Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in Combination With GC4419 in 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 but no later than 60 minutes
following the end 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 at 90 days for patients treated with SBRT given in combination with placebo or
GC4419

- To evaluate tumor resectability after SBRT in combination with placebo or GC4419

- To evaluate the R0 Resection Rate and Pathologic Complete Response Rate (pCR) for
patients who eventually undergo surgical resection

- To compare acute toxicity rate at 90 days for patients treated at the SBRT MTD in
combination with placebo or GC4419

- To compare efficacy rates at 90 days for patients treated at the SBRT MTD with placebo
or GC4419

Exploratory:

- To evaluate patient reported outcomes for patients treated with SBRT in combination with
placebo or GC4419

- To compare genomic changes based on whole exome sequencing, and transcriptome sequencing
from pre and post SBRT core biopsy samples.

- To compare pathologic changes pre and post SBRT based on core biopsy samples

- To compare differences in immune infiltrate pre and post SBRT using IHC for immune
activation, exhaustion and proliferation phenotypes, deep T cell sequencing from core
biopsy specimens and multi parametric flow cytometry (MPFC) from cytology brushings

- To compare changes in circulating tumor cells (CTC's), circulating tumor DNA (ctDNA) and
circulating immune cells (MPFC) pre and post SBRT

Inclusion Criteria:

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

2. Locally advanced, unresectable pancreatic cancer as determined by a pancreaticobiliary
surgeon as part of a multidisciplinary discussion at MDACC, including triphasic CT
demonstrating tumor abutment of the superior mesenteric artery (SMA) or celiac axis,
superior mesenteric vein (SMV) or portal vein (PV) involvement which is not resectable
without vascular reconstruction.

3. Pancreatic tumor size ≤ 5cm

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

5. Completion of at least 3 months, but no more than 7 months of standard induction
chemotherapy for LAPC, which should consist of either FOLFIRINOX or gemcitabine and
nab-paclitaxel, preferably with a washout period no longer than 8 weeks.

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 ≥ 100,000/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 in the patient's primary language (English
or Spanish). If patient is not sufficiently fluent in either English or Spanish to
understand consent, they will not be eligible for the study.

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. Direct invasion of the duodenum by the primary tumor

6. Residual or ongoing ≥ Grade 3 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.