A Study in Metastatic Cancer and Advanced or Metastatic Unresectable Pancreatic Cancer

A Phase 1b/2 Study With Gemcitabine and LY2157299 for Patients With Metastatic Cancer (Phase 1b) and Advanced or Metastatic Unresectable Pancreatic Cancer (Phase 2)

Phase 1b: To determine the safe and tolerable dose of galunisertib in combination with gemcitabine in patients with solid malignancy

Phase 2a: To compare the overall survival (OS) of patients with Stage II to IV unresectable pancreatic cancer when treated with a combination of galunisertib and gemcitabine with that of gemcitabine plus placebo.

Inclusion Criteria: For both Phase 1b and Phase 2 (unless specified in the following), patients are eligible to be included in the study only if they meet all of the following criteria:

For Phase 1b:

• Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic disease; that is refractory to standard therapy and/or therapies known to provide clinical benefit or for which no standard therapy exists; and/or in which gemcitabine therapy at the proposed doses and schedule would be considered appropriate treatment for the metastatic disease (eg, pancreatic cancer)
• Patients may have received prior chemotherapy, radiotherapy, cancer-related hormone therapy, or other investigational therapy as treatment. There is no limit in the number of previous lines of therapy.

For Phase 1b and Phase 2:

• Have measurable disease or non-measurable disease, defined according to Response Evaluation Criteria In Solid Tumors (RECIST)
• Have given written informed consent prior to any study-specific procedures
• Have adequate organ function including: Hematologic: absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L, platelets greater than or equal to 100 x 10^9/L, and hemoglobin greater than or equal to 9 g/dL. Hepatic: bilirubin less than or equal to 1.5 times upper limit of normal (ULN), and alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT)less than or equal to 2.5 times ULN. If the liver has tumor involvement, AST less than or equal to 5 times ULN and ALT less than or equal to 5 times ULN are acceptable. Patients may have endoscopic or radiologic stenting to treat biliary obstructions. If so, then bilirubin must return to less than or equal to 1.5 times ULN and ALP, AST, and ALT to less than or equal to 5 times ULN prior to enrollment. Renal: serum creatinine within normal limits, less than or equal to 1.5 times ULN.
• Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale
• Patients must have recovered from any Grade 3/4 toxicities of previous therapies
• Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
• Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow, and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry.
• Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after discontinuation of study treatment. Women of childbearing potential must have a negative beta-human chorionic gonadotropin (B-HCG) pregnancy test documented within 14 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

For Phase 2:

• Have histological or cytological diagnosis of adenocarcinoma of the pancreas that is locally advanced (Stage II, III) or metastatic (Stage IV) and not amenable to resection with curative intent. Patients with previous radical surgery for pancreatic cancer are eligible after progression is documented. If they received adjuvant chemotherapy or chemoradiotherapy with gemcitabine, they can be enrolled if the treatment was completed 3 months before or longer
• Tumor tissue or unstained slides are available from original biopsy or resection or other tumor biopsies
• Patients may have received previous adjuvant treatment with gemcitabine with or without radiotherapy for pancreatic cancer. Adjuvant treatment must have finished at least 6 months before enrolling.

Exclusion Criteria: Patients will be excluded from the study if they meet any of the following criteria:

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
• Have moderate or severe cardiac disease:
• Myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension
• Major abnormalities documented by echocardiography with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction (LVEF) <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 CT scan or MRI with contrast)
• Are unable to swallow tablets or capsules
• Are pregnant or breastfeeding
• Have any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
• Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ), unless in complete remission and off of all therapy for that disease for a minimum of 3 years
• Have active infection that would interfere with the study objectives or influence study compliance
• Phase 2 only: Endocrine pancreatic tumors or ampullary cancer
• Patients with acute or chronic leukemia or with any other disease likely to have a significant bone marrow infiltration (screening not required)
• Have previously completed or withdrawn from this study or any other study investigating galunisertib or any other TGF-ß inhibitor
• Have known allergy to galunisertib or gemcitabine or any ingredient of galunisertib or gemcitabine formulations