Nintedanib Alone followed by Nintedanib, Gemcitabine Hydrochloride, and Nab-paclitaxel in Treating Participants with Locally Advanced or Metastatic Pancreatic Adenocarcinoma

Inclusion Criteria

• Signed and dated written informed consent prior to admission to the study
• Histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas
• At least one measurable disease lesion according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1)
• No more than one prior line of non-gemcitabine/nab-paclitaxel containing systemic therapy for metastatic/locally advanced pancreatic cancer
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
• Women of childbearing potential must have a negative urine pregnancy test (or serum) within 14 days prior to registration; (Note: patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years)
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14 days prior to registration)
• Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration)
• Hemoglobin >= 9 g/dl (obtained within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x upper limit of normal (ULN) (2.5 x ULN in case of liver metastases) (obtained within 14 days prior to registration)
• Total bilirubin =< ULN (obtained within 14 days prior to registration)
• International normalized ratio (INR) =< 2 (obtained within 14 days prior to registration)
• Prothrombin time and partial thromboplastin time (PT / PTT) =< 50% increase from institutional ULN (obtained within 14 days prior to registration)
• Serum creatinine =< 1.5 x ULN (obtained within 14 days prior to registration)
• If elevated liver function tests develop at the time of initial presentation or develop during workup and are the result of mechanical obstruction of the biliary drainage by tumor compression or invasion, a biliary drain may be placed; if drainage allows the liver function tests to come within inclusion criteria, the patient may be enrolled

Exclusion Criteria

• More than one systemic therapy regimen of any type for metastatic or locally advanced disease; adjuvant gemcitabine that ended more than 6 months prior to diagnosis of recurrent disease is not considered as a regimen
• Prior treatment with nintedanib or any other vascular endothelial growth factor receptor (VEGFR) inhibitor
• Known hypersensitivity to nintedanib, gemcitabine and nab-Paclitaxel, peanut or soy or any other trial drug, their excipients
• Chemotherapy, hormonal therapy, radiotherapy (except for brain and extremities), immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
• Target lesions that have previously received radiation must have shown radiographic progression following radiation or must have other non-radiated lesions present
• Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy
• Active brain metastases (e.g. stable for < 4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before registration)
• Leptomeningeal disease
• Radiographic evidence of cavitary or necrotic tumors
• Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial
• Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325mg per day)
• Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period
• History of clinically significant hemorrhagic or thromboembolic event in the past 6 months
• Known inherited predisposition to bleeding or thrombosis
• Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > New York heart association ([NYHA] II, serious cardiac arrhythmia, pericardial effusion)
• Proteinuria Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater
• Creatinine > 1.5 x ULN or glomerular filtration rate (GFR) < 45 mL/min
• ALT or AST > 1.5 ULN in patients (pts) without liver metastasis
• For pts with liver metastasis: total bilirubin outside of normal limits
• For pts with liver metastasis: ALT or AST > 2.5 ULN
• INR > 2
• Prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN
• Absolute neutrophil count (ANC) < 1500/mL
• Platelets < 100,000/mL
• Hemoglobin < 9.0 g/dl
• Any known active cancer other than pancreatic primary
• Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy
• Known or chronic hepatitis C and/or B infection
• Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
• Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study
• Pregnancy or breast feeding female
• Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
• Active alcohol or drug abuse
• Significant weight loss (> 20% of body weight [BW]) within past 6 months prior to inclusion into the trial or actual body weight of less than 50 kg
• Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectable, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy