Onalespib and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of onalespib (AT13387) in combination
with paclitaxel in patients with advanced triple negative breast cancer (TNBC).

II. To determine the toxicity profile (based on Common Terminology Criteria for Adverse
Events [CTCAE] version [v.]5.0) of the combination of AT13387 in combination with paclitaxel
in patients with advanced TNBC.

SECONDARY OBJECTIVES:

I. To determine the effect of AT13387 on pharmacokinetics of paclitaxel in the study patient
population.

II. To determine the effect of paclitaxel on pharmacokinetics of AT13387 in the study patient
population.

III. To observe anti-tumor activity determining the overall response rate (partial response +
complete response), response duration and progression-free survival.

OUTLINE: This is a dose-escalation study of onalespib.

SAFETY RUN-IN: Patients receive onalespib intravenously (IV) over 1 hour on day -7.

TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1, 8, and 15. Patients also
receive onalespib IV over 1 hour beginning on days 8 and 15 of cycle 1 and on days 1, 8, and
15 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Patients must have histologically confirmed measurable or unmeasurable advanced or
metastatic breast cancer for which standard curative measures do not exist or are no
longer effective

- Measurable disease is defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded for non-nodal
lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional
techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan,
magnetic resonance imaging (MRI), or calipers by clinical exam

- Primary and/or metastatic breast tumor must be negative for over-expression of
estrogen and progesterone receptors; patients with weak estrogen receptor and/or
progesterone receptor expression (< 10% on immunohistochemistry [IHC]) will be
eligible

- Primary and/or metastatic breast tumor must be negative for human epidermal growth
factor receptor (HER-2/neu) over-expression based on immunohistochemistry (IHC) (0 or
1+, 2+ if fluorescence in-situ hybridization [FISH] test is negative) or FISH
(HER2/copy number of centromere of chromosome 17 [CEP17] ratio < 2.0 or < 4 Her-2/neu
signals per nucleus)

- Any number of prior therapies for metastatic breast cancer is allowed; patients with
weakly estrogen receptor positive breast cancer who received any number of endocrine
agents for metastatic breast cancer will also be eligible

- Prior taxane is allowed (as long as the patient is not experiencing grade > 1
neuropathy and had no history of disease progression on a taxane therapy within 3
months prior to study enrollment)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 2,000/uL

- Absolute neutrophil count >= 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin less than or equal to the institution's upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal (except for patients with liver
metastases in whom AST/ALT can be < 5 x institutional upper limit of normal)

- Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min for
patients with creatinine levels above institutional normal

- Left ventricular ejection fraction of > 50% on baseline echocardiography or
multi-gated acquisition (MUGA) scan

- Corrected QT interval (QTc) of < 480 milliseconds

- Female subjects with child bearing potential must have a negative pregnancy test at
screening; child bearing potential is defined as sexually active patients with menses
less than 1 year prior to enrollment, < 65 years of age, have no history of
oophorectomy or hysterectomy

- Women of child-bearing potential and men must agree to use adequate contraception
prior to study entry, for the duration of study participation and 3 months after
completion of study treatment administration; adequate contraception includes methods
such as oral contraceptives, double barrier method (condom plus spermicide or
diaphragm), or abstaining from sexual intercourse; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study

- Patients who are receiving any other investigational agents within 4 weeks or 5
half-lives (whichever is later) prior to the first dose of the study regimen

- Prior radiation therapy within 2 weeks prior to the first dose of the study regimen

- Patients in whom prior treatment related toxicities have not recovered to grade 1 or
less (except for alopecia)

- Recent initiation of bone modifying therapy with a bisphosphonate or denosumab unless
it has been started more than 4 weeks prior to the first dose of the study regimen;
patients who are already enrolled in this study can initiate bone modifying therapy
after the first set of re-staging scans (>= 8 weeks from cycle 1, day 1)

- Prior therapy with AT13387 or another HSP90 inhibitor

- Patients with known brain metastases should be excluded from this clinical trial;
however, patients with previously treated and stable brain metastases are eligible as
long as they are no longer requiring steroids, completed radiation therapy more than 2
weeks prior to the first dose of study regimen and have no seizures or worsening
neurologic symptoms

- History of grade 3-4 immediate hypersensitivity reaction to paclitaxel

- History of clinically significant allergic reactions attributed to compounds of
similar chemical or biologic composition to AT13387 or paclitaxel

- The use of CYP2C8 and CYP3A4 inhibitors/inducers while not prohibited in this study,
is discouraged whenever feasible; concurrent use of strong CYP2C8 and CYP3A4
inhibitors/inducers should be documented and the principal investigator (PI) of the
study shall be notified prior to dosing; as part of the enrollment/informed consent
procedures, the patients will be counseled on the risk of interactions with other
agents, and what to do if new medications need to be prescribed or if the patient is
considering a new over-the-counter medicine or herbal product

- 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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AT13387 and paclitaxel

- Patients who are human immunodeficiency virus (HIV) positive on highly active
anti-retroviral therapy (HAART) will be excluded from the study

- Inability to understand and sign informed consent

- Any other medical or psychiatric condition that in the opinion of the investigator
would make the study therapy unsafe for the patient