Pre-operative Treatment for Patients With Untreated Pancreatic Cancer

Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced
unresectable disease and borderline resectable disease. Typical regimens utilize those that
are used in the metastatic setting for pancreatic cancer, such as FOLFIRINOX (5-FU,
Leucovorin, Irinotecan, and Oxaliplatin) and paclitaxel protein bound plus Gemcitabine.
Currently, the recommendation of utilizing neoadjuvant therapy for potentially resectable
pancreatic cancer has been met with controversy. However a recent study published an analysis
of individuals with potentially resectable pancreatic cancer and showed a median overall
survival of 31.5 months with 44.9 months for the 60 individuals who underwent neoadjuvant
therapy and resection compared to 8.1 months for the 9 patients who were not resected.
Another study examined the use of nab-paclitaxel, gemcitabine, capecitabine, and cisplatin
(PAXG regimen) in individuals with unresectable or borderline resectable pancreatic cancer
patients. A partial response was observed in 67% of the patients along with progression-free
survival at 6 months being 96%. Furthermore, a recent study examining stage I or stage II
pancreas cancer patients who received either neoadjuvant therapy followed by resection or
those who received upfront resection was reported. In those receiving neoadjuvant therapy,
overall survival was 26 months compared to 21 months. Neoadjuvant, as opposed to adjuvant
therapy potentially increases the amount of exposure of drug to the tumor. It allows for the
completion of therapy prior to surgery to prevent patient drop-out due to perioperative
complication. Neoadjuvant therapy also acts as a selection tool for optimal surgical
candidates by identifying aggressive tumor biology prior to surgery and therefore selecting
out those who will not benefit from resection. Radiation therapy may be also employed in the
neoadjuvant setting as a means to help with local control and survival in individuals without
micrometastatic disease.

The combination of nab-paclitaxel (now called paclitaxel protein bound) and gemcitabine had a
high response and survival in the phase I and II study in advanced pancreatic cancer. In this
phase I study with expansion at the phase II dose, 67 pts were accrued. The phase II dose was
determined to be weekly nab-paclitaxel 125 mg/m2 with gemcitabine 1000 mg/m2. Therapy was
well tolerated at the phase II dose. For all patients (n=67), the median time for
progression-free survival (PFS) was 7.1 months (95%CI, 5.7 to 8.0 months), and the median
time for overall survival (OS) was 10.3 months (95% CI, 8.4 to 13.6 months). For patients at
the recommended dose of 125 mg/m2 nab-paclitaxel, the median PFS was 7.9 months (95% CI, 5.8
to 11.0 months), and the median OS time was 12.2 months (95% CI, 8.9 to 17.9 months).
Additionally, the 1-year survival is reported at 48% at the maximum tolerated dose (MTD), and
the overall response rate (ORR) was 46% for all patients (n=67). The combination of
nab-paclitaxel and gemcitabine was generally well tolerated and had substantial antitumor
activity in patients with pancreatic cancer, enough to warrant a phase III clinical trial.

In the phase III (MPACT study, n=861) patients were randomly assigned to nab-paclitaxel plus
gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months
in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group
(P<0.001). The one year survival rate was 35% in the nab-paclitaxel-gemcitabine group versus
22% in the gemcitabine group, and 9% versus 4% at 2 years. The median PFS was 5.5 months in
the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group
(P<0.001); the response rate according to independent review was 23% versus 7% in the two
groups (P<0.001). Adverse events were tolerable with grade > 3 events of neutropenia (38% in
the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%),
and neuropathy (17% vs. 1%) and febrile neutropenia (3% versus 1%). Based on the results of
this study, nab-paclitaxel plus gemcitabine is a FDA approved regimen for pancreatic cancer.

Building on the design and mechanisms of action of the nab-paclitaxel and gemcitabine
combination, a prior protocol introduced a third cytotoxic agent cisplatin, was added to this
doublet. The rationale for adding cisplatin to nab-paclitaxel and gemcitabine was that in a
study of 1,029 patients whose pancreatic cancer tumors were sent for molecular profiling, 57%
of these tumors were negative for ERCC1, indicating sensitivity to a platinum anti-tumor
agent. In addition to the above, in our whole genome/transcriptome sequencing analysis, we
found that abnormal repair pathways were a feature of all of the pancreatic cancers that were
sequenced. Cisplatin prevents cellular DNA repair by binding to and causing crosslinking of
DNA, triggering apoptosis. Cisplatin has been used in other combination regimens to treat
patients with PDA. For example, the cisplatin, epirubicin, 5-fluorouracil and gemcitabine
(PEFG) regimen had an acceptable toxicity profile and was associated with a 24% partial
response rate, 5 month progression-free survival (PFS) and 8.3 month overall survival as
second line therapy.

Prior to 2015, there were no documented reports of the combination of cisplatin with
paclitaxel protein bound and gemcitabine in the treatment of any human cancer. However,
cisplatin had been combined with paclitaxel and gemcitabine in the treatment of patients with
locally advanced or metastatic non-small cell lung cancer (NSCLC) patients and had shown
substantial antitumor activity with an acceptable safety profile. In that phase I-II study of
65 patients with advanced NSCLC, the overall response rate was 57%. The aforementioned
neoadjuvant study led by Reni also utilized cisplatin with albumin bound paclitaxel along
with gemcitabine and capecitabine.

More recently there has been even more compelling science indicating that one should consider
DNA repair as an Achilles heel in pancreatic cancer. A team led by Nurse Practitioner Gayle
Jameson recently reported on the phase Ib/II trial of the combination of paclitaxel
protein-bound plus gemcitabine plus cisplatin. In 24 evaluable patients with stage IV
pancreatic cancer they reported a response rate of 71% (Complete Response (CR) + Partial
Response (PR)) along with a 88% disease control rate (CR + PR+ Stable Disease (SD) at 9
weeks). Utilizing this highly active therapy in the neoadjuvant setting may lead to further
improvement in overall survival and progression free survival in patients with pancreatic
cancer.

Most recently the spectacular work of researchers has awakened the world of pancreatic cancer
research to the possibility that Vitamin D could be a substantial player in normalizing the
tumor microenvironment from an immunologically friendly (to the tumor) one to an
immunologically hostile one (e.g. decreased IL6, decreased CXCL12 etc.). In addition, the
vitamin D analog decreased production of collagen, decreased Myeloid Derived Suppressor cells
(MDSCs) and decreased regulating T cells. In an ongoing neoadjuvant trial utilizing
gemcitabine and paclitaxel protein bound with paricalcitol compared to gemcitabine and
paclitaxel protein bound, a modulation of the tumor microenvironment has been seen including
greater infiltration of CD3 positive lymphocytes. Therefore, a trial utilizing gemcitabine,
paclitaxel protein bound, cisplatin and paricalcitol may yield promising results in the
neoadjuvant setting.

Inclusion Criteria:

1. Patient has histologically or cytologically confirmed resectable, borderline
resectable, or locally advanced (unresectable) PDAC (based upon Tempero et al 2016)

- Definition of Resectable Pancreatic Cancer includes all of the following:

- No evidence of extra pancreatic disease

- No evidence of tumor-arterial abutment (celiac, SMA [superior mesenteric artery]
or HA [hepatic artery])

- If tumor induced narrowing of the SMV [superior mesenteric vein], PV [portal
vein] or SMV-PV [superior mesenteric-portal vein] confluence is present, it must
be <50% of the diameter of the vessel

- Definition of Borderline Resectable Pancreatic Cancer

- To include at least one of the following:

- Tumor abutment <180° of the SMA or celiac axis

- Tumor abutment or encasement of a short segment of the HA

- Tumor induced narrowing of SMV, PV or SMV-PV of >50% of the diameter of the
vessel.

- Short segment occlusion of the SMV, PV or SMV-PV with a suitable PV above and SMV
below, for reconstruction

- Biopsy proven N1 disease (regional lymph nodes involved) from pre-referral biopsy
or EUS-guided FNA

- Definition of Locally Advanced (Unresectable)

- Artery: Tumor encasement (> 180°) of SMA or celiac artery

- Vein Occlusion of SMV, PV or SMV-PV without suitable vessels above and below the
tumor to allow for reconstruction (no distal or proximal target for vascular
reconstruction)

- No extra pancreatic disease: No evidence of peritoneal, hepatic, or
extra-abdominal metastases

2. Age ≥ 18 years.

3. If a female patient is of child-bearing potential, she must have a negative serum
pregnancy test (≥β-hCG) documented within 72 hours of the first administration of
study drug

4. If sexually active, the patient and partner must agree to use contraception considered
adequate and appropriate by the Investigator

5. Patient must have received no prior chemotherapy or radiation therapy for PDAC

6. Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥ 1,500/mm3

- platelets ≥ 100,000/mm3

- Hematocrit level > 27%

- total bilirubin within institutional upper limit of normal (ULN)

- AST/ALT ≤ 2.5 × institutional ULN

- Alkaline phosphatase (AP) ≤ 2.5 x institutional ULN

- Creatinine < 1.5 mg/dl

7. Patient has acceptable coagulation status as indicated by an INR ≤ 1.5 x ULN. Patients
on anticoagulation can be included at the discretion of the investigator.

8. Karnofsky Performance Status (KPS) of ≥70%.

9. Have an elevated CA 19-9

Exclusion Criteria:

1. Patient will be excluded from this study if any of the following criteria apply:
Evidence of metastatic disease. No metastatic disease defined as any one or more of
the following:

- Suspicious lymphadenopathy outside of the standard surgical field (i.e.
aortocaval nodes, distant abdominal nodes)

- Radiographic evidence for metastatic disease in distant organs, peritoneum, or
ascites

2. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic
therapy.

3. Known infection with HIV, hepatitis B, or hepatitis C.

4. Has undergone major surgery, other than diagnostic surgery (i.e. surgery done to
obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to
Day 1 of treatment in this study.

5. History of allergy or hypersensitivity to the study drugs.

6. Serious medical risk factors involving any of the major organ systems such that the
Investigator considers it unsafe for the patient to receive an experimental research
drug.

7. Current, serious, clinically significant cardiac arrhythmias as determined by the
investigator.

8. Patient is unwilling or unable to comply with study procedures.

9. Patient is enrolled in any other therapeutic clinical protocol or investigational
trial.

10. Patient with a history of interstitial lung disease, history of slowly progressive
dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,
pulmonary hypersensitivity pneumonitis or multiple allergies.

11. Use of non-FDA approved cannabinoids are prohibited. Total daily usage of up to 40 mg
per day of marinol is acceptable.