LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer

Transforming growth factor-beta (TGFβ) is a pleiotropic cytokine which belongs to a
superfamily of ligands, including bone morphogenetic proteins and activins [1-5]. Under
normal conditions, members of the TGFβ family maintain homeostasis in many organ systems. In
normal and non-cancerous cells, TGFβ limits the growth of epithelial, endothelial, neuronal,
and hematopoietic cell lineages through anti-proliferative and apoptotic responses. In
addition, TGFβ exerts potent effects that influence immune function, cell proliferation/
functional differentiation, cell adhesion, extracellular matrix production, cell motility,
angiogenesis, and cytokine production. TGFβ has been implicated as an important factor in the
growth, progression, and metastatic potential of advanced cancers. Although TGFβ has been
shown to suppress the growth of epithelial cells in the early stages of tumor development
(premalignant conditions), the effect on advanced cancers is more complex [1, 5-6]. Increased
production of TGFβ has been found in many neoplasms such as breast, prostate, gastric, renal,
and epidermal carcinomas, and elevated plasma TGFβ levels in patients have been correlated
with advanced disease, metastases, and lower survival rates [7-13]. In these later stage
cancers, TGFβ induced growth suppression is lost, and instead, TGFβ promotes tumor growth and
metastasis.

Eli Lilly has developed and produced a Transforming Growth Factor-beta (TGF-β) receptor
type-1 kinase inhibitor. LY2157299 monohydrate (LY2157299) is a small molecule that inhibits
the TGF-β receptor type 1 kinase activity. LY2157299 was developed to investigate its
activity in patients with glioblastoma where TGF-β has been demonstrated to play a specific
role in tumor progression. In addition, LY2157299 was investigated in other patient
populations, either as a stand-alone therapy or in combination with standard anti-tumor
treatment regimens for indications including hepatocellular carcinoma and pancreatic cancer.
Future investigations include indications with likely TGF-β associated pathway activation,
such as melanoma, breast and prostate cancer as well as hematologic malignancies.

Inclusion Criteria :

1. Biopsy proven breast carcinoma which is persistent and metastatic or recurrent and
metastatic.

2. Patients must have failed at least one line of chemotherapy for metastatic disease.

3. Patients who are Human epidermal growth factor 2 +(HER2+) as defined by American
Society of Clinical Oncology and College of American Pathologists (ASCO CAP)
guidelines must have failed all prior therapy known to confer clinical benefit

4. Patients must have at least 3 distinct metastatic sites with at least one measurable
lesion which is at least 1 cm or larger in largest diameter

5. At the time of enrollment, patients must be ≥ 4 weeks since all of the following
treatments (and recovered from the toxicity of prior treatment to <= Grade 1,
exclusive of alopecia):

major surgery; radiotherapy; chemotherapy (note: must be ≥ 6 weeks since therapy if
treated with a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab);
immunotherapy; Biotherapy/targeted therapies.

6. Patient ≥ 18 years of age. Patient life expectancy > 6 months. Eastern cooperative
group (ECOG) of 0 or 1

7. Adequate organ function including:

1. Marrow: Hemoglobin >= 10.0 g/dL, absolute neutrophil count (ANC) >=1,500/mm3, and
platelets >=100,000/mm3.

2. Hepatic: Serum total bilirubin <=1.5 x upper limit of normal (ULN) (Patients with
Gilbert's Disease may be included if their total bilirubin is <= 3.0 mg/dL),
alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5 x
ULN. If the patient has known liver metastases, an ALT and/or AST <= 5 x ULN are
allowed.

3. Renal: Estimated or measured creatinine clearance >= 60 mL/min.

4. Other: Prothrombin time (PT) and partial thromboplastin time (PTT) < ULN.

8. Patients must have negative tests (antibody and/or antigen) for hepatitis viruses B
and C unless the result is consistent with prior vaccination or prior infection with
full recovery.

9. Male and female patients of child-producing potential must agree to use effective
contraception while enrolled on study and receiving the experimental drug, and for at
least 3 months after the last treatment.

Exclusion Criteria :

1. Patients diagnosed with another malignancy - unless following curative intent therapy,
the patient has been disease free for at least 2 years and the probability of
recurrence of the prior malignancy is < 5%. Patients with curatively treated
early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or
cervical intraepithelial neoplasia (CIN) are eligible for this study.

2. Concurrent cancer therapy is not permitted.

3. Uncontrolled central nervous system (CNS) metastases, meningeal carcinomatosis,
malignant seizures, or a disease that either causes or threatens neurologic compromise
(e.g., unstable vertebral metastases).

4. History of ascites or pleural effusions, unless successfully treated.

5. Patients with an organ transplant, including those that have received an allogeneic
bone marrow transplant.

6. Patients on immunosuppressive therapy including:

1. Systemic corticosteroid therapy for any reason, including replacement therapy for
hypoadrenalism. Patients receiving inhaled or topical corticosteroids may
participate (if therapy is < 5 days and is limited to systemic steroids as
antiemetics).

2. Patients receiving cyclosporine A, tacrolimus, or sirolimus are not eligible for
this study.

7. Use of investigational agents within 4 weeks prior to study enrollment (within 6 weeks
if the treatment was with a long-acting agent such as a monoclonal antibody).

8. Patients with moderate or severe cardiac disease:

1. have 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.

2. have documented major electrocardiogram (ECG) abnormalities (not responding to
medical treatments) at the investigator's discretion (for example, symptomatic or
sustained atrial or ventricular arrhythmias, second- or third-degree atrio
ventricular block, complete bundle branch block, ventricular hypertrophy, or
recent myocardial infarction).

3. have major abnormalities documented by echocardiography (ECHO) with Doppler (for
example, moderate or severe heart valve function defect and/or left ventricular
ejection fraction <50%, evaluation based on the institutional lower limit of
normal). For additional details, refer to ECHO protocol.

4. have 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 with contrast).

9. B-type Natriuretic Peptide (BNP) above 3 times the baseline value and above the ULN
that is sustained consecutive, scheduled blood draws. Troponin I above ULN, high
sensitive C-reactive protein (hsCRP) above ULN or Cystatin above ULN.

10. Patients with a remote history of asthma or active mild asthma may participate.

11. Active infection, including unexplained fever (temperature > 38.5 deg.C).

12. Systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid
arthritis, Marfan Syndrome, etc.).

13. A known allergy to any component of LY2157299.

14. Patients who, in the opinion of the Investigator, have significant medical or
psychosocial problems that warrant exclusion. Examples of significant problems
include, but are not limited to:

1. Other serious non-malignancy-associated medical conditions that may be expected
to limit life expectancy or significantly increase the risk of Serious Adverse
Events (SAEs).

2. Any condition, psychiatric, substance abuse, or otherwise, that, in the opinion
of the Investigator, would preclude informed consent, consistent follow-up, or
compliance with any aspect of the study

15. Pregnant or nursing women, due to the unknown effects ofLY2157299 on the developing
fetus or newborn infant.