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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Intervention: Hsp90 Inhibitor AT13387 (Drug); Laboratory Biomarker Analysis (Other); Paclitaxel (Drug); Pharmacological Study (Other)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Robert Wesolowski, Principal Investigator, Affiliation: Ohio State University Comprehensive Cancer Center LAO

Summary

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.

Clinical Details

Official title: Phase 1b Study of HSP90 Inhibitor, AT13387 in Combination With Paclitaxel in Patients With Advanced, Triple Negative Breast Cancer

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

R2PD or maximum tolerated dose of HSP90 inhibitor AT13387 in combination with paclitaxel defined as the dose level at which no more than 1 of 3-6 patients experiences a dose limiting toxicity

Toxicity profile of HSP90 inhibitor AT13387 in combination with paclitaxel, based on the CTCAE v.4.03

Secondary outcome:

Molecular subtype of triple negative breast cancer (basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem cell-like and androgen luminal type)

Overall response rate (partial response [PR]+ complete response [CR]) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Pharmacokinetic (PK) parameters of HSP90 inhibitor AT13387

PK parameters of paclitaxel

Progression-free survival

Response duration, based on RECIST 1.1 criteria

Detailed description: 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 by determining the overall response rate (partial response + complete response), response duration and progression-free survival. TERTIARY OBJECTIVES: I. To explore the association between response and molecular subtype of triple negative breast cancer (basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem cell-like and androgen luminal type). 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 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Locations and Contacts

Ohio State University Comprehensive Cancer Center LAO, Columbus, Ohio 43210, United States; Not yet recruiting
Robert Wesolowski, Phone: 614-293-9273, Email: Robert.wesolowski@osumc.edu
Robert Wesolowski, Principal Investigator
Additional Information

Starting date: October 2015
Last updated: June 15, 2015

Page last updated: August 23, 2015

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