A Pilot Preoperative Trial of Ganetespib With Paclitaxel for Triple-Negative Breast Cancer

STUDY OBJECTIVES

Primary:

• To determine tumor GR, AR, JAK and other Hsp90 client protein expression before and after
two weeks of ganetespib monotherapy

Secondary:

- To determine the pathological Complete Response (pCR) rate associated with weekly
treatment of ganetespib plus paclitaxel followed by the combination treatment of
doxorubicin plus cyclophosphamide

- To characterize the toxicity of study treatment

Inclusion Criteria:

- Invasive carcinoma of the breast

- ER negative and PR negative tumors defined as < 1% of tumor nuclei that are
immunoreactive for ER and PR

- HER2 non-overexpressing status documented as:

- FISH ratio of less than 2.0, OR

- IHC staining of 0 or 1+

- No evidence of distant metastatic disease. Patients with regional lymph node
involvement are eligible.

- >18 years old

- Female

- No prior treatment for the disease under study

- No prior treatment within 5 years for any other cancer including chemotherapy,
surgery (except for diagnostic biopsy), radiotherapy, hormonal therapy, or
investigational agents, unless curative treatment of non-melanoma skin-cancer or
in-situ cancer

- Able to understand and sign an informed consent (or have a legal representative who
is able to do so)

- Clinically or radiologically measureable disease in the breast after diagnostic
biopsy, defined as longest diameter greater than or equal to 2cm

- Willing to undergo three mandatory core biopsies after diagnosis to obtain tissue for
biologic expression profiling.

- An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1

- Adequate bone marrow reserves as evidenced by:

- Leukocytes > 3,000/μL

- Absolute neutrophil count (ANC) > 1,500/μL without the use of hematopoietic growth
factors,

- Platelet count > 100,000/μL, and

- Hemoglobin > 9 g/dL

- Adequate hepatic function as evidenced by:

- Serum total bilirubin within institutional normal limits

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline
phosphatase less than or equal to 2.5 × ULN

- Adequate renal function as evidenced by a serum creatinine within ULN or creatinine
clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional
normal

- Eligible for treatment with paclitaxel, doxorubicin and cyclophosphamide

- If of childbearing potential, are willing to abstain from sexual intercourse or to
use an effective form of contraception (e.g., a double-barrier method) during the
study and for 90 days following the last dose of ganetespib

Exclusion Criteria:

- • Patients may not be receiving any other investigational agents.

- Patients may not have a known hypersensitivity to any of the components of
ganetespib

- Patients may not have a history of severe allergic reactions to paclitaxel or
other drugs formulated in Cremaphor® EL.

- Patients with a QTc > 470 ms, a family history of long QT Syndrome, and those on
medications known to cause Torsades de Pointes will be excluded from the study.

- Patients may not have an uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.

- Patients may not have New York Heart Association (NYHA) Class III or IV
congestive heart failure or left ventricular ejection fraction (LVEF) < 50%.

- As patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study.

- Patients may not have a need for chronic systemic steroid therapy

- Patients may not be pregnant or breastfeeding