Ganetespib, Paclitaxel, Trastuzumab and Pertuzumab for Metastatic Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer
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 and pertuzumab in treating patients with human epidermal growth
 factor receptor 2 positive (HER2+) metastatic breast cancer (MBC).
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