Intra-arterial Gemcitabine vs. IV Gemcitabine and Nab-Paclitaxel Following Radiotherapy for LAPC

The study is a multi-center, open-label, randomized active controlled study of subjects with locally advanced pancreatic adenocarcinoma which is unresectable.

All subjects will receive induction therapy of IV gemcitabine plus nab-paclitaxel, as well as SBRT radiation therapy for approximately a total of four months. Subjects who remain eligible will then be randomized to receive either intra-arterial chemotherapy with gemcitabine; or to continue gemcitabine plus nab-paclitaxel. Subjects will receive the randomized treatments for up to 16 weeks or until progression. Both groups will receive either IV gemcitabine and nab-paclitaxel or oral capecitabine following the 16-week treatment course until disease progression at the discretion of the Investigator and then followed for survival for five years.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or Cytopathology confirmed pancreatic adenocarcinoma with initial diagnosis within 6 weeks of consent for patients who enroll at cycle 1, and from the start of cycle 1 of gemcitabine + nab-paclitaxel chemotherapy for patients who enroll at cycle 2
2. Locally advanced, unresectable disease at screening and prior to randomization, as defined by NCCN criteria determined by an on-site, experienced, multidisciplinary team (as confirmed by CT or MRI within 30 days of the start of cycle 1)
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
4. Age ≥ 18 years
5. Adequate laboratory values prior to receiving the first dose of nab-paclitaxel and gemcitabine: (criterion must be met prior to cycle 2.) For a subject with elevated bilirubin, AST or ALT, who has had a biliary stent placed, if the subject's lab values have returned to within the required range for eligibility noted below in sub-criteria e and f \[(AST) ALT ≤ 3.0 X the upper normal limit, and total bilirubin ≤ 1.5 X the upper normal limit\] after placement of stent and prior to cycle 2, he/she is eligible for the study. Additional detail regarding eligibility for subjects who have had biliary stents recently placed is outlined in sub-criteria f and h below.

   1. Absolute neutrophil count (ANC) ≥ 1,500/μL
   2. Platelet count ≥ 100,000/μL
   3. Hemoglobin ≥ 9.0 g/dL
   4. Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine \>1.5 mg/dL
   5. \*Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 X the upper normal limit of institution's normal range
   6. \*Total bilirubin ≤ 1.5 X the upper normal limit of institution's normal range -OR- If biliary stent is placed or planned to be placed within 6 weeks of Cycle 1 Day 1 (C1D1), total bilirubin ≤ 2.0 X the upper normal limit of institution's normal range (see section 9.1.4 for dose modification due to elevated bilirubin)
   7. Prothrombin time (PT) and partial thromboplastin time (PTT) must be ≤ 1.5 X upper normal limit of institution's normal range. Subjects who are currently taking anti-coagulant therapy are eligible if not meeting this criterion
   8. International normalized ration (INR) ≤ 1.5 X upper normal limit of institution's normal range. Subjects who are currently taking anti-coagulant therapy are eligible if not meeting this criterion \*For elevated AST, ALT, and total bilirubin at screening, subject must have a normalized result prior to initiation of Cycle 2 if abnormal labs are considered related to bile duct obstruction and a biliary stent has been placed
6. Life expectancy \> 12 weeks
7. Negative pregnancy test for women of childbearing potential (either serum or urine) within one day prior to administration of the first dose of chemotherapy. Women of childbearing potential should use highly effective methods of contraception during treatment and for up to 6 months following treatment cessation
8. Provide written informed consent
9. Subjects willing to participate in the study for at least 8 months if randomized to IA gemcitabine OR IV gemcitabine + nab-paclitaxel

Exclusion Criteria:

1. Any prior treatment for pancreatic cancer OR more than one cycle of gemcitabine and nab-paclitaxel treatment. For subjects who have started on their first cycle of gemcitabine and nab-paclitaxel treatment prior to consent, Inclusion Criterion #1 only applies to the first gemcitabine and nab-paclitaxel dose and must be within 6 weeks of confirmed diagnosis
2. Any evidence of metastatic disease or another active malignancy within the past one year except for cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin.
3. Subjects unable or unwilling to have their first randomized treatment within 3 weeks of the post induction imaging and within 5 weeks of their last induction treatment
4. Subjects without baseline tumor imaging
5. As determined by the Sponsor:

   Arterial anatomy unsuitable for IA delivery of gemcitabine to the intended tumor site, determined by CT or MRI, as determined and approved by the Sponsor Imaging Advisor, which includes the following:
   1. Stenosis or occlusion in the intended artery for treatment
   2. Inability to exclude major side branches in the area of the intended RenovoCath® catheter occlusion
   3. No suitable artery with a diameter greater than 3 mm in proximity of at least one side of the tumor
   4. Superior mesenteric vein (SMV) occlusion or stenosis that cannot be resolved with medication or intervention prior to randomization, if the superior mesenteric artery (SMA) is the only viable treatment artery Note: Arterial Anatomy will be reviewed by the Sponsor, RenovoRx Imaging Advisor, and RenovoRx Medical Monitor for approval
6. Contraindications for SBRT planning which includes the following:

   1. Gastrointestinal mucosal infiltration evident at the time of diagnostic endoscopy
   2. Prior abdominal radiotherapy judged to have clinically significant degree of overlap with planned SBRT dose distribution Note: Primary tumors with a diameter greater than 7 cm must be assessed on a case-by-case basis with the RenovoRx Imaging Advisor prior to excluding the subject from the trial.
7. Subjects with known HIV infection or active viral hepatitis
8. Severe infections requiring hospitalization within 4 weeks prior to the first study treatment, including but not limited to complications of infection, bacteremia or severe pneumonia
9. Signs or symptoms of infection within 2 weeks prior to the first study treatment, as assessed by the Investigator
10. Received antibiotics for treatment of an infection within 48 hours prior to initiation of study treatment. Subjects receiving prophylactic antibiotics are eligible
11. History of severe allergic, anaphylactic, or other hypersensitivity reactions to gemcitabine or nab-paclitaxel
12. Any anti-cancer therapy including chemotherapy, hormonal therapy for prostate cancer, or radiotherapy within 2 weeks prior to initiation of study treatment; or herbal therapy intended as anti-cancer therapy within 1 week prior to initiation of study treatment
13. Subjects with uncontrolled seizures
14. Cardiovascular disease including unstable angina or life-threatening cardiac arrhythmia, myocardial infarction, stroke; or New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) within the last 3 months prior to the first study treatment. Subjects with prior history of Myocardial Infarction (MI), congestive heart failure (CHF), coronary artery bypass grafting, or prior valve surgery need to have assessment of ejection fraction (EF) to ensure EF is not ≤ 40% (as determined by MRI, ECHO, or Nuclear Scan), within the last 3 months prior to the initiation of study treatment
15. Other severe concurrent disease or comorbidities which make it difficult to participate in this study, as assessed by Investigator
16. Any of the following procedures prior to initiation of study treatment:

    1. Catheterization, endoscopy, stent or drain placement within 48 hours. (Diagnostic laparoscopy without surgical intervention and/or port placement do not require any wait time prior to study treatment)
    2. Minor surgery requiring light sedation (such as surgical laparoscopy) within 2 weeks
    3. Major surgery within 4 weeks
17. Women who are breastfeeding
18. Male or female subjects of reproductive potential who do not agree to either remain abstinent or employ highly effective and acceptable forms of contraception throughout their participation in the study and for 6 months after the last study treatment
19. Subjects receiving any other investigational agents within 2 weeks prior to the initiation of treatment
20. Any social situations or psychiatric illness that would limit compliance with study requirements
21. Subjects unable or unwilling to have standard catheterization procedure