Paclitaxel Protein Bound Plus Cisplatin Plus Gemcitabine and Paricalcitol for Pancreatic Adenocarcinoma (NABPLAGEMD)

Pancreatic cancer continues to be a highly lethal disease with an overall 5 year survival of
only 8%. Since 2004, the incidence of pancreatic cancer has been increasing by 1.5% per year
and it is estimated that there will be 53,670 new cases diagnosed in the United States in
2017, with 43,090 expected deaths. Pancreatic cancer is the third most common cause of
cancer-related deaths in both men and women, and the incidence is about equal in both sexes.
Of all types of pancreatic cancers, pancreatic ductal adenocarcinoma (PDA) is by far the most
common, representing 80% of cases. Due to lack of adequate screening techniques, greater than
80% of patients at the time of diagnosis present with unresectable, advanced disease.
Standard treatment options for inoperable patients with locally advanced and metastatic PDA
have been quite limited. Gemcitabine monotherapy, approved by the Food and Drug
Administration (FDA) in 1996, demonstrated a median survival of 5.7 months, and has been the
mainstay in treating patients with PDA. The first combination regimen to demonstrate any
survival benefit compared with gemcitabine alone was gemcitabine plus erlotinib, with median
survival of 6.24 months versus 5.91 months for single agent gemcitabine.

A meta-analysis of randomized trials by Heinemann and colleagues showed that patients with
advanced pancreatic cancer and a good performance status may benefit from combination
chemotherapy with gemcitabine plus a platinum agent or a fluoropyrimidine. Multiple
combination regimens are being utilized.

Recently, the regimen of 5-fluorouracil/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX)
compared with gemcitabine demonstrated improvement in both progression-free survival (PFS,
6.4 vs. 3.3 months) and overall survival (OS, 11.1 vs. 6.8 months) for patients with a good
performance status. FOLFIRINOX, however, is associated with substantial grade 3 and 4
toxicities, including diarrhea, nausea, vomiting, fatigue, neutropenia and febrile
neutropenia, and cannot be given to patients >76 years of age or in some cases patients with
head of the pancreas tumors. An international phase III trial comparing paclitaxel protein
bound (now called paclitaxel protein bound) plus gemcitabine to gemcitabine single agent
demonstrated a statistically significant improvement in OS (8.5 vs. 6.7 months) for advanced
pancreatic cancer patients using the gemcitabine and paclitaxel protein bound over
gemcitabine alone.

A recently completed phase Ib/II trial of the combination of paclitaxel protein bound plus
gemcitabine plus cisplatin in previously untreated stage IV pancreatic adenocarcinoma
patients was presented at the 2017 Gastrointestinal Cancer Symposium. In 24 patients with
stage IV pancreatic cancer they reported 8.3% complete response (CR), 62.5% partial response
(PR), 16.7% stable disease and 12.5% progressive disease. The rationale for adding cisplatin
to paclitaxel protein bound and gemcitabine is that in a study of 1,029 patients whose
pancreatic cancer tumors underwent molecular profiling, 57% of these tumors were negative for
expression of the excision repair cross-complementation group 1 (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
deoxyribonucleic acid (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 PFS
and 8.3 month OS as second line therapy.

Most recently, a study showed that Vitamin D can change the pancreatic tumor microenvironment
from an immunologically suppressive (tumor promoting) one to an immunologically hostile one
(e.g. decreased IL-6, decreased CXCL12 etc.). In addition, in the same study, the vitamin D
ligand calcipotriol decreased production of collagen, decreased myeloid derived suppressor
cells (MDSCs) and decreased regulatory T cells. Remarkably, in clinical practice, the vitamin
D analogue paricalcitol was observed to reverse chemotherapy resistance. Two individuals with
pancreatic adenocarcinoma who were receiving paclitaxel protein bound and gemcitabine based
combination chemotherapy developed progressive disease which was reversed by the addition of
paricalcitol.

Based upon these promising clinical and pre-clinical data we are initiating a clinical trial
combining paclitaxel protein bound, gemcitabine, and cisplatin for patients with metastatic
PDA. When these patients develop progressive disease the vitamin D analog paricalcitol will
be added to the regimen. The treatment will continue until further disease progression.

Inclusion Criteria:

1. Age ≥18 years of age; male or female.

2. Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma.

3. Capable of providing informed consent and complying with trial procedures including
obtaining paired biopsies during therapy

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

5. Life expectancy ≥ 12 weeks.

6. Measurable tumor lesions according to RECIST 1.1 criteria.

7. Women must agree not to become pregnant (e.g. post-menopausal for at least 1 year,
surgically sterile, or practicing adequate birth control methods) for the duration of
the study and until 90 days after last dose of study treatment. Women of child bearing
potential must have a negative serum or urine pregnancy test at the Screening Visit
and be non-lactating. Both male and female patients of reproductive potential must
agree to use a reliable method of birth control during the study.

Exclusion Criteria:

1. Patients must have received no previous radiotherapy, surgery, chemotherapy or
investigational therapy for the treatment of metastatic disease. Prior treatments in
the adjuvant setting with gemcitabine and/or Fluorouracil (5-FU) or gemcitabine
administered as a radiation sensitizer are allowed, provided at least 6 months have
elapsed since completion of the last dose and no lingering toxicities are present.

2. Palliative surgery and/or radiation treatment less than 4 weeks prior to initiation of
study treatment.

3. Exposure to any investigational agent within 4 weeks prior to initiation of study
treatment.

4. Evidence of central nervous system (CNS) metastasis (negative imaging study, if
clinically indicated, within 4 weeks of Screening Visit).

5. History of other malignancies (except cured basal or squamous cell carcinoma,
superficial bladder cancer, prostate cancer in active surveillance, or carcinoma in
situ of the cervix) unless documented free of cancer for ≥2 years.

6. Laboratory values: Screening serum creatinine >1.5 mg/dL; total bilirubin > (ULN);
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 2.5x ULN or ≥
5.0×ULN if liver metastases are present; absolute neutrophil count <1,500/mm3,
platelet concentration <100,000/mm3, hematocrit level <27% for females or <30% for
males, or coagulation tests (prothrombin time [PT], partial thromboplastin time [PTT],
International Normalized Ratio [INR]) >1.5×ULN unless on anticoagulation agents.

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

8. History of HIV infection.

9. Active, clinically significant serious infection requiring treatment with antibiotics,
antivirals or anti-fungals.

10. Any condition that might interfere with the patient's participation in the study or in
the evaluation of the study results.