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Galunisertib and Paclitaxel in Treating Patients with Metastatic Androgen Receptor Negative or Triple Negative Breast Cancer

This phase I trial studies the side effects and best dose of galunisertib when given together with paclitaxel in treating patients with androgen receptor negative or triple negative breast cancer that has spread to other places in the body. Some tumors need growth factors, which are made by the body's white blood cells, to keep growing. Galunisertib may interfere with growth factors and help cause tumor cells to die. 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. Giving glunisertib together with paclitaxel may kill more tumor cells.
Phase I
Chemotherapy - cytotoxic, Mol. targeted/Immunotherapy/Biologics
LY2157299, Paclitaxel
Abramson, Vandana
Vanderbilt University


18 Years
Inclusion Criteria:

Patients must provide informed written consent

Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Patients must have a life expectancy of > 12 weeks

Clinical stage IV invasive mammary carcinoma that is estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) negative (triple negative) previously documented by conventional methods (immunohistochemistry [ISH], fluorescence in situ hybridization [FISH]); ER negative is defined as expression of ER in =
Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1

Patients must have available tissue (archived formalin-fixed paraffin embedded blocks [FFPB] or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies; patients will not be able to start study drugs without tumor tissue availability; patients without available tumor tissue can still participate if willing to have a fresh biopsy of a metastatic lesion that is deemed to be medically safe (except for bone metastases)

Any number of prior therapies as long as patients have adequate performance status and meet all other eligibility criteria

Absolute neutrophil count (ANC) >= 1000/mm^3

Platelet count >= 100,000/mm^3

Hemoglobin >= 9 g/dL

Creatinine =
International normalized ratio (INR) =
Total serum bilirubin =
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =
Patients must be able to swallow and retain oral medication

Pre-menopausal patients must have a negative pregnancy test and agree to use birth control methods while participating in the study; women of childbearing age and their male counterparts should use a barrier method of contraception during and for 3 months following protocol therapy

Patients must complete all screening assessments as outlined in the protocol

Exclusion Criteria:

Locally recurrent resectable breast cancer

Known androgen receptor (AR) positive breast cancer (AR staining > 10% by immunohistochemistry is considered positive); if the AR status is unknown, the patient can go on study

Pregnant or lactating women

Patients with untreated or symptomatic metastatic central nervous system (CNS) disease; however patients with CNS involvement may participate if: * Clinically stable with respect to the CNS tumor at the time of screening and > 2 weeks from prior therapy completion (including radiation and/or surgery) to the start of study treatment * Not on steroid therapy * Not receiving enzyme inducing anti-epileptic medications that were started for brain metastases (these include carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate, and vigabatrin)

Patient has a history of another malignancy within 2 years prior to starting study treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix

Patient who has had systemic therapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry

Patient who has undergone major surgery =
Patient has a clinically significant cardiac disease or impaired cardiac function, such as: * The presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association class III/IV congestive heart failure, or uncontrolled hypertension * Documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) * Major abnormalities documented by echocardiography (ECHO) with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular [LV] ejection fraction
Patient who has any severe and/or uncontrolled medical conditions such as: * Active or uncontrolled severe infection, * Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA]) and/or positive hepatitis B virus surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) * Known severely impaired lung function (spirometry and diffusing capacity of the lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air) * Active bleeding diathesis * Uncontrolled arterial hypertension defined by blood pressure > 170/100 mm Hg at rest (average of 3 consecutive readings 5 min apart) * Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary

Prior treatment with paclitaxel in the metastatic setting is not allowed (patients who received neoadjuvant paclitaxel can be included)

Chronic treatment with corticosteroids or other immunosuppressive agents

Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

Patient with known positive serology for human immunodeficiency virus (HIV)

Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment: * Sexually active males should use a condom during intercourse while taking drug and for 8 weeks after the final dose of study treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months following the discontinuation of study treatment; highly effective contraception methods include: ** Total abstinence (when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods]) and withdrawal are not acceptable methods of contraception ** Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment ** Male sterilization (at least 6 months prior to screening); for female subjects on the study the vasectomized male partner should be the sole partner for that subject ** Combination of the following (a+b): *** a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) *** b. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

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