Trial of Ascorbic Acid (AA) + Nanoparticle Paclitaxel Protein Bound + Cisplatin + Gemcitabine (AA NABPLAGEM)

Pancreatic cancer continues to be a very lethal disease. It was estimated that in 2016,
53,070 Americans would be diagnosed with pancreatic ductal adenocarcinoma (PDA), and 41,780
would die from the disease. This makes pancreatic cancer the third leading cause of death
from cancer in the US.

PDA is the twelfth most common cancer in the world with 338,000 new cases diagnosed in 2012.
It is estimated that worldwide there will be > 300,000 deaths from pancreatic cancer.
Furthermore unfortunately PDA is projected to be the second leading cause of death from
cancer in the US by 2030.

Detection of pancreatic cancer has notoriously been very late in the disease and therefore
the 5-year survival rate is only 8%, which is actually a slight improvement over the last few
years. Right now the only potential cure for pancreatic cancer is surgical resection (if the
disease is caught early). However only about 20% of PDA patients are eligible for potentially
curable resection and unfortunately most (> 80%) have recurrence of their cancer within 2
years of resection, and those recurrences are almost universally fatal.

Recently it has been shown that there are regimens that actually improve survival for
patients with advanced stage IV PDA. Conroy and colleagues have developed the Folfirinox
regimen, which in a large randomized trial improved survival over gemcitabine as a single
agent. Von Hoff and colleagues developed the nanoparticle albumin (nab) associated paclitaxel
plus gemcitabine regimen which improved survival over single agent gemcitabine. Even more
recently Jameson and colleagues have presented a combined regimen of nab-paclitaxel +
gemcitabine + cisplatin in a small 24 patient phase Ib/II trial which showed a response rate
of 71% with 2 patients having complete response, a 1-year survival of 65% and a median
survival of 16+ months.

While there have been multiple investigators and investigations into the use of ascorbic acid
for patients with cancer (see ClinTrials.gov), its use has generally not been found to be of
help for patients particularly when given orally - e.g. 10 grams daily.

Inclusion Criteria:

Patients must meet the following criteria to be included in the trial:

- Be willing and able to provide written informed consent/assent for the trial.

- Be ≥ 18 years of age on day of signing informed consent.

- Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (with
measurable disease according to RECIST 1.1 criteria).

- Have a performance status of 0 or 1 on the ECOG performance scale.

- Demonstrate adequate organ function as defined below in table 4. All screening labs
should be performed within 14 days of treatment initiation.

- Female participants of childbearing potential should have a negative serum pregnancy
test within 72 hours prior to receiving first dose of study medication.

- Female participants of childbearing potential must be willing to use adequate method
of contraception (as outlined in section 4.4.2) for the duration of the trial.

- Male participants must agree to use adequate contraception (as outlined in section
4.4.2) for the duration of the trial.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the participant.

Exclusion Criteria:

Patients must not meet any of the following criteria in order to be eligible for the trial:

- 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 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.

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

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

- Patients who need constant use of finger stick blood glucose monitoring for tight
contro l of their diabetes being the ascorbic acid causes false low readings of
glucose via that technology (Vasudevan and Hirsch 2014) 39

- Any person with a G6PD deficiency

- History of renal oxalate stones (if type of stone is unknown, need to assess urine
oxalates level if >60mg/dL, then patient is not eligible for the study)

- Patient is taking acetaminophen at any dose, or any medication that contains
acetaminophen within 72 hours of first dose of ascorbic acid.

- Hypersensitivity to any of the agents proposed for treatment.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

- Has an active infection requiring systemic therapy.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through one week from the last dose of trial treatment.

- Patients with evidence of iron overload, defined as a transferrin saturation > 45
percent AND serum ferritin > 200 ng/mL (males) or >150 ng/mL (females).

- Current, serious, clinically significant cardiac arrhythmias as determined by the
investigator, or patient receiving a digitalis derivative.