Fulvestrant With or Without Ganetespib in HR+ Breast Cancer

• Number of participants with adverse events after treatment with Ganetespib Plus Fulvestrant [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  To describe the grade and frequency of adverse events according to CTCAE v 4.0 in patients treated with ganetespib in combination with fulvestrant and in patients treated with fulvestrant alone
• Objective Response Rate Between Arms by RECIST [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To describe and compare the objective response rate by RECIST 1.1 between arms, limited to patients with measurable disease at baseline
• Comparison of Clinical Benefit Rate Between Arms [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To describe and compare the clinical benefit rate, defined as complete response (CR)+partial response (PR)+stable disease >/= 6 months between arms
• Comparison of Overall Survival Between Arms [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  To describe and compare overall survival (OS) between arms

Ganetespib is a drug that may stop cancer cells from growing. This drug has been used in other research studies and laboratory experiments. It has also been studied in phase I trials, where the appropriate dosing has been determined. Ganetespib is considered an "HSP90 inhibitor". By blocking HSP90, ganetespib is thought to reduce the ability of cancer cells to become resistant to treatment.

Fulvestrant is a hormonal therapy that works by attaching to estrogen receptors. In doing so, it can block the effect of estrogen on cancer cells. In addition, fulvestrant causes a decrease in the number of estrogen receptors. Fulvestrant is a drug that is approved by the FDA for treatment of metastatic, hormone receptor positive breast cancer, based upon the results of phase III clinical trials.

In the laboratory, adding ganetespib to fulvestrant appears to improve its effectiveness. It is not known whether this is true in humans. In this research study, we are evaluating the effect of the addition of ganetespib to fulvestrant in participants with hormone receptor-positive, metastatic breast cancer.

Because no one knows which of the study options is best, you will be "randomized" into one of the study groups: Arm A: Fulvestrant or Arm B: Fulvestrant plus Ganetespib. You will have a one-third chance of being placed in Arm A and a two-thirds chance of being placed in Arm B.

If you are initially placed in Arm A but your disease progresses, you will have the option of receiving the combination of fulvestrant plus ganetespib as part of Arm C.

You will undergo the following procedures during the research study: study drug(s), blood tests, clinical exams and scans/imaging tests.

• Drug: Fulvestrant
  injection on day 1 and 15 of cycle 1, day 1 of cycle 2 and each subsequent cycle
• Drug: Ganetespib
  Intravenous, on days 1, 8 and 15 eof each cycle

• Active Comparator: Fulvestrant
  Fulvestrant
  Intervention: Drug: Fulvestrant
• Active Comparator: Fulvestrant+Ganetespib
  Fulvestrant and Ganetespib
  Interventions:

  • Drug: Fulvestrant
  • Drug: Ganetespib
• Active Comparator: Cross-Over
  Fulvestrant and Ganetespib for participants originally assigned to arm A
  Interventions:

  • Drug: Fulvestrant
  • Drug: Ganetespib

Inclusion Criteria:

• Histologically confirmed invasive breast cancer that is metastatic or unresectable locally advanced
• Estrogen and/or progesterone receptor positive breast cancer
• HER2 negative
• Measurable or evaluable disease is allowed
• Endocrine resistant breast cancer
• May have received up to one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer
• May have initiated bisphosphonate therapy prior to start of protocol therapy
• Must be at least 2 weeks from prior chemotherapy or radiotherapy
• ECOG performance status of 0 or 1
• Availability of tissue block from initial breast cancer diagnosis and/or metastatic recurrence
• For subjects with biopsy-accessible disease, must be willing to undergo a required on-treatment research biopsy
• Adequate IV access

Exclusion Criteria:

• Pregnant or breastfeeding
• Prior treatment with HSP90 inhibitor
• Prior treatment with fulvestrant
• Concurrent treatment with commercial agents or other agents with the intent to treat the participant's malignancy
• Untreated or progressive brain metastases
• 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
• Other malignancies within 3 years