A Study of Napabucasin Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma
A Study of Napabucasin Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma
This is a randomized, open-label, multi-center, phase 3 study of napabucasin plus weekly
 nab-paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine for adult
 patients with Metastatic Pancreatic Ductal Adenocarcinoma.
Inclusion Criteria:

 1. Written, signed consent for trial participation must be obtained from the patient
 appropriately in accordance with applicable International Conference on Harmonization
 (ICH) guidelines and local and regulatory requirements prior to the performance of any
 study specific procedure.

 2. Must have histologically or cytologically confirmed advanced pancreatic ductal
 adenocarcinoma (PDAC) that is metastatic. The definitive diagnosis of metastatic PDAC
 will be made by integrating the histopathological data within the context of the
 clinical and radiographic data. Patients with islet cell neoplasms are excluded.

 3. Must not have previously received chemotherapy or any investigational agent for the
 treatment of PDAC. A fluoropyrimidine or gemcitabine administered as a radiation
 sensitizer in the adjuvant setting is allowed for as long as last dose was
 administered > 6 months prior to randomization and no lingering toxicities are
 present.

 4. Nab-paclitaxel with gemcitabine therapy is appropriate for the patient and recommended
 by the Investigator.

 5. Patient has one or more metastatic tumors evaluable by CT scan with contrast (or MRI,
 if patient is allergic to CT contrast media) per RECIST 1.1. Imaging investigations
 including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all
 sites of disease must be performed within 14 days prior to randomization. Qualifying
 scans performed as part of standard of care prior to patient signature of the study
 informed consent will be acceptable as baseline scanning as long as scanning is
 performed < 14 days prior to randomization.

 6. Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1,
 assessed within 14 days prior to randomization. Two observers qualified to perform
 assessment of the performance status will be required to perform this assessment. If
 discrepant, the one with the most deteriorated performance status will be considered
 true.

 7. Must have life-expectancy of > 12 weeks.

 8. Must be ≥ 18 years of age. Due to increased risk of sepsis in patients >80 years old,
 candidate patients in this age group should be thoroughly evaluated prior to study
 randomization to ensure they are fit to receive chemotherapy. In addition to all of
 the inclusion/exclusion criteria listed, clinical judgment should be used regarding
 patients' susceptibility to infection (including but not limited to presence of
 ascites or diabetes mellitus increasing risk of infection). Furthermore, the expected
 stability of their performance status while receiving repeat weekly chemotherapy
 cycles should be given special attention. Patients in this age group should not be
 randomized on the study should there be any hesitation on any of these considerations.

 9. For male or female patients of child producing potential: Must agree to use
 contraception or take measures to avoid pregnancy during the study and for 180 days
 after the final dose of nab-paclitaxel and gemcitabine or for 30 days for female
 patients and for 90 days for male patients, after the final napabucasin dose if
 nab-paclitaxel and gemcitabine were not administered.

 10. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy
 test within 5 days prior to randomization.

 11. Patient has adequate biological parameters as demonstrated by the following blood
 counts at baseline (obtained < 14 days prior to randomization; laboratory testing
 performed as part of standard of care prior to patient signature of informed consent
 for the study will be acceptable as baseline laboratory work as long as testing is
 performed < 14 days prior to randomization):

 1. Absolute neutrophil count (ANC) > 1.5 x 10^9/L

 2. Platelet count > 100,000/mm^3 (100 x 10^9/L). Must not have required transfusion
 of platelets within 1 week of baseline platelet count assessment.

 3. Hemoglobin (HgB) > 9 g/dL. Must not have required transfusion of red blood cells
 within 1 week of baseline Hgb assessment.

 12. Patient has the following blood chemistry levels at baseline (obtained < 14 days prior
 to randomization; laboratory testing performed as part of standard of care prior to
 patient signature of informed consent for the study will be acceptable as baseline
 laboratory work as long as testing is performed < 14 days prior to randomization):

 1. AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional upper limit of normal (ULN) [≤ 5
 × ULN in presence of liver metastases]

 2. Total bilirubin ≤ 1.5 x institutional ULN. If total bilirubin is > ULN and < 1.5
 x ULN, it must be non-rising for at least 7 days.

 3. Serum creatinine within normal limits or calculated clearance > 60 mL/min/1.73
 m^2 for patients with serum creatinine levels above or below the institutional
 normal value. If using creatinine clearance, actual body weight should be used
 for calculating creatinine clearance (eg. Using the Cockcroft-Gault formula). For
 patients with a Body Mass Index (BMI) > 30 kg/m^2, lean body weight should be
 used instead.

 13. Patient not on anticoagulation has acceptable coagulation studies (obtained < 14 days
 prior to randomization; laboratory testing performed as part of standard of care prior
 to patient signature of informed consent for the study will be acceptable as baseline
 laboratory work as long as testing is performed < 14 days prior to randomization) as
 demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) below or
 within normal limits (+15%).

 Patients on anticoagulation must have coagulation values within the therapeutic range
 appropriate for the anti-coagulation indication.

 14. Patient has no clinically significant abnormalities on urinalysis results (obtained <
 14 days prior to randomization; laboratory testing performed as part of standard of
 care prior to patient signature of informed consent for the study will be acceptable
 as baseline laboratory work as long as testing is performed < 14 days prior to
 randomization).

 15. Patient must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m^2
 and body weight of > 40 kg with serum albumin > 3 g/dL.

 16. Baseline laboratory evaluations must be done within 14 days prior to randomization and
 some must be repeated < 72 hours prior to randomization.

 17. Patients requiring biliary stent placement must have biliary stent placed > 7 days
 prior to screening.

 18. Pain symptoms should be stable (of tolerable Grade 2 or less).

 19. Only patients with available archival tumor tissue must consent to provision of, and
 Investigator(s) must confirm access to and agree to submit a representative formalin
 fixed paraffin block of tumor tissue in order that the specific correlative marker
 assays (Correlative Studies) of this protocol may be conducted. Submission of the
 tissue does not have to occur prior to randomization. Where local center regulations
 prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block
 and 5-20 unstained slides of whole sections of representative tumor tissue are
 preferred. Where it is not possible to obtain two 2 mm cores of tumor from the block,
 5-20 unstained slides of representative tumor tissue are also acceptable. Where no
 previously resected or biopsied tumor tissue exists or is available, on the approval
 of the Sponsor/designated CRO, the patient may still be considered eligible for the
 study.

 20. Patient must consent to provision of a sample of blood in order that the specific
 correlative marker assays (Correlative Studies) may be conducted.

 21. Patients must be accessible for treatment and follow up. Patients registered on this
 trial must receive protocol treatment and be followed at the participating center.
 This implies there must be reasonable geographical limits placed on patients being
 considered for this trial. Investigators must ensure that the patients randomized on
 this trial will be available for complete documentation of the treatment, response
 assessment, adverse events, and follow-up.

 22. Protocol treatment is to begin within 2 calendar days of patient randomization for
 patients randomized to Arm 1. Patients randomized to Arm 2 must begin protocol
 treatment within 7 calendar days of randomization.

 23. The patient is not receiving therapy in a concurrent clinical study and the patient
 agrees not to participate in other interventional clinical studies during their
 participation in this trial while on study treatment. Patients participating in
 surveys or observational studies are eligible to participate in this study.

 Exclusion Criteria:

 1. Patients with no evidence of metastatic disease as well as patients with a local
 recurrence following surgical resection of primary lesion.

 2. Patient has experienced a decline in ECOG performance status between Baseline visit
 and within 72 hours prior to randomization.

 3. Patient has a > 20% decrease in serum albumin level between Baseline visit and within
 72 hours prior to randomization.

 4. Patient has a > 10% decrease in weight between Baseline visit and within 72 hours
 prior to randomization.

 5. Any prior anti-cancer chemotherapy, biologic or investigational therapy for PDAC.

 1. Patients receiving immunotherapy for non-cancer related treatment within < 4
 weeks of first planned dose of study treatment will be excluded.

 2. A fluoropyrimidine or gemcitabine administered as a radiation sensitizer in the
 adjuvant setting is allowed for as long as last dose was administered > 6 months
 prior to randomization.

 6. Major surgery within 4 weeks prior to randomization.

 7. Any known brain or leptomeningeal metastases are excluded, even if treated.

 8. Patients with clinically significant ascites or pleural effusions.

 9. Women who are pregnant or breastfeeding. Women should not breastfeed while taking
 study treatment and for 4 weeks after the last dose of napabucasin or while undergoing
 treatment with nab-paclitaxel and gemcitabine and for 180 days after the last dose of
 nab-paclitaxel and gemcitabine.

 10. Gastrointestinal disorder(s) which, in the opinion of the Principal Investigator,
 would significantly impede the absorption of an oral agent (e.g. active Crohn's
 disease, ulcerative colitis, extensive gastric and small intestine resection).

 11. Unable or unwilling to swallow napabucasin capsules daily.

 12. Uncontrolled inter-current illness including, but not limited to, ongoing or active
 infection, clinically significant non-healing or healing wounds, symptomatic
 congestive heart failure, unstable angina pectoris, clinically significant cardiac
 arrhythmia, significant pulmonary disease (shortness of breath at rest or mild
 exertion), uncontrolled infection or psychiatric illness/social situations that would
 limit compliance with study requirements.

 1. History of cardiac disease: congestive heart failure (CHF) > New York Heart
 Association (NYHA) Class II; active coronary artery disease, myocardial
 infarction or coronary stenting within 6 months prior to randomization;
 unevaluated new onset angina within 3 months or unstable angina (angina symptoms
 at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers
 or digoxin are permitted).

 2. Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or
 diastolic pressure > 90 mmHg despite optimal medical management) as well as prior
 history of hypertensive crisis or hypertensive encephalopathy.

 3. Significant vascular disease (e.g., aortic aneurysm, aortic dissection,
 symptomatic peripheral vascular disease including claudication, Leo Buerger's
 disease). Treated peripheral vascular disease that is stable for at least 6
 months is allowed.

 4. Evidence of bleeding diathesis or clinically significant coagulopathy.

 5. Major surgical procedure (including open biopsy, significant traumatic injury,
 etc.) within 28 days, or anticipation of the need for major surgical procedure
 during the course of the study as well as minor surgical procedure (excluding
 placement of a vascular access device or bone marrow biopsy) within 7 days prior
 to randomization.

 6. Patients with clinically significant abnormalities on urinalysis at < 14 days
 prior to randomization.

 7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
 abscess within 6 months prior to randomization.

 8. Ongoing serious, non-healing wound, ulcer, or bone fracture.

 9. Known infection with Human Immunodeficiency Virus (HIV), and/or active infection
 with hepatitis B, or hepatitis C.

 10. 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. History of hemolytic-uremic syndrome.

 12. History of connective tissue disorders (eg, lupus, scleroderma, arteritis
 nodosa).

 13. Serious medical risk factors involving any of the major organ systems, or serious
 psychiatric disorders that could compromise the patient's safety or the study
 data integrity.

 13. Known hypersensitivity to gemcitabine, taxanes or any of their excipients, or the
 patient exhibits any of the events outlined in the Contraindications or Special
 Warnings and Precautions sections of the product or comparator Summary of Product
 Characteristics or Prescribing Information. Possible hypersensitivity to napabucasin
 or one of the excipients which include the azo dyes sunset yellow and allura red.

 14. Neurosensory neuropathy > grade 2 at baseline.

 15. Uncontrolled chronic diarrhea > grade 2 at baseline.

 16. Patients being treated with Warfarin.

 17. Patients with active, uncontrolled bacterial, viral or fungal infection(s) requiring
 systemic therapy

 18. Patients with a history of other malignancies except: adequately treated non-melanoma
 skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors
 curatively treated by surgery alone or surgery plus radiotherapy with no evidence of
 disease continuously for > 5 years.

 19. Any active disease condition which would render the protocol treatment dangerous or
 impair the ability of the patient to receive protocol therapy.

 20. Any condition (e.g. psychological, geographical, etc.) that does not permit compliance
 with the protocol, including patients with history of poor compliance or history of
 drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere
 with the ability to comply with the study protocol. Patients planning to take a
 vacation for 14 or more consecutive days during the course of the study are
 ineligible.