Treatment With Pazopanib for Neoadjuvant Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the treatment of a doxorubicin in combination with cyclophosphamide followed by a combination of pazopanib in combination with paclitaxel prior to surgery results in a pathological complete response in females with breast cancer.

Detailed Description
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This is a phase II non-randomized, multi-center study aimed to evaluate the efficacy and safety of the combination of pazopanib and paclitaxel following treatment with cyclophosphamide and doxorubicin for the treatment of neoadjuvant breast cancer. Patients will receive standard doses of AC every 21 days for 4 cycles. This will be followed by weekly paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 every 28 days for 4 cycles given concurrently with pazopanib 800 mg PO daily starting with the first paclitaxel dose and continuing until 7 days before surgery. Clinical complete response rate will be determined by tumor assessments performed by palpation at two time points: following AC (before paclitaxel/pazopanib begins) and 2-4 weeks following the last dose of paclitaxel (before surgery). Following recovery from preoperative therapy, patients will undergo the clinically-indicated surgery. Pazopanib will resume 4-6 weeks after surgery and continue daily for 6 months of postoperative pazopanib therapy.

Official Title
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A Phase II Clinical Trial of Four Cycles of Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel Given Concurrently With Pazopanib as Neoadjuvant Therapy Followed by Postoperative Pazopanib for Women With Locally Advanced Breast Cancer

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: doxorubicin + cyclophosphamide
* Drug: paclitaxel + pazopanib
* Procedure: surgery
* Drug: pazopanib monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must have consented to participate and must have signed and dated an appropriate IRB-approved consent form that conforms to federal and institutional guidelines for the study treatment and submission of tumor and blood samples required for the FB-6 correlative science studies The ECOG performance status must be 0 or 1 Patients must have the ability to swallow oral medication. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or limited incisional biopsy. Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed. (Patients are eligible with either hormone receptor-positive or hormone receptor-negative tumors.) Patients must have clinical stage IIIA, IIIB, or IIIC disease with a mass in the breast or axilla measuring at least 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in which case measurable disease by physical exam is not required. Adequate organ function LVEF assessment by 2-D echocardiogram or MUGA scan performed within 3 months prior to study entry must be greater or equal to 50% regardless of the facility's LLN. ECG performed within 4 weeks before study entry must demonstrate a QTc interval that is less than or equal to 0.47 seconds. The TSH level must be within normal limits for the laboratory. Exclusion Criteria: Tumor that has been determined to be HER2-positive by immunohistochemistry (3+) or by FISH or CISH (positive for gene amplification), or has been determined to be HER2-equivocal and the investigator plans to administer trastuzumab or other targeted therapy. FNA alone to diagnose the primary breast cancer. Excisional biopsy or lumpectomy performed prior to study entry. Surgical axillary staging procedure prior to study entry. Definitive clinical or radiologic evidence of metastatic disease. History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with RT. Contralateral invasive breast cancer at any time. Non-breast malignancies unless the patient is considered to be disease-free for 5 or more years prior to study entry and is deemed by her physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin. Requirement for chronic use of any of the prohibited medications or substances Previous therapy with anthracyclines, taxanes, or pazopanib for any malignancy. Treatment including RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to study entry. Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other SERM. Any sex hormonal therapy, e.g., birth control pills and ovarian hormone replacement therapy History of hepatitis B or C. Symptomatic pancreatitis or asymptomatic greater or equal to grade 2 elevation of amylase or lipase as per NCI CTCAE v3.0. History of documented pancreatitis. Uncontrolled hypertension defined as systolic BP greater than 140 mmHg or diastolic BP greater greater than 90 mmHg, with or without anti-hypertensive medication. History of hypertensive crisis or hypertensive encephalopathy. Cardiac disease that would preclude the use of any of the drugs included in the FB-6 treatment regimen. History of TIA or CVA. History of any arterial thrombotic event within 12 months prior to study entry. Pulmonary embolism or DVT within 6 months prior to study entry. Symptomatic peripheral vascular disease. Any significant bleeding within 6 months prior to study entry, exclusive of menorrhagia in premenopausal women. Known bleeding diathesis, coagulopathy, or requirement for therapeutic doses of coumadin. Serious or non-healing wound, skin ulcers, or bone fracture. Gastroduodenal ulcer(s) determined by endoscopy to be active. History of GI perforation, abdominal fistulae, or intra-abdominal abscess. Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal function. Sensory/motor neuropathy greater or equal to grade 2, as defined by the NCI's CTCAE v3.0. Conditions that would prohibit intermittent administration of corticosteroids for paclitaxel premedication. Anticipation of need for major surgical procedures (other than the required breast surgery) during the course of study therapy and for at least 3 months following the last dose of pazopanib. Pregnancy or lactation at the time of study entry. Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up. Known immediate or delayed hypersensitivity reaction to doxorubicin, cyclophosphamide, paclitaxel, pazopanib, or drugs chemically related to pazopanib. Use of any investigational agent within 4 weeks prior to enrollment in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Preoperative Cycles 1-4 Doxorubicin 60 mg/m2 IV over 15 minutes + Cyclophosphamide 600 mg/m2 IV over 30 minutes of Day 1 every 21 days followed by: Cycles 5-8 Paclitaxel 80 mg/m2 IV over 60 minutes (Days 1, 8, and 15) every 28 days in combination with pazopanib (800 mg) PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning on Day 1 of the first paclitaxel cycle Until 7 days before surgery Followed by Surgery Postoperative Pazopanib 800 mg PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning 4-6 weeks after surgery 6 months from first postoperative dose | Drug: doxorubicin + cyclophosphamide<br>* 4 cycles of doxorubicin + cyclophosphamide followed by 4 cycles of paclitaxel + pazopanib.<br>Drug: paclitaxel + pazopanib<br>* 4 cycles of paclitaxel + pazopanib<br>Procedure: surgery<br>* neoadjuvant surgery for breast cancer<br>Drug: pazopanib monotherapy<br>* 6 months of treatment with pazopanib monotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathologic Complete Response (pCR) in the Breast and Nodes | pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after neoadjuvant chemotherapy. | From the start of the study until the time of surgery (average of 221.9 days [standard deviation of 23.65 days] after study entry) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathologic Complete Response (pCR) in the Breast | pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen. | From the start of the study until the time of surgery (average of 221.9 [standard deviation of 23.65 days] days after study entry) | 
| Number of Participants With Clinical Complete Response (cCR) in the Breast and Nodes at the Completion of the Doxorubicin and Cyclophosphamide (AC) Period | cCR was determined by tumor assessments performed by palpation. All clinical response assessments were to be performed by physical examination of the breast and the axilla. cCR was defined as the resolution of all target and non-target lesions identified at Baseline and no new lesions or other signs of disease progression. The criteria to be used for the determination of progressive disease were at the investigator's discretion. | From the start of the study until an average of 86.2 days (standard deviation of 5.76 days) after study entry | 
| Number of Participants With Clinical CR (cCR) in the Breast and Nodes at the Completion of the AC and Weekly Paclitaxel (WP) + Pazopanib Preoperative Periods | cCR was determined by tumor assessments performed by palpation. All clinical response assessments were to be performed by physical examination of the breast and the axilla. cCR was defined as the resolution of all target and non-target lesions identified at Baseline and no new lesions or other signs of disease progression. The criteria to be used for the determination of progressive disease were at the investigator's discretion. | From the start of the study until the preoperative evaluation (an average of 203.0 days [standard deviation of 23.19 days] after study entry) | 
| Invasive Recurrence-free Interval (IRFI) | IRFI was assessed as the time from study entry until the diagnosis of the first invasive local (evidence of invasive/in situ breast cancer [except LCIS] in the ipsilateral breast [IB]/skin of the breast), regional (development of tumor in the ipsilateral [IP] internal mammary, IP supraclavicular, IP infraclavicular, and/or IP axillary nodes, as well as the soft tissue of the IP axilla, following surgery), or distant (evidence of tumor in all areas, with the exception of those described for local and regional recurrence) breast cancer recurrence during the 24 months after study entry. | up to 24 months after study entry | 
| Number of Participants With Cardiac Toxicity (Per Common Terminology Criteria for Adverse Events Version 3) at the Completion of the AC Period | The number of participants with cardiac toxicity was defined as those who had cardiac events of Grades (G) 3 and 4 leftventricular dysfunction (LVD) (CTCAE Version 3.0) and/or who had definite or probable cardiac death. Grade refers to the severity of the AE: G 1, mild AE; G 2, moderate AE; G 3, severe AE; G 4, life-threatening/disabling AE; G 5, death related to the AE. A G3 LVD event is defined as symptomatic congestive heart failure (CHF) responsive to intervention. A G4 event is defined as poorly controlled refractory CHF; ventricular assist device or heart transplant indicated. | From the start of the study until the preoperative evaluation (an average of 86.2 days [standard deviation of 5.76 days] after study entry) | 
| Number of Participants With Cardiac Toxicity (Per CTCAE Version 3) at the Completion of the AC and Weekly Paclitaxel (WP) + Pazopanib Preoperative Periods | The number of participants with cardiac toxicity was defined as those who had cardiac events of Grades (G) 3 and 4 leftventricular dysfunction (LVD) (CTCAE Version 3.0) and/or who had definite or probable cardiac death. Grade refers to the severity of the AE: G 1, mild AE; G 2, moderate AE; G 3, severe AE; G 4, life-threatening/disabling AE; G 5, death related to the AE. A G3 LVD event is defined as symptomatic congestive heart failure (CHF) responsive to intervention. A G4 event is defined as poorly controlled refractory CHF; ventricular assist device or heart transplant indicated. | From the start of the study until the preoperative evaluation (an average of 203.0 days [standard deviation of 23.19 days] after study entry). | 
| Number of Participants With Cardiac Toxicity (Per CTCAE Version 3.0) During the Postoperative Pazopanib Period | The number of participants with cardiac toxicity was defined as those who had cardiac events of Grades (G) 3 and 4 leftventricular dysfunction (LVD) (CTCAE Version 3.0) and/or who had definite or probable cardiac death. Grade refers to the severity of the AE: G 1, mild AE; G 2, moderate AE; G 3, severe AE; G 4, life-threatening/disabling AE; G 5, death related to the AE. A G3 LVD event is defined as symptomatic congestive heart failure (CHF) responsive to intervention. A G4 event is defined as poorly controlled refractory CHF; ventricular assist device or heart transplant indicated. | From the start of the study until the end of the postoperative pazopanib period, which coincides with the start of the end of treatment period (an average of 310.8 days [standard deviation of 85.29 days] after study entry) | 
| Participants With Normal Thyroid Stimulating Hormone (TSH) Levels at Baseline Who Had an Elevated TSH Level at Least Once During the Study and During the Individual Study Periods | The number of participants with normal thyroid function at Baseline who had an elevation in TSH during the study were recorded. TSH elevation was derived based on local laboratory ranges. | up to 24 months after study entry | 
| Number of Participants With the Indicated Radiotherapy-related Complications |  | up to 24 months after study entry | 
| Number of Participants With Recurrence Events | The number of participants with recurrence events during the 24 months after study entry are reported. A recurrence event is defined as invasive local (evidence of invasive/in situ breast cancer [except LCIS] in the ipsilateral breast [IB]/skin of the breast), regional (development of tumor in the ipsilateral [IP] internal mammary, IP supraclavicular, IP infraclavicular, and/or IP axillary nodes, as well as the soft tissue of the IP axilla, following surgery), or distant (evidence of tumor in all areas, with the exception of those described for local and regional recurrence) breast cancer recurrence during the 24 months after study entry. | up to 24 months after study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Breast Cancer, Pazopanib (GW786034), NSABP Foundation, Inc., cyclophosphamide, Paclitaxel, Doxorubicin