GVAX Pancreatic Cancer Vaccine, Pembrolizumab, and Stereotactic Body Radiation Therapy in Treating Patients with Locally Advanced Pancreatic Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• Patients with histologically proven, surgically unresectable, locally advanced pancreatic adenocarcinoma (at diagnosis) or with mixed cell type with predominant histology of adenocarcinoma (by NCCN guidelines)
• Patients must have received last dose of either fluorouracil, oxaliplatin, leucovorin calcium, and irinotecan hydrochloride (FOLFIRINOX) based or gemcitabine/abraxane based chemotherapy for 4-8 cycles with last dose of therapy between 1-5 weeks of study enrollment, with no evidence of metastatic disease * Note: ** 12-24 doses of gemcitabine (Gem)/abraxane that must be given over 16-38 weeks ** 8-16 doses of folfirinox (FFX) that must be given over 16-38 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy greater than 3 months
• White blood cell count >= 3,500 cells/mm^3
• Absolute neutrophil count >= 1,500 cells/mm^3
• Hemoglobin >= 9 g/dL
• Platelets >= 80 K/mm^3
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN * Subjects with Gilbert’s syndrome should have direct bilirubin within normal institutional limits
• Female patient of childbearing potential (WOCBP) (free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) must have a negative urine or serum pregnancy test; if the urine test is positive or cannot be confirmed as negative a serum pregnancy test will be required to be shown as negative for the patient to be eligible
• WOCBP must be willing to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with visit 1 through 120 days after the last dose of study therapy; approved contraceptive methods include for example; intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives; spermicides alone are not an acceptable method of contraception; male patients must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study therapy
• Must be willing to be treated with SBRT and have surgical resection (if eligible) only at Johns Hopkins Hospital
• Patients must be able to have fiducials placed; if not, the tumor must be posterior and adjacent to the aorta and treatment will only be permitted at the discretion of the principal investigator
• Ability to understand and the willingness to sign a written informed consent document
• ADDITIONAL INCLUSION CRITERIA FOR POST-OPERATIVE/POST-CHEMOTHERAPY COMBINATION IMMUNOTHERAPY
• ECOG performance status 0-1.
• Absolute neutrophil count >= 1,000 cells/mm^3.
• Hemoglobin >= 8g/dL.
• Platelets >= 80K/mm^3.
• Serum creatinine =< 2.0 mg/dL.
• AST and ALT =< 3 x ULN.
• Total bilirubin =< 1.5 x ULN *Subjects with Gilbert’s Syndrome should have direct bilirubin within normal institutional limits.
• Female patients of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be require to be shown as negative for the patient to be eligible.
• WOCBP must be willing to use either two adequate barrier methods OR a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study.
• Male patients must agree to use an adequate method of contraception.

Exclusion Criteria

• Patients who have been off of FOLFIRINOX or gemcitabine/abraxane therapy for more than 49 days prior to treatment on study
• Patients who have had more than one line of chemotherapy for LAPC (other than the 4-8 cycles of FOLFIRINOX or gemcitabine/abraxane based chemotherapy); patients will be allowed to switch between FOLFIRINOX and gemcitabine/abraxane due to intolerance, but cannot have switched chemotherapy regimens due to radiographic or clinical disease progression
• Patients who have only received single agent gemcitabine chemotherapy; abraxane component may be reduced or modified but must be included for a minimum of two cycles
• Presence of duodenal or gastric invasion by the tumor as noted by esophagogastroduodenoscopy (EGD) at time of fiducial placement
• Patients with a history of prior treatment with immunotherapy agents (including, but not limited to: interleukin [IL]-2, interferon, anti-PD-1, anti-PD-L1, anti-programmed cell death 1 ligand 2 [PD-L2], anti-cluster of differentiation [CD]137, anti-tumor necrosis factor receptor superfamily member 4 [OX-40], anti-CD40, or anti-cytotoxic t-lymphocyte-associated protein 4 [CTLA-4] antibodies)
• Is currently participating or has participated in a study of an investigational agent or using an investigational device
• Patients receiving active immunosuppressive agents or chronic use of systemic corticosteroids within 14 days of vaccine treatment * Note: special considerations for vaccination: study-related treatments may be given after short-term steroid use (=< 4 days) with prior approval by the protocol chair and investigational new drug (IND) sponsor
• History of any autoimmune disease, including any history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, as well as history of symptomatic disease (e.g. rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis); patients with thyroid disease will be allowed; autoimmune diagnoses not listed here must be approved by the principal investigator
• Known history of interstitial lung disease, has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has a pulse oximetry < 92% on room air
• Requires the use of home oxygen
• Has a known history of human immunodeficiency virus (HIV) (HIV1/2 antibodies), hepatitis B, or hepatitis C infection
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
• Patients who have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment; examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine * Note: seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live-attenuated vaccines, and are not allowed within 28 days of study treatment
• Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration; use of such agents while on study is also prohibited
• History of severe hypersensitivity reaction to any monoclonal antibody
• Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or any other component of GVAX pancreas vaccine.
• Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix; patients with a previous non-pancreatic, non-periampullary malignancy without evidence of disease for > 5 years will be allowed to enter the trial
• Women who are pregnant or breastfeeding
• Women of child bearing potential or sexually active fertile men with partners who are women of child bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 120 days after the last dose of investigational product
• Patient is unwilling or unable to follow the study schedule for any reason
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft; patients with a history of allogeneic hematopoietic stem cell transplant will be excluded
• ADDITIONAL EXCLUSION CRITERIA FOR POST-OPERATIVE/POST-CHEMOTHERAPY COMBINATION IMMUNOTHERAPY
• Radiographic evidence of metastatic disease.
• Patients receiving active immunosuppressive agents or chronic use of systemic corticosteroids within 14 days of vaccine treatment. * Note: Special considerations for vaccination: Study-related treatments may be given after short-term steroid use (=< 4 days) with prior approval by the protocol chair and IND sponsor.
• Has pulse oximetry of < 92% on room air, or requires the use of home oxygen.
• Uncontrolled illness or infection.
• Breastfeeding or pregnancy.
• New diagnosis of cancer other than non-melanoma skin cancer, non-invasive bladder cancer, early stage prostate cancer, or carcinoma in situ of the cervix.
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures.
• Patients who have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine. * Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-Mist) are live-attenuated vaccines, and are not allowed within 28 days of study treatment.
• Patients receiving growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration. Use of such agents while on study is also prohibited
• Patient is a WOCBP or male who is unwilling or unable to use adequate method of birth control to avoid pregnancy for the entire study and up to 120 days after the last dose of investigational product.
• Patient is currently participating or has participated in a study of an investigational agent or using an investigational device.
• Patient is unwilling or unable to follow the study schedule or procedures for any reason.