Trial of Radiotherapy in Combination with TTI-101 in Patients with Borderline Resectable Pancreatic Cancer

Inclusion Criteria:

• Patients must have pathologically confirmed pancreatic adenocarcinoma withborderline resectable PDAC as defined by NCCN guidelines, with no expected arterialresection-reconstruction.

• Age ≥ 18 years at time of study entry.

• Provision to sign and date the consent form.

• Stated willingness to comply with all study procedures and be available for theduration of the study.

• Ability to swallow tablets by mouth.

• ECOG performance status ≤2 or KPS ≥60%

• Absolute neutrophil count ≥ 1,000/mcL

• Platelets ≥ 70,000/mcL

• Hemoglobin ≥ 9 g/dL, patients may be transfused to meet this criterion

• Serum albumin ≥ 2.8 g/dL

• Total Bilirubin ≤ 2mg/dL

• AST(SGOT)/ALT(SGPT)/ALP ≤ 3 x institutional upper limit of normal (IULN)

• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL >40 mL/minby the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urinecollection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 / 72 x serum creatinine (mg/dL)

• INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR orPTT is within therapeutic range of intended use of anticoagulants

• aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INRor PTT is within therapeutic range of intended use of anticoagulants

• Sexually active women of childbearing potential (defined in section 7.1) and menmust agree to use at least 1 highly effective method of contraception (defined insection 7.1) from screening and for at least 30 days after administration of thelast dose of the study treatment. Should a woman become pregnant or suspect she ispregnant while participating in this study, she must inform her treating physicianimmediately.

Exclusion Criteria:

• Pregnant or breastfeeding. Patient must have a negative serum or urine pregnancytest within 5 days of study treatment.

• Previous treatment of the current malignancy with a STAT inhibitor.

• Herbal preparations are not allowed throughout the study. These herbal medicationsinclude but are not limited to St. John's wort, kava, ephedra (Ma Huang), gingkobiloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.Participants should stop using herbal medications 7 days prior to the first dose ofstudy treatment.

• Senna and flaxseed are permitted.

• Is not fully recovered from all COVID-19-related symptoms for 2 weeks prior to Cycle 1 Day 1, if previously tested positive for COVID-19.

• Ongoing toxicity (except alopecia) due to a prior therapy, unless returned tobaseline or Grade 1 or less.

• Has had major surgery within 3 weeks prior to starting IP or has not recovered frommajor side effects due to surgery.

• Significantly impaired cardiac function such as unstable angina pectoris,symptomatic congestive heart failure with New York Heart Association Class III orIV, myocardial infarction within the last 12 months prior to study entry; seriousarrhythmia (including QTc prolongation of >470 ms and/or pacemaker) or priordiagnosis of congenital long QT syndrome.

• Pleural effusion, pericardial effusion, or ascites requiring recurrent drainageprocedures (once monthly or more frequently). Participants with indwelling cathetersfor control of effusions or ascites are allowed.

• History of cerebrovascular accident or stroke within the previous 2 years.

• History of hepatic encephalopathy.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12mg/dL, or corrected serum calcium >ULN).

• Evidence of bleeding diathesis or significant coagulopathy (in the absence oftherapeutic anticoagulation).

• History of Grade 3 or 4 allergic reactions attributed to compounds of similarchemical or biologic composition as TTI- 101 (hydroxyl-naphthalene sulfonamides).

• Known active metastases in the central nervous system (unless stable by brainimaging studies for at least 1 month without evidence of cerebral edema and norequirements for corticosteroids or anticonvulsants).

• History of malabsorption, or other chronic gastrointestinal disease or conditionsthat may hamper compliance and/or absorption of the IP.

• Participants with chronic HBV infection, unless screening viral load <500 IU/mL onstable doses of antiviral therapy.

Note: Participants with chronic HCV infection are allowed to enroll into the study but do not have a defined maximum viral load requirement for study entry. Participants with both HBV and HCV infection are excluded unless they have negative HCV RNA.

• History of malignancy other than PDAC within 3 years prior to screening, with theexception of malignancies with a negligible risk of metastasis or death (eg, 5-yearoverall survival [OS] rate >90%), such as adequately treated carcinoma in situ ofthe cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinomain situ, or Stage I uterine cancer.

• Has any other concurrent severe and/or uncontrolled medical condition that would, inthe investigator's judgment, cause unacceptable safety risks, contraindicateparticipation in the clinical study, or compromise compliance with the protocol suchas:

• Chronic pancreatitis.

• Active untreated or uncontrolled fungal, bacterial, or viral infections (including COVID-19), sepsis, etc.

• Acute and chronic, active infectious disorders including viral and nonmalignantmedical illnesses that are uncontrolled or whose control may be jeopardized bythe complications of this study therapy.

• Prior treatment for pancreatic cancer in the past 2 years and outside of theinduction chemotherapy received for the current diagnosis.

• Measurable distant metastases on re-staging imaging post chemotherapy that meetsRECIST1.1 criteria.

• Currently receiving any other investigational agents or has participated in a studyof an investigational agent or using an investigational device overlapping withstudy treatments within 3-6 months preceding diagnosis at the discretion of the PI.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to TTI-101.