Gemcitabine in Combination With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma

• Phase 1/2 Safety and Feasibility of Gemcitabine in combination with LDE-225 as Neoadjuvant Therapy in Patients with Borderline Resectable Pancreatic Adenocarcinoma. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

  Primary objective for phase I component of the trial:

  • To find the maximal tolerated dose of the combination of gemcitabine and LDE225 as neoadjuvant therapy in patients with borderline resectable pancreatic adenocarcinoma.

  Primary objective for phase II component of the trial:

  • To evaluate the resection rate of two preoperative chemotherapy regimens in patients with borderline resectable pancreatic adenocarcinoma.

  
  

• Phase 1/2 Safety and Feasibility of Gemcitabine in combination with LDE-225 as Neoadjuvant Therapy in Patients with Borderline Resectable Pancreatic Adenocarcinoma. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Overall survival from cycle one day 1
  
  
• Phase 1/2 Safety and Feasibility of Gemcitabine in combination with LDE-225 as Neoadjuvant Therapy in Patients with Borderline Resectable Pancreatic Adenocarcinoma. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Objective tumor response (complete response, partial response) by RECIST 1.1 criteria
  
  

Drug: LDE-225

Phase 1 Stage:

Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with escalating doses of LDE-225.

Phase 2 Stage:

1. Arm A: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose.
2. Arm B: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15.
Drug: Gemcitabine

Phase 1 Stage:

Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with escalating doses of LDE-225.

Phase 2 Stage:

1. Arm A: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose.
2. Arm B: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15.

The investigators propose treating 6-12 patients during the phase 1 portion and 40 patients in the phase 2 stage.

Phase 1 Stage:

1. Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with escalating doses of LDE-225. After completion of neoadjuvant therapy if the patients are eligible for resection this will be performed followed by combined chemotherapy and radiation and two additional cycles of Gemcitabine 1000 mg/m2 in combination with LDE-225.

Phase 2 Stage: In the Phase 2 stage the patients will be randomized to receive gemcitabine with or without the hedgehog inhibitor LDE225:

1. Arm A: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose.
2. Arm B: Four cycles of gemcitabine 1000 mg/m2 on days 1, 8 and 15.

After completion of neoadjuvant therapy if the patients are eligible for resection this will be performed followed by combined chemotherapy and radiation and two additional cycles of the pre-surgical therapy.

Several correlative laboratory studies will be conducted during the course of this study. They were designed around the goals of providing us with a better understanding of how the stroma-tumor interaction and the intra-tumoral drug levels of gemcitabine are affected with the use of LDE-225. Two additional biopsies are required to participate in this study.