Inclusion Criteria

• Must have signed written informed consent documented according to International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), the local regulatory requirements, and permission to use private health information in accordance with the Health Insurance Portability and Accountability Act (HIPAA) prior to study-specific screening procedures
• Must have histologic or cytologic evidence of adenocarcinoma of the pancreas, such as a core tissue biopsy or a surgical resection specimen
• Must have metastatic disease
• Must have baseline imaging of chest, abdomen and pelvis (CT or MRI) within 21 days prior to initiation of protocol therapy
• Must have measurable disease as defined by RECIST 1.1
• Can not have locally advanced unresectable pancreatic ductal adenocarcinoma
• Arm A (Gemcitabine and nab-Paclitaxel) or Arm B (mFOLFIRINOX) may have up to two prior lines of systemic therapy
  • Adjuvant therapy is counted as one line of therapy as long as disease recurrence occurred > 6 months from last dose of therapy
  • Can have prior systemic therapy in the metastatic setting if the therapy contained BBI608 in combination with either Gemcitabine and nab-Paclitaxel or mFOLFIRINOX
  • Toxicities related to prior therapy must have completely resolved (except for alopecia and anemia), or be deemed irreversible
  • Can have received Gemcitabine-based therapy in an adjuvant setting for Arm A of the trial (Gemcitabine with nab-Paclitaxel) as long as the last Gemcitabine administration was at least 6 months prior to the first dose of BBI608
  • Arm A (Gemcitabine with nab-Paclitaxel) can have prior mFOLFIRINOX in combination with BBI608 in the metastatic setting
  • Arm B (mFOLFIRINOX) can have prior Gemcitabine with nab-Paclitaxel in combination with BBI608 in the metastatic setting
  • Prior treatment with radiotherapy is allowed
• Arm C (FOLFIRI) or Arm D (MM-398 with 5-FU and leucovorin) must have failed one prior line of gemcitabine-based therapy with or without BBI608 in the metastatic setting
  • Can not have additional lines of therapy in the metastatic setting
  • Can have prior adjuvant therapy with gemcitabine as long as disease recurrence occurred > 6 months from the last dose of therapy
  • Toxicities related to prior therapy must have completely resolved, except for alopecia and anemia, or be deemed irreversible.
  • Can have had prior radiotherapy
• ≥ 18 years of age
• Must have an ECOG Performance Status ≤ 1
• Male or female patients of child-producing potential agree to use contraception or measures to avoid pregnancy  during the study and for 30 days after the last BBI608 dose
• Females of childbearing potential must have a negative serum pregnancy test in the preceding 72 hours of the first day of BBI608 treatment
• Basiliary or gastro-duodenal obstruction must have drainage or surgical bypass prior to starting chemotherapy
• Significant or symptomatic amount of ascites should be drained prior to first dose of BBI608
• Warfarin/Dabigatran/Rivaroxaban anticoagulation acceptible if will undergo weekly INR checks for the first 2 months of therapy
  • If switched to low molecular weight heparin  weekly INR labs are not mandated
• Aspartate transaminase (AST) level ≤ 2.5 x upper limit of normal (ULN) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN)
• Liver metastases with AST ≤ 5 ULN, and AST ≤ 5 ULN can be agreed upon by the investigator and medical monitor for the sponsor
• Total bilirubin level ≤ 1.5 x ULN
  • ≤ 2 x ULN accepted if it is non-rising for a period of 10 days prior to initiation of therapy
• Creatinine level < 1.0 x ULN 
  • Creatinine clearance ≥ 60 mL/min/1.73 m^2 if creatinine levels above or below the institutional normal as determined by Cockcroft-Gault equation
• If Body Mass Index (BMI) > 30 kg/m^2, lean body weight should be used to calculate the GFR
• Hemoglobin (Hgb) ≥ 9 g/dl
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Acceptable coagulation studies as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (+/-15%)
• No clinically significant abnormalities on urinalysis results
• Life expectancy estimated at ≥ 3 months

Exclusion Criteria

• Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 14 days of the first dose of BBI608, except for BBI608 for which a washout period is not required
  • May begin BBI608 on a date determined by the investigator and medical monitor for the sponsor after a minimum of 14 days since last receiving anti-cancer treatment which did not include BBI608, provided that all treatment-related adverse events have resolved or have been deemed irreversible (except for alopecia)
  • Previously received BBI608 for treatment of PDAC on the BBI608-118 (BBI608-201PANC) study may be continued with BBI608 in monotherapy between discontinuation of the first chemotherapy backbone and start of the second chemotherapy backbone
  • May begin chemotherapy backbone on a date determined by the investigator and medical monitor for the sponsor after a minimum of 14 days and a maximum of 30 days since last receiving anti-cancer treatment which included BBI608, provided that all treatment-related adverse events have resolved or have been deemed irreversible (except for alopecia)
• Neuroendocrine neoplasms
• Major surgery, other than diagnostic surgery done to obtain a biopsy for diagnosis without removal of an organ, within 4 weeks prior to first dose
• Any brain metastases including leptomeningeal metastases even if treated and stable
• History of posterior reversible encephalopathy syndrome
• Neurosensory neuropathy ≥ grade 2 at baseline
• Pregnant or breastfeeding
• Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent 
  • Crohn's disease
  • Ulcerative colitis
  • Extensive gastric resection 
  • Small intestinal resection
• Unable or unwilling to swallow BBI608 capsules daily
• Uncontrolled chronic diarrhea ≥ grade 2 at baseline
• Uncontrolled intercurrent illness including, but not limited to
  • Uncontrolled active infection including bacterial, viral or fungal requiring systemic therapy
  • Clinically significant non-healing or healing wounds
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Uncontrolled cardiac arrhythmia
  • Significant pulmonary disease (shortness of breath at rest or mild exertion)
  • Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • History of other active malignancies
• Any additional investigational agent study.
  • Concurrent observational study is allowed following consultation with the Sponsor
• Planning to take a vacation for 7 or more consecutive days during the course of the study
• Arm A (Gemcitabine with nab-Paclitaxel) 
  • Known hypersensitivity to Gemcitabine or taxanes
  • History of Gemcitabine toxicity in the adjuvant setting requiring more than 1 dose level reduction 
  • Significant cardiac disease, including 
    • Unstable angina
    • New York Heart Association class III-IV congestive heart failure
    • Myocardial infarction within six months prior to study enrollment
  • History of hemolytic-uremic syndrome
  • History of posterior reversible encephalopathy syndrome
  • Known infection with Human Immunodeficiency Virus (HIV), and/or active infection with hepatitis B, or hepatitis C
  • History of active Peripheral Artery Disease that is treated and stable for at least 6 months
• Arm B (mFOLFIRINOX) or Arm C (FOLFIRI)
  • Known hypersensitivity to 5-fluorouracil/leucovorin
  • Known dihydropyrimidine dehydrogenase (DPD) deficiency
  • Known hypersensitivity to oxaliplatin or other platinum containing compounds
  • Known hypersensitivity to irinotecan
  • Uncontrolled seizure disorder, active neurological disease, or known CNS disease
  • Known Gilbert's syndrome
  • Significant cardiac disease, including
    • Unstable angina
    • New York Heart Association class II-IV congestive heart failure
    • Myocardial infarction within six months prior to study enrollment
• Arm D (MM-398 with 5-FU and leucovorin)
  • Prior irinotecan treatment
  • Arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) < 6 months prior to enrollment
  • Known hypersensitivity to any of the components of MM-398, other liposomal products, fluoropyrimidines or leucovorin
  • Known dihydropyrimidine dehydrogenase (DPD) deficiency