The survival rate for patients with pancreatic cancer remains at a dismal 10% or less at 5 years, and although trials integrating stereotactic body radiation therapy (SBRT) alone have shown improvement in local control, initial invigoration of immune response, and relief of symptom burden, SBRT has not demonstrated any improvement in survival. Preclinical research has established that STAT3 inhibition given concurrently with SBRT and in the maintenance phase acts as a synergistic agent that enhances the pro-inflammatory effects of SBRT while reducing its undesired effects (including fibrosis and immunosuppression). This study exploits the window of opportunity post-chemotherapy to advance the hypothesis that the addition of STAT3 inhibition in combination with SBRT will be safe and will enhance 2-year progression-free survival.

Inclusion Criteria:

• Pathologically confirmed pancreatic adenocarcinoma that is borderline resectable or locally advanced as defined by NCCN guidelines, with no expected arterial resection/reconstruction.

• Patients who are borderline resectable must have completed standard of care induction chemotherapy between 1 and 3 weeks prior to planned start of TTI-101 + SBRT. Patients who exceed this window may be considered for enrollment if they complete an additional cycle of induction chemotherapy prior to initiation of study treatment (per provider discretion). The amount of induction chemotherapy cycles allowed will be left to the discretion of the treating medical oncologist. There is no timing restriction for patients with locally advanced disease.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.0 K/cumm
  • Platelets ≥ 70 K/cumm
  • Hemoglobin ≥ 9.0 g/dL (patients may be transfused to meet this criterion)
  • Total bilirubin ≤ 2 mg/dL
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Serum albumin ≥ 2.8 g/dL
  • Ionized calcium ≤ 1.5 mmol/L, calcium ≤ 12 mg/dL, or corrected serum calcium ≤ IULN)
  • Measured creatinine clearance > 40 mL/min or calculated creatinine clearance > 40 mL/min by Cockcroft-Gault or by 24-hour urine collection for determination of creatinine clearance (calculations in protocol).

• Able to swallow pills.

• INR and aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy (in which case INR and PTT must be within therapeutic range of intended use of anticoagulants)

• The effects of TTI-101 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use at least 1 highly effective method of contraception from screening through the duration of study participation, and for 30 days after last dose of TTI-101. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform the treating physician immediately.

• Agreement to adhere to Lifestyle Considerations throughout study duration.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior treatment for pancreatic cancer in the past 2 years (outside of the induction chemotherapy received for the current diagnosis).
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently receiving any other investigational agents or has participated in a study of an investigational agent or using an investigational device overlapping with study treatments within 3 months preceding study entry at the discretion of the PI.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to TTI-101 or other agents used in the study.
• Uncontrolled intercurrent illness including but not limited to: ongoing or active infection (fungal, bacterial, or viral (including COVID-19)), sepsis, acute and chronic active infectious disorders (including viral and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy), and chronic pancreatitis. Patients with a recent COVID-19 diagnosis must have fully recovered from all COVID-19 symptoms for 2 weeks prior to the start of study treatment.
• Significantly impaired cardiac function such as symptomatic congestive heart failure with NYHA Class III or IV, unstable angina pectoris, myocardial infarction within the last 12 months prior to study entry, serious cardiac arrhythmia (including QTc prolongation of > 470 ms and/or pacemaker), or prior diagnosis of congenital long QT syndrome.
• Ongoing toxicity due to induction chemotherapy, unless returned to baseline or grade 1 or less (except alopecia and labs noted in inclusion criterion #5).
• Has had major surgery within 3 weeks prior to starting TTI-101 or has not recovered from major side effects due to surgery.
• Presence of pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequent). Participants with indwelling catheters for control of effusions or ascites are allowed.
• History of cerebrovascular accident or stroke within the previous 2 years.
• History of hepatic encephalopathy.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• History of malabsorption or other chronic gastrointestinal disease or condition that may hamper compliance or absorption of TTI-101.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 5 days of study entry.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.