Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

HSP90 Inhibitor AT13387 and Paclitaxel in Treating Patients with Advanced Triple Negative Breast Cancer

Protocol: OSU-15149

Full Title

Phase 1b Study of HSP90 Inhibitor, AT13387 in Combination with Paclitaxel in Patients with Advanced, Triple Negative Breast Cancer

Purpose

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.

Study Objective

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of AT13387 (HSP90 inhibitor 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.]4.03) 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 HSP90 inhibitor AT13387.

SAFETY RUN-IN: Patients receive HSP90 inhibitor AT13387 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 HSP90 inhibitor AT13387 IV over 1 hour beginning on days 8 and 15 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 every 3 weeks.

Are you eligible?

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 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)

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 aminotransferase (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 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

Breast Cancer