Galunisertib and Paclitaxel in Treating Patients With Metastatic Androgen Receptor Negative (AR-) Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of paclitaxel when administered with LY2157299
(Galunisertib).

II. To determine the maximally tolerated dose (MTD) of paclitaxel + LY2157299. III. To
determine the recommended dose of paclitaxel with LY2157299 for phase II studies.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy, as measured by median progression free survival (PFS), of
paclitaxel + LY2157299 in patients with metastatic androgen receptor negative triple negative
metastatic breast cancer.

II. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of paclitaxel +
LY2157299 in patients with androgen receptor negative metastatic triple negative metastatic
breast cancer.

III. To determine the overall response rate (ORR) of paclitaxel + LY2157299 in patients with
androgen receptor negative metastatic triple negative breast cancer.

TERTIARY OBJECTIVES:

I. To interrogate the entire coding sequence of 236 cancer-related genes (3,769 exons) plus
47 introns from 19 genes often rearranged or altered in cancer.

II. Nanostring analysis of established gene expression signatures. III. Determine breast
cancer subtype by PAM50 testing and correlate with response.

IV. To measure changes in circulating plasma transforming growth factor beta 1 (TGFB1),
interleukin (IL)-6, and cluster of differentiation 34 (CD34) positive (+), peripheral blood
mononuclear cells (PBMCs) induced by LY2157299.

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

Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15. Patients also receive
Galunisertib orally (PO) twice daily (BID) on days 1-14. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must provide informed written consent

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

- Clinical stage IV invasive mammary carcinoma that is ER, PR, HER2 negative (triple
negative) previously documented by conventional methods (IHC, FISH). ER negative is
defined as expression of ER in <1% cells, PR negative is defined as expression of PR
in <1% cells, HER2 negative [acceptable methods of HER2 analysis include IHC (0, 1+),
fluorescence in situ hybridization (FISH) with HER2/CEN-17 ratio <2, and/or
chromogenic in situ hybridization (CISH) with HER2/CEN-17 ratio <2], as previously
documented by histological analysis.

- 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.

- Patients must have adequate hematologic, hepatic, and renal function. All laboratory
tests must be obtained less than 21 days from study entry. These include:

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

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Creatinine =< 1.5 X upper limits of normal

- International normalized ratio (INR) =< 2

- Total serum bilirubin =< 1.5 x upper limit of normal (ULN) unless attributable to
Gilbert's syndrome

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
(or =< 4.0 x ULN if hepatic metastases are present)

- 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 =< 4 weeks prior to starting study treatment
or who has not recovered from side effects of such procedure

- 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 < 50%, evaluation based on the institutional lower limit
of normal)

- Predisposing conditions that are consistent with development of aneurysms of the
ascending aorta or aortic stress (for example, family history of aneurysms,
Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels
of the heart documented by computed tomography [CT] scan/magnetic resonance
imaging [MRI] with contrast)

- 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