This phase Ib trial studies the side effects and best dose of heat shock protein (HSP)90
inhibitor AT13387 when given together with paclitaxel in treating patients with triple
negative breast cancer that has spread to other places in the body and usually cannot be
cured or controlled with treatment (advanced). HSP90 inhibitor AT13387 works by blocking
proper processing of proteins that are important for cancer growth. This results in
inability of these proteins to work properly. Paclitaxel kills breast cancer cells by
interfering with their ability to divide. Giving HSP90 inhibitor AT13387 together with
paclitaxel may be better in treating patients with breast cancer.
TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1 of course 1 only.
Patients receive HSP90 inhibitor AT13387 IV over 1 hour beginning on day 8 of course 1 and
on days 1, 8, and 15 of subsequent courses. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 8 weeks.
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
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 6
months prior to study enrollment)
- Patients who consent to pre-treatment tumor biopsy must have at least 1 tumor site
that is amenable to a biopsy
- 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 within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aninotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2. 5 × 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 4 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 or radiotherapy 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 2 weeks prior to the first dose of the study regimen
- 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 cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and
cytochrome P450, family 3, subfamily A, polypeptide 4 (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 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