Pancreatic Cancer Clinical Trials

• Histologically or cytologically confirmed advanced pancreatic adenocarcinoma that is considered borderline resectable or locally advanced per institutional standardized criteria of unresectability or medical inoperability (NCCN guidelines 2.2021 PANC-C 1 of 2).

• Patients with locoregional adenopathy are eligible as long as all suspicious lymph nodes are deemed to be adjacent to the primary tumor as per radiation oncologist assessment.

• Patients must have received at least 2 months of systemic chemotherapy, such as FOLFOX, FOLFIRINOX, gemcitabine, nab-paclitaxel, cisplatin, or other regimens, for this disease without progression of local or systemic disease. Newly diagnosed patients may be screened for enrollment in this study and can be enrolled once they have completed 2 months of systemic chemotherapy (and still meet all eligibility criteria) prior to randomization. The last dose of chemotherapy must be ≥ 2 weeks prior to randomization.

• At least 18 years of age.

• ECOG performance status ≤ 1.

• Life expectancy \> 3 months

• Adequate bone marrow and organ function as defined below:

‣ Absolute neutrophil count ≥ 1.5 K/cumm

⁃ Platelets ≥ 100 K/cumm

⁃ Hemoglobin ≥ 9.0 g/dL without transfusion in the preceding 14 days.

⁃ Total bilirubin ≤ 1.5 x IULN; no prior history of Gilbert's syndrome

⁃ AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN or ≤ 5.0 x IULN if due to liver involvement by tumor

⁃ Creatinine clearance ≤ 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

⁃ Albumin ≥ 2.5 mg/dL

⁃ Creatine phosphokinase (CPK) ≤ 2.5 x IULN

• Adequate cardiac function with left ventricular ejection fraction ≥ 55% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.

• Corrected QT interval (QTc) \< 480 ms (as calculated by the Fridericia correction formula).

• The effects of defactinib and avutometinib on the developing human fetus are unknown. For this reason and because radiation therapy is known to be teratogenic, women of childbearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control, abstinence) 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 and up to 30 days after completion of treatment, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 90 days after completion of the study

• 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.