LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Radiation therapy; Study Drug
Intervention description: Imaging by PET/CT will be performed at baseline, 5 weeks and 15 weeks. The chosen metastatic sites will receive conformal external beam radiation 7.5 Gy/fraction x 3, to a total of 22.5 Gy over the course of one week.; Patients will receive 300 mg/day of study drug administered via oral drug tablet every day for 14 days on and 14 days off (=28 day cycle) .
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No

Summary:

      Patients with metastatic breast cancer receiving at least one single agent chemotherapy and
      demonstrating stable disease or disease progression at two consecutive clinical/radiological
      assessments (at an interval of at least 2 weeks).

      Transforming growth factor-beta (TGFΒ) blockade will enhance response of irradiated tumors
      and improve the function of Dendritic and T cells. Patients will receive 300 mg/day of study
      drug administered via oral drug tablet every day for 14 days on and 14 days off (=28 day
      cycle). Radiation to a metastatic site will be delivered at a dose of 7.5 Gy, given
      consecutively on days 1-3-5.
    

Eligibility criteria:

        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.