Fulvestrant with or without Ganetespib in Treating Patients with Hormone-Receptor Positive, Advanced or Metastatic Breast Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• Participants must have histologically confirmed invasive breast cancer that is metastatic or unresectable locally advanced; histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer
• Estrogen and/or progesterone receptor positive breast cancer, as determined by pathology from either primary or metastatic site(s); central confirmation is not required
• HER2 negative, defined as 0-1+ by immunohistochemistry or FISH-negative (ratio < 2.2); central confirmation is not required
• Postmenopausal women are eligible; postmenopausal is defined as any of the following: * Age > 60 years * Age > 45 with intact uterus and amenorrhea for 12 months or more * Follicle stimulating hormone (FSH) levels within postmenopausal range according the ranges established by the testing facility * Premenopausal women who have been on a gonadotropin-releasing hormone (GnRH) agonist for at least 3 consecutive months prior to study entry are eligible; women in this group MUST remain on the GnRH agonist for the duration of protocol treatment * Status-post bilateral oophorectomy after adequate healing post-surgery
• Women and men, age >= 18 years of age
• Measurable disease is required; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan; bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses identified by physical exam that are not measurable by reproducible imaging techniques, and cystic lesions are all considered nonmeasurable; as of 4/30/14, the evaluable/non-measurable cohort has been filled and only patients with measurable disease are allowed moving forward; prior to 4/30/14, up to 20% of patients entered on this trial (i.e. 14 patients) were entered with evaluable but nonmeasurable disease
• Endocrine resistant breast cancer, defined as either: * Relapsed while on adjuvant endocrine therapy or within 1 year of completion of adjuvant endocrine therapy or * Progression through at least one line of endocrine therapy for metastatic or locally advanced breast cancer; there is no limit on the number of prior endocrine therapies received
• Patients may have received up to one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer
• Patients may have initiated bisphosphonate therapy prior to start of protocol therapy; bisphosphonate therapy may continue during protocol treatment; such patients will have bone lesions considered evaluable for progression
• Patients must be at least 2 weeks from prior chemotherapy or radiotherapy, or any investigational drug product with adequate recovery of toxicity to baseline, or grade =< 1, with the exception of alopecia and hot flashes; there is no washout period for prior endocrine therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Availability of a tissue block from initial breast cancer diagnosis and/or metastatic recurrence; if a tissue block is not available, 10-20 unstained slides may be provided as an alternative; if unstained slides will be provided, they should not be sent until specifically requested by the Dana-Farber Cancer Institute (DFCI) study coordinator
• For patients with biopsy-accessible disease, patients must be willing to undergo a required on-treatment research biopsy; this biopsy will occur on cycle 2 day 9; * Biopsies may be done with local anesthesia or intravenous conscious sedation, according to standard institutional guidelines * Research biopsies requiring general anesthesia are not allowed on this protocol unless a biopsy is being obtained simultaneously for clinical reasons, in the judgment of the patients’ treating physician * Patients who undergo an attempted on-treatment research biopsy and in whom inadequate tissue is obtained are still eligible to continue protocol therapy; they will not be required to undergo a repeat biopsy attempt
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin (Hgb) >= 9 mg/dL (which may be post transfusion)
• Total bilirubin < 1.5 X institutional upper limit of normal (patients with documented Gilbert’s disease are allowed total bilirubin up to 3 X upper limit of normal [ULN])
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of if no liver metastases; and < 5 X institutional upper limit if liver metastases are present
• Creatinine =< 2 X institutional upper limit of normal
• Adequate IV access
• Fulvestrant is contraindicated in pregnancy (category D); the effects of ganetespib on the developing human fetus are unknown. For these reasons, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; premenopausal women who have been on a GnRH agonist for at least 3 consecutive months prior to study entry are eligible; women in this group MUST remain on the GnRH agonist for the duration of protocol treatment; such patients should be counseled that GnRH agonists alone may not be adequate contraception and that adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation should be employed
• Ability to understand and the willingness to sign a written informed consent document
• Patients on therapeutic dose anti-coagulation with warfarin, low molecular weight heparin (LMWH), or other anti-coagulants will be allowed to participate in the study; however, the anti-coagulants should be held pre- and post- research biopsy (when applicable) as per institutional standards; the risks of a temporary hold of anti-coagulation should be carefully considered and explained to the patient as part of the informed consent process; if it is not felt to be in the best interest of the patient to have anti-coagulation held, the patient may still enter the study, but should not undergo a research biopsy

Exclusion Criteria

• Prior treatment with an HSP90 inhibitor (e.g. 17-AAG, IPI-504, AUY922, STA-9090 [ganetespib] etc.)
• Prior treatment with fulvestrant
• Participants may not be receiving any other investigational agents
• Concurrent treatment with commercial agents or other agents with the intent to treat the participant’s malignancy, including endocrine therapy, chemotherapy, and/or targeted therapy, with the exception of bisphosphonates and GnRH agonists
• Untreated or progressive brain metastases; patients with treated brain metastases not requiring chronic corticosteroids for symptom control are eligible
• Pending visceral crisis, in the opinion of the treating investigator
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to fulvestrant or ganetespib
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Serious cardiac illness, defined as follows: * Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker * Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a class Ia antiarrhythmic drug (eg, quinidine, procainamide, disopyramide) or class III antiarrhythmic drug (e.g. sotalol, amiodarone, dofetilide); use of other antiarrhythmic drugs is permissible * Use of medications that have been linked to the occurrence of torsades de pointes; investigators should note that Zofran (ondansetron) has been linked to corrected QT (QTc) prolongation and the occurrence of torsades de pointes; therefore it should not be used in patients being treated with ganetespib; the use of all other serotonin 5 HT3 antagonists is acceptable (e.g., palonosetron, granisetron, tropisetron) * Second-or third degree atrioventricular block (AV block) unless treated with a permanent pacemaker * Complete left bundle branch block (LBBB) * History of long QT syndrome or a family member with this condition
• Corrected QTc > 470 msec; the corrected QTc may be corrected using either Bazett’s or Fridericia’s formula; in general Fridericia corrected QT interval (QTcf) is the preferred correction method
• Pregnant women are excluded from this study because fulvestrant is contraindicated in pregnancy (category D) and ganetespib is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with fulvestrant or ganetespib, breastfeeding should be discontinued if the mother is treated on either arm of the trial
• Individuals with the following cancers are eligible if diagnosed and definitively treated prior to study entry: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin; individuals with a history of other malignancy are ineligible unless disease-free for at least 3 years or deemed by the investigator to be at low risk (< 10%) for recurrence of that malignancy