A Study of Napabucasin Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma
Condition: Carcinoma, Pancreatic Ductal
MeSH terms: Adenocarcinoma; Carcinoma, Pancreatic Ductal
Intervention: Napabucasin; Nab-paclitaxel; Gemcitabine
Intervention description: Napabucasin will be administered orally, twice daily, with doses separated by approximately 12 hours.; Nab-paclitaxel 125 mg/m^2 immediately followed by gemcitabine 1000 mg/m^2 will be administered on Days 1, 8 and 15 of every 28-day cycle via intravenous infusion.; Nab-paclitaxel 125 mg/m^2 immediately followed by gemcitabine 1000 mg/m^2 will be administered on Days 1, 8 and 15 of every 28-day cycle via intravenous infusion.
Intervention MeSH terms: Paclitaxel; Gemcitabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1134.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Albumin-Bound Paclitaxel; Gemcitabine

Summary:

      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.
    

Eligibility criteria:

        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.