Phase I/II study of LDE225 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastasized pancreatic cancer

1. Patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures.
2. Male or female adult patients (> 18 years)
3. Patients with histologically/cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma.
4. a. Phase I Patients with non resectable or metastasized pancreatic ductal adenocarcinoma.
b. Phase II Patients with non resectable or metastasized pancreatic ductal adenocarcinoma not pre-treated with chemotherapy or radiotherapy, unless adjuvant treatment with gemcitabine > 6 months
5. Measurable disease as assessed by RECIST 1.1
6. ECOG (WHO) performance status 0-2
7. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
* Absolute Neutrophil Count (ANC) > 1.5 x 109/L
* Hemoglobin (Hgb) > 9.0 g/dL (5.6 mmol/L)
* Platelets > 100 x 109/L
* Serum total bilirubin within normal range (or * 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert*s syndrome)
* INR < 1.5
* Potassium, calcium, within normal limits for the institution
* Serum creatinine < 1.5 x ULN or creatinine clearance >60 mL/min/1.73 m2
* Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within normal range or < 3.0 x ULN if liver metastases are present
* Blood creatinine phosphokinase (CK) level < 1.5 ULN

2. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. If it is essential that the patient remains on a statin to control hyperlipidemia, only Pravastatin may be used with extra caution.
4. Patients who require the use of warfarin (substrate of CYP2C9) cannot be enrolled as LDE225 is a competitive inhibitors of CYP2C9 based on in-vitro data.
5. Patient is currently being treated with drugs known to be strong inhibitors or inducers of CYP3A4/5, which cannot be discontinued or switched to a different medication 7 days prior to starting study treatment and for the duration of the study.
6. Current medical history of the following:
* History of or presence of clinically significant uncontrolled ventricular or atrial tachyarrhythmia
* Clinically significant resting bradycardia (< 45 beats per minute) or any primary of secondary heart block
* History of unstable angina pectoris
* Clinically significant cardio-vascular disease (e.g. congestive heart failure NYHA Class III-IV, atherosclerosis, labile hypertension or uncontrolled hypertension
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
8. Sexually active males who are unwilling to use a condom during intercourse while taking drug and for 6 months after stopping investigational medications and agree not to father a child in this period.
9. Patient is currently receiving increasing or chronic treatment with corticosteroids or another immunosuppressive agent.
10. Patient has been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) * 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated before enrollment, may be continued
12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LDE225 (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)