Phase 1/2 Safety and Feasibility of Gemcitabine and Nab-Paclitaxel in Combination With LDE-225 as Neoadjuvant Therapy in Patients With Borderline Resectable Pancreatic Adenocarcinoma.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins1 site in 1 country23 target enrollmentDecember 27, 2011

ConditionsPancreatic Ductal Adenocarcinoma

InterventionsLDE225-600mg Gemcitabine nab-paclitaxel LDE225-400mg LDE225-800mg

DrugsLDE225-600mg Gemcitabine nab-paclitaxel LDE225-400mg LDE225-800mg

Overview

Phase: Phase 1
Intervention: LDE225-600mg
Conditions: Pancreatic Ductal Adenocarcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Enrollment: 23
Locations: 1
Primary Endpoint: 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
Status: Terminated
Last Updated: 6 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.

Detailed Description

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.

Registry

clinicaltrials.gov

Start Date

December 27, 2011

End Date

November 5, 2018

Last Updated

6 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Histologically or cytologically confirmed adenocarcinoma of the pancreas.
•Must have borderline resectable pancreatic adenocarcinoma
•Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension
•No previous radiotherapy, surgery, chemotherapy or investigational drug therapy.
•Age \>18 years
•Life expectancy of greater than 1 month.
•ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1
•Adequate organ and marrow function
•Asymptomatic for jaundice and ascites. Pain symptoms should be stable.
•Negative serum pregnancy test

Exclusion Criteria

•Patients who have had previous radiotherapy, surgical resection, chemotherapy or investigational drug therapy for pancreatic adenocarcinoma.
•Patient has known metastatic disease.
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to LDE225 or other agents used in the study.
•Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
•Uncontrolled illness including, but not limited to, ongoing or active infection requiring IV antibiotics, symptomatic congestive heart failure not controlled with medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
•Pregnant women are excluded
•Patient has undergone a major surgery, other than diagnostic surgery within four weeks prior to starting treatment on this study.
•Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE
•Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE
•Patients with neuromuscular disorders.

Arms & Interventions

Phase I-Gem,nab-paclitaxel,LDE225-600mg

Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 600 mg daily.

Intervention: LDE225-600mg

Phase I-Gem,nab-paclitaxel,LDE225-600mg

Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 600 mg daily.

Intervention: Gemcitabine

Phase I-Gem,nab-paclitaxel,LDE225-600mg

Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 600 mg daily.

Intervention: nab-paclitaxel