cannon Research Institute |
Phone | 1-877-691-7274 |
asksarah@scresearch.net |
- SCRI BRE 133