Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in Combination With GC4419 in Pancreatic Cancer
Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in Combination With GC4419 in Pancreatic Cancer
The purpose of the phase I/II clinical study is to determine the best dose of fractionated
 stereotactic radiation therapy (SBRT) given either with GC4419 or placebo to patients who
 have been diagnosed with locally advanced pancreatic cancer.
This is a parallel arm adaptive design phase I-II dose-finding study to determine the optimal
 dose of fractionated stereotactic radiation therapy (SBRT), given either with the
 radiomodulating agent GC4419 or placebo for treatment of locally advanced pancreatic cancer.
 Dose-finding will be done using the sequentially adaptive phase I-II Late onset
 Efficacy-Toxicity (LO-ET) trade-off-based design [1-3].

 A maximum of 48 patients will be randomized 1:1 to Arm A or Arm B. Patients in Arm A will
 receive GC4419 in combination with their assigned SBRT dose, and patients in Arm B will
 receive Placebo (PBO) with their assigned SBRT dose. The randomization will be restricted so
 that the sample size within each arm is exactly 24 patients.

 GC4419/placebo will be given intravenously in a one hour infusion. SBRT must be initiated as
 soon as possible upon completion of the GC4419/placebo infusion.

 GC4419/placebo will be given beginning on the first day of radiation and continuing daily,
 concurrent M-F throughout the administration of SBRT

 Objectives:

 Primary:

 • To determine the Maximum Tolerated Dose (MTD) of Stereotactic Body Radiation Therapy (SBRT)
 when given in combination with placebo or GC4419

 Secondary:

 -  To evaluate Progression-free survival (PFS) at MTD for patients treated with SBRT given
 in combination with placebo or GC4419

 -  To evaluate Overall Response Rate (ORR) including stable disease, partial/ complete
 response for patients treated with SBRT given in combination with placebo or GC4419

 -  To evaluate late (12 month) toxicity of SBRT in combination with placebo or GC4419
Inclusion Criteria:

 1. Cytologic or biopsy confirmed adenocarcinoma of the pancreatic head, body or tail

 2. Disease that is appropriate for SBRT by virtue of being:

 a. Locally advanced and technicallyunresectable, as determined by a pancreaticobiliary
 surgeon as part of a multidisciplinary review at the investigative site, including
 multi-phasic CT demonstrating: i.Greater than 180 degree tumor involvement of the
 superior mesenteric artery ii. Greater than 180 degree tumor involvement of the celiac
 axis, including major branches of the celiac axis that render it unresectable (e.g.
 common hepatic artery).

 iii. Tumor involvement of the first branch of the SMA that is not surgically
 reconstructible iv. Long segment involvement of the superior mesenteric vein/portal
 vein or hepatic artery that is not surgically reconstructible b. Potentially
 resectable, but patient is judged not a candidate for surgery, after multidisciplinary
 review at the investigative site; c. Potentially resectable, but the patients refuses
 surgery and is considered an acceptable candidate for SBRT after multidisciplinary
 review at the investigative site; d. "Borderline" resectable, as determined by
 multidisciplinary review, including absence of distant lymphadenopathy and the primary
 tumor characterized by one of more of the following: i. A tumor-vessel interface (TVI)
 with the mesenteric vein (SMV) or portal vein (PV) measuring ≥180° of the
 circumference of either vein's wall or short-segment occlusion of either vein with a
 normal vein above or below the obstruction amenable to reconstruction; ii. Any TVI
 with the common hepatic artery (CHA) with normal artery proximal and distal to the TVI
 amenable to reconstruction; iii. A TVI with the superior mesenteric artery (SMA)
 measuring <180° of the circumference of the vessel wall

 3. Pancreatic tumor size and limited bowel involvement by tumor must be judged acceptable
 for SBRT at the discretion of the treating investigator

 4. No evidence of distant metastasis either prior to or after induction chemotherapy.

 5. Completion of at least 3 months of standard induction chemotherapy for LAPC, which
 should consist of either FOLFIRINOX, gemcitabine or nab-paclitaxel or another standard
 combination of induction chemotherapy agents

 6. Patient must have metal stent in place if duodenal stent is required. If patient has
 plastic stent, this must be replaced prior to radiation.

 7. Ability to understand and follow the breathing instructions involved in the
 respiratory gating procedure or to tolerate compression sufficient to reduce fiducial
 motion to <= 5mm.

 8. Age 18 years or older

 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (0, 1 or 2)

 10. Adequate hematologic function as indicated by i. Absolute neutrophil counts (ANC) ≥
 1,500/mm3 ii. Hemoglobin (Hgb) ≥ 8.0 g/dL iii. Platelet count ≥ 75,000/mm3

 11. Adequate renal and liver function as indicated by:

 i. Creatinine ≤ 1.5 x upper-normal limit (ULN) ii. Total bilirubin ≤ 1.5 x
 upper-normal limit (ULN) iii. Aspartate aminotransferase (AST) and alanine
 aminotransferase (ALT) ≤ 2.5 x ULN iv. Alkaline phosphatase ≤ 2.5 x ULN

 12. Properly obtained written informed consent

 Exclusion Criteria:

 1. Prior radiation therapy to the abdomen that would overlap with treatment field

 2. Prior surgical resection of pancreatic tumor

 3. Receiving any approved or investigational anti-cancer agent other than those provided
 for in this study

 4. Uncontrolled or active gastric or duodenal ulcer disease within 30 days of enrollment

 5. Visible invasion of tumor into the lumen of the bowel or stomach on endoscopy (Note:
 Radiological infiltration into bowel is allowed, unless deemed clinically unsafe.)

 6. Residual or ongoing ≥ Grade 3 non-hematologic toxicity from chemotherapy

 7. Contraindication to IV contrast

 8. Concurrent participation in another interventional clinical trial or use of another
 investigational agent within 30 days of study entry Note: Patients who are
 participating in non-interventional clinical trials (e.g., QOL, imaging,
 observational, follow-up studies, etc.) are eligible, regardless of the timing of
 participation.

 9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, renal
 failure, cardiac arrhythmia, or psychiatric illness that would limit compliance with
 treatment

 10. Second primary malignancy within the last 5 years, unless treated definitively and
 with low risk of recurrence in the judgment of the treating investigator

 11. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for
 hepatitis B and do not have a history of infection are eligible)

 12. Female patients who are pregnant or breastfeeding

 13. Women of child-bearing potential who are unwilling or unable to use an acceptable
 method of birth control to avoid pregnancy for the entire study period and for 30 days
 after the last dose of GC4419. This includes any woman who has experienced menarche
 but has not undergone successful surgical sterilization or is not postmenopausal
 (defined as amenorrhea for at least 12 consecutive months, or women on hormone
 replacement therapy with serum FSH levels greater than 35 mIU/mL. A negative urine or
 serum pregnancy test must be obtained within 14 days prior to the start of study
 therapy in all women of child-bearing potential.

 14. Male subjects who are unwilling or unable to use an acceptable method of birth control
 to avoid pregnancy for the entire study period and for up to 90 days after the last
 dose of GC4419 are excluded.

 15. Requirement for concurrent treatment with nitrates or other drugs that may, in the
 judgment of the treating investigator, create a risk for a precipitous decrease in
 blood pressure.

 16. Medical history that includes any condition, or requires the use of concomitant
 medications which, in the investigator's judgment, are associated with or create a
 risk of increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal
 episodes.