Defactinib Combined With Pembrolizumab and Gemcitabine in Patients With Advanced Cancer

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.