This is an open-label phase 1/2 study that will combine the chemotherapy agents gemcitabine and nab-paclitaxel with an oral hedgehog inhibitor LDE225 (Sonidegib). The objective is to assess tolerability and the resection rate of patients with borderline resectable pancreatic adenocarcinoma who use this treatment.
The investigators propose treating 6-12 patients during the phase 1 portion and 40 patients in the phase 2 stage. Phase 1 Stage: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in combination with escalating doses (400mg, or 600mg, or 800mg) of LDE-225. After completion of neoadjuvant therapy, the subjects will receive combined chemotherapy and radiation. Then subjects who are eligible for resection will go ahead with surgery. Following resection, subjects will complete two additional cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 in combination with LDE-225. Phase 2 Stage: In the Phase 2 stage the patients will be randomized to receive gemcitabine and nab-paclitaxel with or without the hedgehog inhibitor LDE225: 1. Arm A: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m 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 and nab-paclitaxel 125 mg/m on days 1, 8 and 15. After completion of neoadjuvant therapy, the subjects will receive combined chemotherapy and radiation. Then subjects who are eligible for resection will go ahead with surgery. Following resection, subjects will complete 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
Phase I: oral LDE225 (Sonidegib), 600mg daily. Phase II Arm A: LDE225 at the recommended phase 2 dose on Days 1, 8 and 15. Cycles repeated every 28 days.
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Phase I - Safety and Feasibility of Gemcitabine and Nab-Paclitaxel in Combination With LDE-225 as Neoadjuvant Therapy as Measured by Number of Participants Who Tolerated the Maximal Dose of LDE-225
Number of participants who tolerated the maximal dose of LDE-225 in combination with gemcitabine, nab-paclitaxel as neoadjuvant therapy in patients with borderline resectable pancreatic adenocarcinoma (PDA).
Time frame: 5 years
Phase II - Resection Rate of Two Preoperative Chemotherapy Regimens in Patients With Borderline Resectable PDA
Number of participants with borderline resectable pancreatic adenocarcinoma (PDA) who undergo resection after therapy
Time frame: 5 years
Overall Survival
Number of months alive from cycle 1, Day 1 until 5 years post-intervention or death, whichever comes first.
Time frame: 5 years
Overall Tumor Response as Determined by Number of Participants With Complete or Partial Response
Number of participants who experienced complete response (CR) or partial response (PR), as defined by RECIST v1.0; where CR is a disappearance of all target lesions and PR is ≥30% reduction of target lesions.
Time frame: 5 years
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Phase I: oral LDE225 (Sonidegib), 400mg daily.
Phase I: oral LDE225 (Sonidegib), 800mg daily.