Neo-adjuvant Therapy With Anastrozole Plus Pazopanib in Stage II and III ER+ Breast Cancer
Condition: Estrogen Receptor-positive Breast Cancer; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Male Breast Cancer; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer
MeSH terms: Breast Neoplasms; Breast Neoplasms, Male
Intervention: anastrozole; pazopanib hydrochloride; therapeutic conventional surgery
Intervention description: Given PO; Given PO; Undergo definitive surgery
Intervention MeSH terms: Anastrozole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well giving pazopanib hydrochloride and anastrozole before
      surgery works in treating patients with stage II-III estrogen receptor-positive breast
      cancer. Pazopanib hydrochloride and anastrozole may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth. Giving pazopanib hydrochloride and
      anastrozole together before surgery may make the tumor smaller and reduce the amount of
      normal cells that have to be removed
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must provide written informed consent prior to performance of study-specific
             procedures or assessments, and must be willing to comply with treatment and follow-up;
             procedures conducted as part of the subject's routine clinical management (e.g., blood
             count, imaging study) and obtained prior to signing of informed consent may be
             utilized for screening or baseline purposes provided these procedures are within the
             protocol determined screening or baseline timeframes, and equivalent to the
             specifications in the protocol; also note, a written waiver/approval from the
             Investigator/Sponsor is still required

          -  Histologically confirmed diagnosis of estrogen receptor-positive (ER+), HER2 negative
             breast cancer, with clinical stage II or III disease

          -  Stage IIA T0-1 N1 M0, T2 N0 M0, OR

          -  Stage IIB T2 N1 M0, T3 N0 M0 OR

          -  Stage IIIA T0-2 N2 M0, T3 N1-2 M0, OR

          -  Stage IIIB T4 N0-2 M0

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  No evidence of distant metastatic disease

          -  Baseline Oncotype DX score of 29 or lower; patients with known Oncotype DX recurrence
             score (RS) of 30 or greater are not eligible

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Hemoglobina >= 10 g/dL (5.6 mmol/L); subjects may not have had a transfusion within 7
             days of screening assessment

          -  Platelets >= 100 x 10^9/L

          -  Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 x upper limit of
             normal (ULN); subjects receiving anticoagulant therapy are eligible if their INR is
             stable and within the recommended range for the desired level of anticoagulation

          -  Activated partial thromboplastin time (aPTT) =< 1.2 x ULN

          -  Total bilirubin =< 1.5 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN;
             concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN is not permitted

          -  Serum creatinine =< 1.5 mg/dL (133 umol/L) or, if > 1.5 mg/dL: calculated creatinine
             clearance (CLCR) >= 50 mL/min

          -  Urine protein to creatinine ratio (UPC) < 1; if UPC >= 1, then a 24-hour urine protein
             must be assessed; subjects must have a 24-hour urine protein value < 1 g to be
             eligible

          -  A female is eligible to enter and participate in this study if she is:

          -  Is post-menopausal

          -  Subjects not using hormone replacement therapy (HRT) must have experienced total
             cessation of menses for >= 1 year and be greater than 45 years in age, OR, in
             questionable cases, have follicle stimulating hormone (FSH) value > 40 mIU/mL and an
             estradiol value < 40 pg/mL (< 140 pmol/L)

          -  Subjects using HRT must have experienced total cessation of menses for >= 1 year and
             be greater than 45 years of age OR have had documented evidence of menopause based on
             FSH and estradiol concentrations prior to initiation of HRT; patients will be required
             to be off of HRT for at least 2 weeks prior to initiating therapy

        Exclusion Criteria:

          -  Prior malignancy; note: subjects who have had another malignancy and have been
             disease-free for >= 5 years, or subjects with a history of completely resected
             non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible

          -  Known distant metastases at any site; history or clinical evidence of central nervous
             system (CNS) metastases or leptomeningeal carcinomatosis

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including, but not limited to:

          -  Active peptic ulcer disease

          -  Known intraluminal metastatic lesion/s with risk of bleeding

          -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or

          -  Other gastrointestinal conditions with increased risk of perforation

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 28 days of registration to the study; clinically significant gastrointestinal
             abnormalities that may affect absorption of investigational product including, but not
             limited to:

          -  Malabsorption syndrome

          -  Major resection of the stomach or small bowel

          -  Presence of uncontrolled infection

          -  Corrected QT interval (QTc) > 480 msecs using Bazett's formula

          -  History of any one or more of the following cardiovascular conditions within 6 months
             of registration on the study:

          -  Cardiac angioplasty or stenting

          -  Myocardial infarction

          -  Unstable angina

          -  Coronary artery bypass graft surgery

          -  Symptomatic peripheral vascular disease

          -  Class III or IV congestive heart failure, as defined by the New York Heart Association
             (NYHA)

          -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140
             mmHg or diastolic blood pressure (DBP) of >= 90 mm Hg]; note: initiation of adjustment
             of antihypertensive medication(s) is permitted prior to study entry

          -  History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
             of registration on the study; note: subjects with recent DVT who have been treated
             with therapeutic anti-coagulating agents for at least 6 weeks of registration to the
             study are eligible

          -  Prior major surgery or trauma within 28 days of registration on the study prior to
             first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer
             (procedures such as catheter placement not considered to be major)

          -  Evidence of active bleeding or bleeding diathesis

          -  Hemoptysis within 8 weeks of registration to the study

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with subject's safety, provision of informed consent, or compliance to
             study procedures

          -  Treatment with any of the following anti-cancer therapies for the current diagnosis of
             stage 2-3 estrogen positive breast carcinoma:

          -  Radiation therapy, surgery or tumor embolization within 14 days prior to first dose of
             pazopanib OR

          -  Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal
             therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the
             first dose of pazopanib

          -  Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
             progressing in severity, except alopecia

          -  Concomitant anti-cancer therapies are not permitted

          -  Patients may not be receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Pazopanib or Anastrozole used in the study

          -  Concomitant use of medications or substances that are inhibitors or inducers of strong
             CYP3A4 inhibitors are ineligible

          -  Concomitant: the concomitant use of strong CYP3A4 inhibitors (e.g. ketoconazole,
             ritonavir, clarithromycin) may increase pazopanib concentrations and should be
             avoided; if coadministration of a strong CYP3A4 inhibitor is warranted, reduce the
             dose of pazopanib to 400 mg; further dose reductions may be needed if adverse effects
             occur during therapy; this dose is predicted to adjust the pazopanib AUC to the range
             observed without inhibitors; however, there are no clinical data with this dose
             adjustment in patients receiving strong CYP3A4 inhibitors; grapefruit juice should be
             avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of
             pazopanib

          -  Concomitant strong CYP3A4 inducer: the concomitant use of strong CYP3A4 inducers (e.g.
             rifampin) may decrease pazopanib concentrations and should be avoided