Sorafenib Tosylate, Vorinostat, Gemcitabine Hydrochloride, and Radiation Therapy in Treating Patients with Pancreatic Cancer

Inclusion Criteria

• Adenocarcinoma of the pancreas
• Prior therapy with >= 1 prior systemic therapy over a period of at least 2 months (eg, at least two 4-week cycles of a regimen such as gemcitabine and nab-paclitaxel; or at least four 2-week cycles of a regimen such as fluorouracil/leucovorin calcium/oxaliplatin [FOLFOX], fluorouracil/irinotecan/leucovorin calcium/oxaliplatin [FOLFIRINOX], or folinic acid-fluorouracil-irinotecan [FOLFIRI])
• Candidate for additional therapy consisting of radiation with gemcitabine–radiosensitization
• Able to initiate study treatment no later than 9 weeks from last dose of any antineoplastic component of prior therapy regimen
• Recovery from >= grade 2 toxicities of prior therapy regimen to grade 1 or baseline, with the exception of anemia and lymphopenia and chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of gemcitabine, sorafenib, and vorinostat (eg, alopecia, changes in pigmentation, stable endocrinopathies); patients with =< grade 2 peripheral sensory or motor neuropathy are eligible
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) for the laboratory
• Total bilirubin =< 1.5 x ULN for the laboratory at the time of enrollment, all forms of biliary stents allowed
• Creatinine clearance >= 45 mL/min as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine and gender
• International normalized ratio (INR) =< 1.5
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelets >= 100,000/mm^3 (may not be transfused to meet this level for enrollment)
• Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version [v]1.1)
• Ability to understand and the willingness to sign a written informed consent document
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment
• Women of childbearing potential and men must agree to use a medically accepted form of birth control during the treatment and for 2 months following completion of study treatment

Exclusion Criteria

• Prior radiotherapy for pancreatic cancer
• Prior surgical resection of pancreatic cancer
• Evidence of metastatic disease
• Any investigational agent within 4 weeks of study treatment initiation
• Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy
• Intolerance of protocol agents as follows: * Known or presumed intolerance of gemcitabine, vorinostat or sorafenib * Experienced any of the following toxicities with prior gemcitabine administration (if given): capillary leak syndrome, posterior reversible encephalopathy, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, unexplained dyspnea or other evidence of severe pulmonary toxicity, or severe hepatic toxicity
• Unable to swallow medication
• Suspected malabsorption or obstruction; note: use of pancreatic enzyme supplements is allowed to control malabsorption
• Contraindication to antiangiogenic agents, including: * Bronchopulmonary hemorrhage/bleeding event >= grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] v4.0) within 12 weeks prior to of initiation of treatment * Any other hemorrhage/bleeding event >= grade 3 (CTCAE v4.0) within 12 weeks prior to initiation of treatment * Serious non-healing wound, ulcer, or bone fracture
• Arterial thrombotic or embolic events such as a myocardial infarction or cerebrovascular accident (including transient ischemic attacks) within the 6 months prior to initiation of treatment; incidental clinically insignificant embolic phenomena that do not require anti-coagulants are not excluded; also, tumor-associated thrombus of locally-involved vessels does not count as an exclusion criterion
• Clinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy, recent (within 6 months) myocardial infarction or unstable coronary artery disease
• Concomitant use of other histone deacetylase (HDAC) inhibitors
• Planned ongoing administration of STRONG cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers
• Persistent heart rate (HR) < 50 or > 120 beats per minute (bpm)
• Corrected QT(c) >= 481 ms (>= grade 2) on electrocardiogram (ECG) prior to initiation of treatment * If baseline QTc on screening ECG meets exclusion criteria: ** Check potassium and magnesium serum levels ** Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm exclusion of patient due to QTc * For patients with HR 60-100 bpm, no manual read of QTc is required * For patients with baseline HR < 60 or > 100 bpm, manual read of QT by cardiologist is required, with Fridericia correction applied to determine QTc
• Planned ongoing treatment with other drugs thought to potentially adversely interact with study drugs; if such medications have been used, patients must be off of these agents for >= 2 weeks prior to initiation of treatment: * Anticoagulants at therapeutic doses * Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast, pimecrolimus
• Serious uncontrolled infection > grade 2 (CTCAE v4.0)
• Medical, psychological, or social conditions that, in the opinion of the investigator, may increase the patient’s risk or interfere with the patient’s participation in the study or hinder evaluation of the study results