Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib
Condition: Breast Cancer; Breast Neoplasm
MeSH terms: Breast Neoplasms
Intervention: Pazopanib
Intervention description: Oral, 800mg tablet daily per cycle
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced; Breast; Cancer; Hormone Resistance; Pazopanib; anastrozole; arimidex; letrozole; femara

Summary:

      The purpose of this study is to evaluate the clinical benefit rate at 12 weeks from the
      addition of pazopanib to a non-steroidal aromatase inhibitor (NSAI) (letrozole or
      anastrozole) in patients with hormone receptor positive advanced breast cancer progressing on
      the same NSAI hormone therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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 a part of routine clinical management of the subject (e.g.,
             blood count, imaging study) and obtained prior to signed informed consent may be
             utilized for Screening or Baseline purposes provided these tests are obtained as
             specified in the protocol).

          2. Subjects must have measurable or evaluable disease. Disease sites that are evaluable
             for progression but not measurable per RECIST guidelines include:

               -  Bone lesions

               -  Previously irradiated lesions

               -  Cutaneous manifestations (non-discreet lesions only)

          3. Age ≥ 18 years.

          4. Postmenopausal women defined by one of the criteria:

               -  No spontaneous menses for at least 12 months if the subject is ≥ 50 years old;

               -  Amenorrheic for at least 12 months if the subject is < 50 years old, with serum
                  estradiol within the institutional postmenopausal range;

               -  Bilateral oophorectomy;

               -  If prior hysterectomy but intact ovaries, must be ≥ 55 years old, or have serum
                  estradiol within the postmenopausal range;

               -  If premenopausal, must be on a GnRH agonist (leuprolide or goserelin) with serum
                  estradiol levels within the institutional postmenopausal range.

          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.

          6. Histologically or cytologically confirmed estrogen receptor (ER) and/or progesterone
             receptor (PgR) positive carcinoma of the breast with unresectable, locally advanced
             and/or metastatic (AJCC Stage IV) disease.

          7. Subjects must have received prior hormonal therapy for the treatment of breast cancer
             as follows:

               -  Progression must be documented while taking a nonsteroidal aromatase inhibitor
                  including anastrozole or letrozole.

               -  No more than 2 prior hormonal therapies for metastatic disease.

               -  If hormonal therapy was administered in the adjuvant setting, subjects must have
                  received therapy for at least 6 months prior to developing metastatic disease.

             Note: A regimen of sequential tamoxifen/AI in the adjuvant setting is considered to be
             one therapy

             - If hormonal therapy was administered in the metastatic setting, subjects must have
             received therapy for at least 3 months prior to progression

          8. Subjects whose tumors overexpress ErbB2 are eligible provided that they have
             progressed following therapy which included trastuzumab and/or lapatinib.

             Note for prior lapatinib: Subjects must have completed therapy with lapatinib at least
             7 days prior to the first dose of study drug.

             Note for prior trastuzumab: Subjects who received Q3 weekly, Q2 weekly or Q1 weekly
             must have completed therapy with trastuzumab at least 3 weeks, 2 weeks or 1 week,
             respectively, prior to the first dose of study drug.

          9. Adequate hematologic and hepatic function as defined in Protocol Table 1

         10. Subjects must have discontinued hormone replacement therapy (HRT) (e.g., conjugated
             estrogens tablets, USP or premarin), at least 28 days prior to receiving the first
             dose of randomized therapy.

         11. Radiotherapy prior to initiation of therapy is allowed to a limited area (e.g.,
             palliative treatment for painful bone metastases), if it is not the sole site of
             disease. Subjects must have completed treatment at least one week prior to starting
             study drugs, and must have recovered from all treatment-related toxicities.

         12. Bisphosphonate or RANK ligand inhibitor therapy for bone metastases is allowed.
             Prophylactic use of bisphosphonates in subjects without bone disease, except for the
             treatment of osteoporosis, is not permitted;

         13. Ability to swallow and retain oral medication.

        Exclusion Criteria:

          1. Prior use of pazopanib

          2. Premenopausal levels of estradiol, or ongoing menses (see definitions of menopause
             above).

          3. Known central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
             Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance
             imaging [MRI]) is required only if the subject has clinical findings suggestive of CNS
             metastasis.

          4. History of another active 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.

          5. Clinically significant gastrointestinal abnormalities which might interfere with oral
             dosing, including, but not limited to:

               -  Malabsorption syndrome

               -  Major resection of the stomach or small bowel that could affect the absorption of
                  study drug

               -  Inflammatory bowel disease

               -  Ulcerative colitis, or other gastrointestinal conditions with increased risk of
                  perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal
                  abscess within 28 days prior to beginning study treatment

          6. Presence of uncontrolled infection.

          7. Prolongation of corrected QT interval (QTc) >480msecs.

          8. History of any one or more of the following cardiovascular conditions within the past
             6 months:

               -  Angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Coronary artery by-pass graft surgery

               -  Symptomatic peripheral vascular disease

          9. Class II, III or IV congestive heart failure, as defined by the New York Heart
             Association (NYHA).

         10. Use of an investigational agent, including an investigational anti-cancer agent,
             within 14 days prior to the first dose of study drug.

         11. Prior use of an investigational drug that targets VEGF or VEGF receptors.

         12. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
             progressing in severity.

         13. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥140mmHg
             or diastolic blood pressure (DBP) of ≥ 90mmHg).

             Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
             study entry. Blood pressure must be re-assessed prior to start of study therapy. The
             mean SBP/DBP values must be <140/90mmHg (OR 150/90mmHg, if this criterion is approved
             by Safety Review Team) in order for a subject to be eligible for the study.

         14. History of cerebrovascular accident (CVA), pulmonary embolism or untreated deep venous
             thrombosis (DVT) within the past 6 months.

             Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant
             agents for at least 6 weeks are eligible.

         15. Major surgery or trauma within 28 days prior to first dose of study drug and/or
             presence of any non-healing wound, fracture, or ulcer not related to cancer
             (procedures such as catheter placement not considered to be major).

         16. Evidence of active bleeding or bleeding diathesis.

         17. 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