Inclusion Criteria:

• Dose escalation cohort: Histologically or cytologically confirmed diagnosis of advanced 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 cancer.
  • 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 of 5FU-based therapy for advanced pancreatic cancer at least one line of chemotherapy indicated 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 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 CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
• At least 18 years of age.
• ECOG performance status ≤ 1
• Life expectancy > 3 months
• Normal bone marrow and organ function as defined below:
  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9.0 g/dL
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(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
  • INR ≤ 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
  • 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
• Corrected QT interval (QTc) < 480 ms (as calculated by the Fridericia correction formula).
• Women of childbearing potential and men must agree to use adequate 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 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 clinically evident ascites that requires therapeutic paracentesis.
• At risk of bowel perforation
• Prior treatment with a drug of the FAK inhibitor class or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 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 treatment with systemic gemcitabine less than 6 months
• Currently receiving any other investigational agents
• Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• 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-Guérin (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 an active autoimmune disease requiring systemic treatment within the past 2 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidisms stable on hormone replacement or Sjorgen's syndrome would not e excluded from the study.
• 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); or any history of congestive heart failure with most recent ejection fraction < 45% (screening LVEF assessment without history of 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 HCV RNA [qualitative] is detected)
• Requires continued use of warfarin for anticoagulation and cannot stop warfarin or 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 HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with pembrolizumab and/or defactinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.