Ganetespib, Paclitaxel, Trastuzumab and Pertuzumab for Metastatic Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer

This phase I trial studies the side effects and best dose of ganetespib when given with
paclitaxel, trastuzumab, pertuzumab in treating patients with human epidermal growth factor
receptor 2 positive (HER2+) breast cancer that has spread to other places in the body and
usually cannot be cured or controlled with treatment (advanced) or has returned after a
period of improvement (metastatic). HER2+ describes cancer cells that have too much of a
protein called HER2 on their surface. In normal cells, HER2 helps to control cell growth.
When it is made in larger than normal amounts by cancer cells, the cells may grow more
quickly and be more likely to spread to other parts of the body.

Ganetespib may stop the growth of tumor cells by blocking some of the proteins needed for
cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop
the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Monoclonal antibodies, such as trastuzumab and pertuzumab, bind
to HER2+ cancer cells and may kill them. Giving ganetespib with paclitaxel, trastuzumab, and
pertuzumab may be a better treatment for patients with HER2+ breast cancer.

This phase I study has two parts. During the first part of this study, patients with HER2+
MBC receive trastuzumab in combination with ganetespib and paclitaxel to evaluate the safety,
toxicity and maximum tolerated dose (MTD) of this triplet regimen. There are dose escalations
for ganetespib. Paclitaxel and trastuzumab are administered at standard doses without
escalation. Part 1 is ongoing.

During the second part of this study, pertuzumab at standard dose will be added to the
triplet regimen of ganetespib, paclitaxel and trastuzumab, using the MTD of ganetespib
determined in part one. The MTD of ganetespib and the safety of the four-drug regimen will be
evaluated. The MTD for ganetespib in combination with paclitaxel and trastuzumab is 150
mg/m2.

Inclusion Criteria:

- Pathologically confirmed diagnosis of breast cancer (central confirmation is not
required)

- Patients must be at least 18 years of age

- Metastatic or advanced breast cancer that is evaluable OR metastatic or advanced
breast cancer that is measurable for response as per Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Life expectancy of at least 3 months as assessed by the investigator

- Patients with estrogen receptor (ER)+ breast cancer must have received prior treatment
with at least one hormone therapy

- Absolute neutrophil count ≥ 1,500 cells/uL

- Platelets ≥ 100,000/uL

- Hemoglobin ≥ 9.0g/dL

- Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

- Albumin ≥ 3.0 g/dL

- Adequate renal function as defined by a serum creatinine ≤ 1.5 x ULN

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures

- Female subjects of childbearing potential and males must agree to use adequate
contraception (e.g., hormonal or barrier method of birth control; abstinence) for the
duration of study treatment

- Female subjects of childbearing age must have a negative serum pregnancy test at study
entry

- Patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome
(AIDS) are allowed on study if they have an undetectable viral load, cluster of
differentiation (CD)4 > 300 and are on a stable highly active antiretroviral therapy
(HAART) regimen for 1 month prior to study enrollment

- Patients are required to have HER2+ breast cancer defined as a fluorescent in situ
hybridization (FISH)- ratio of >= 2.0 or immunohistochemistry (IHC) 3+

- Patients for the triplet regimen (ganetespib, paclitaxel, trastuzumab):

- Any number of prior chemotherapies or biological therapies are allowed, patients
are required to have prior treatment with pertuzumab and ado-trastuzumab
emtansine with the exceptions listed below:

- Metastatic patients who have not received prior pertuzumab are eligible if:
heavily pretreated prior to Food and Drug Administration (FDA) approval of
pertuzumab (08-Jun-2012) for first line treatment of HER2+ MBC

- Metastatic patients who have not received ado-trastuzumab emtansine are
eligible if: heavily pretreated prior to FDA approval of ado-trastuzumab
emtansine (22-Feb-2013) for the treatment of patients with HER2+ MBC who
previously received trastuzumab and a taxane, separately or in combination

- Patients for the triplet regimen + pertuzumab:

- Prior hormonal therapy for ER+ and/or PR+ HER2+ disease in the metastatic setting
is allowed.

- Prior T-DM1 in the metastatic setting is allowed if patients have progressed
within 6 months after treatment for early-stage disease.

- No prior history of intolerance or hypersensitivity to trastuzumab and/or adverse
events related to trastuzumab, murine proteins, or any of the excipients that resulted
in trastuzumab being permanently discontinued

Exclusion Criteria:

- Fewer than 21 days since last anti-tumor therapy, including chemotherapy, biologic
except trastuzumab, experimental, immune, radiotherapy for the treatment of breast
cancer, with the following exceptions:

- Hormone therapy

- Palliative radiation therapy involving =< 25% of marrow-bearing bone is allowed
if completed within >= 14 days prior to first study treatment

- Surgery, radiotherapy, or lesion ablative procedure to the only area of
measurable/evaluable disease

- Major surgery within 4 weeks prior to first dose of ganetespib

- Poor venous access for study drug administration

- Study drug administration via indwelling catheters is allowed only if the
catheter is made of silicone material

- No prior chemotherapy in the metastatic setting is allowed.

- Prior pertuzumab is not allowed in the metastatic setting. Pertuzumab given in the
neoadjuvant and/or adjuvant setting is allowed.

- History of intolerance or hypersensitivity to trastuzumab and/or pertuzumab

- Adverse events related to trastuzumab, murine proteins, or any of the excipients that
resulted in trastuzumab being permanently discontinued

- History of severe (grade 3 or 4) allergic or hypersensitivity reactions to excipients
(e.g., polyethylene glycol [PEG] 300 and polysorbate 80)

- History of intolerance or hypersensitivity to paclitaxel and/or adverse events related
to paclitaxel that resulted in paclitaxel being permanently discontinued

- Peripheral neuropathy of grade >= 2 per National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE), version 4.0, at the time of or within
3 weeks prior to the first study therapy

- Baseline QTc > 470 msec (average of triplicate ECG recordings); a consistent method of
QTc calculation must be used for each patient's QTc measurements. QTcF (Fridericia's
formula) is preferred

- Use of medications that have been linked to the occurrence of torsades de pointes

- Patients will be eligible for the study if they discontinue any of the listed
medications two weeks prior to registration and study enrollment

- Stable regimen of antidepressants of the SSRI class is allowed (common SSRIs
include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline and
fluoxetine)

- Left ventricular ejection fraction (EF) < 50% at baseline

- Serum potassium, magnesium, and calcium levels (corrected for albumin) outside the
laboratory's reference range despite correction

- Treatment with chronic immunosuppressants (e.g., cyclosporine following
transplantation)

- Women who are pregnant or lactating

- Current known active infection with HIV, hepatitis B or C viruses

- Uncontrolled systemic disease (e.g., clinically significant cardiac, pulmonary or
metabolic disease)

- Other medications, or severe acute/chronic medical or psychiatric condition, or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration, or may interfere with the interpretation of study
results in the judgment of the investigator

- History of clinically significant cardiac dysfunction, including:

- Unstable angina

- Unstable atrial fibrillation

- Symptomatic bradycardia

- Indwelling temporary pacemaker

- History of MI within 6 months prior to first study treatment

- History of symptomatic CHF (grade > 3 by NCI CTCAE or Class > II by New York
Heart Association (NYHA) criteria

- Ventricular tachycardia or a supraventricular tachycardia that requires treatment
with a Class 1a antiarrhythmic drug (eg quinidine, procainamide, disopyramide) or
Class III antiarrhythmic drug (eg sotalol, amiodarone, dofetilide). Use of other
antiarrhythmic drugs is permitted

- Second or third degree atrioventricular (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

- Brain metastases that are:

- Progressive or

- Have required any type of therapy (including radiation, surgery or steroids) to
control symptoms from brain metastases within 60 days prior to the first study
treatment

- History of an invasive second primary malignancy diagnosed within the previous 3
years, except for appropriately treated stage I endometrial or cervical carcinoma or
prostate carcinoma treated surgically, and non-melanoma skin cancer