A Randomized, Double-Blind, Phase 3 Study of the JAK1/2 Inhibitor Ruxolitinib or Placebo in Combination With Capecitabine in Subjects With Advanced or Metastatic Adenocarcinoma of the Pancreas Who Have Failed or Are Intolerant to First-Line Chemotherapy (The JANUS 2 Study)

- Male or female, 18 years or older.
- Histologically or cytologically confirmed adenocarcinoma of the pancreas.
- Advanced adenocarcinoma of the pancreas that is inoperable or metastatic.
- mGPS of 1 or 2 as defined below:
o mGPS of 1: C-reactive protein (CRP) > 10 mg/L and albumin * 35 g/L
o mGPS of 2: CRP > 10 mg/L and albumin < 35 g/L
**Received 1 prior chemotherapy regimen for advanced or metastatic disease (not including
neoadjuvant and/or adjuvant therapy).
o Use of a fluoropyrimidine-containing regimen (eg, FOLFIRNOX, FOLFOX, CapeOx, chemoradiation,etc) in
the first-line setting is permitted provided the subject discontinued treatment for reasons other
than disease progression and the subject received * 8 weeks of therapy. Subjects who received
single-agent capecitabine as first-line therapy are not eligible.
- * Neoadjuvant regimens will be considered first-line therapy if the subject has disease progression during treatment. Adjuvant regimens will be considered first-line therapy if the subject has disease progression during treatment or * 6 months after the last dose.
o There is no restriction on the use of fluoropyrimidine-containing regimens in the neoadjuvant
or adjuvant setting.
o *History of palliative radiotherapy to disease sites is allowed provided there are other sites of
disease or subsequent progression of the disease in the radiation field, and * 4 weeks have
elapsed since the completion of radiotherapy and all treatment-related toxicities have resolved
or are at a new stable baseline.
- Able to tolerate and benefit from therapy as evidenced by:
o Absolute neutrophil count * 1.5 × 109/L with white blood cell count < 20 × 109/L.
o Platelets * 75 × 109/L.
o Hemoglobin * 9 g/dL (transfusions are permitted to achieve baseline hemoglobin level).
o Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) * 2.5 × upper limit of
normal (ULN); or * 5 × ULN in the presence of liver metastases.
o Total bilirubin * 1.5 × ULN; if total bilirubin is > 1.5 × ULN then direct bilirubin must be
* 1.5 × ULN (use of biliary stent to achieve bilirubin levels is permitted).
o Alkaline phosphatase < 3 × ULN.
o Lactate dehydrogenase (LDH) < 3 × ULN in the absence of hemolysis.
o Creatinine clearance * 50 mL/min measured or calculated by Cockroft-Gault equation.
o ECOG performance status 0 to 2.
o Body mass index (BMI) > 16 kg/m2.
o Absence of significant concurrent, uncontrolled medical condition including, but not limited to renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease.
o Able to swallow and retain oral medication.
- * 2 weeks elapsed from the completion of previous treatment regimen and subjects must have
recovered or be at a new stable baseline from any related toxicities.
- Radiographically measurable or evaluable disease (based on local evaluation), per RECIST (v1.1).

- Received more than 1 prior regimen (eg chemotherapy, biologic, targeted, immune, investigational therapies alone or in combination) for advanced or metastatic disease.
- Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
- Known brain or central nervous system metastases or history of uncontrolled seizures.
- Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy.
- Ongoing radiation therapy or radiation therapy administered within 30 days of enrollment.;- Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization).
- Subjects who participated in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) prior to the first dose.
- Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.
- Recent (* 3 months) history or ongoing partial or complete bowel obstruction, unless surgically corrected.
- Prior severe reaction to fluoropyrimidines, known DPD deficiency, or other known hypersensitivity to active substances, including fluorouracil (5-FU), or ruxolitinib, or any of their excipients.
- Known history of human immunodeficiency virus infection.
- Active hepatitis B or C infection that requires treatment.
- Unwilling to be transfused with blood components.
- Prior treatment with a JAK inhibitor for any indication.