Defactinib, Pembrolizumab, and Gemcitabine Hydrochloride in Treating Patients with Advanced Pancreatic Cancer or Solid Tumors

Inclusion Criteria

• DOSE ESCALATION COHORT: Histologically or cytologically confirmed diagnosis of advanced extracranial solid tumor for which standard curative or palliative measures do not exist or are no longer effective
• EXPANSION COHORT: Histologically or cytologically confirmed diagnosis of advanced pancreatic adenocarcinoma; * Maintenance group (n=10): Patients must be stable on front-line therapy (defined as at least 4 months stable disease on nab-paclitaxel + gemcitabine) * Second-line group (n=10): Patients must have failed or could not tolerate the front-line fluorouracil (5FU)-based therapy for advanced pancreatic cancer
• EXPANSION COHORT: There should be a 2- to 4-week break between the patient’s last dose of standard chemotherapy to initiation of the first cycle of study drugs; longer than 4-week break may be permitted at the discretion of the principal investigator (PI)
• EXPANSION COHORT: No more than one line of prior systemic therapy for advanced pancreatic adenocarcinoma allowed
• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with computed tomography (CT) scan or magnetic resonance imaging (MRI), as >= 20 mm by chest x-ray, or >= 10 mm with calipers by clinical exam
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Life expectancy > 3 months
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN); no prior history of Gilbert’s syndrome
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x IULN, or =< 5.0 x IULN if due to liver involvement by tumor
• Creatinine =< 1.5 x IULN or glomerular filtration rate of >= 60 mL/min
• International normalized ratio (INR) =< 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
• Albumin >= 2.5 mg/dL
• Corrected QT (QTc) interval < 480 ms (as calculated by the Fridericia correction formula)
• Women of childbearing potential and men must agree to use contraceptive methods prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately
• Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria

• A history of other malignancy =< 2 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix
• No clinical evident ascites that required therapeutic paracentesis
• At risk of bowel perforation
• Prior treatment with a drug of the focal adhesion kinase (FAK) inhibitor class or with an anti-programmed cell death 1 (PD1), anti-programmed cell death ligand 1 (PDL1), anti- programmed cell death 1 ligand 2 (PDL2), anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Prior anti-human antibody response (anti-heart antibodies [AHA] or anti-drug antibody [ADA])
• Has received other investigational agents within 4 weeks or 5 half-lives of planned first dose of study agents
• Known brain metastases
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to defactinib, pembrolizumab, gemcitabine, or other agents used in the study
• Received a live vaccine within 30 days prior to the first study treatment; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab
• Has a known history of active Bacillus tuberculosis (TB)
• Has an active autoimmune disease requiring systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Major surgery within 28 days prior to the first study treatment
• History or evidence of cardiac risk including any of the following: history or evidence of current clinically significant uncontrolled arrhythmias or arrhythmia requiring treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia; history of acute coronary syndromes within 6 months prior to the first dose of study therapy (including myocardial infarction and unstable angina, coronary angioplasty, or stenting); history of uncontrolled hypertension; or any history of congestive heart failure with most recent ejection fraction < 45% (screening left ventricular ejection fraction [LVEF] assessment without history of congestive heart failure CHF is not required)
• Known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Requires continued use of warfarin for anticoagulation and cannot stop warfarin to be safely switched to another anticoagulant
• Gastrointestinal condition that could interfere with the swallowing or absorption of study medication
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and/or breastfeeding; women of childbearing potential must have a negative pregnancy test within 14 days of study entry
• Known human immunodeficiency virus (HIV)-positivity on combination antiretroviral therapy