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Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01431794
Recruitment Status : Terminated (Study was terminated due to cease in manufacturing of study drug.)
First Posted : September 12, 2011
Results First Posted : June 25, 2019
Last Update Posted : January 22, 2020
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Viragh Foundation
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Condition or disease Intervention/treatment Phase
Pancreatic Ductal Adenocarcinoma Drug: LDE225-600mg Drug: Gemcitabine Drug: nab-paclitaxel Drug: LDE225-400mg Drug: LDE225-800mg Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : December 27, 2011
Actual Primary Completion Date : November 5, 2018
Actual Study Completion Date : November 5, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: LDE225-600mg

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.

Other Name: Sonidegib

Drug: Gemcitabine
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: gem

Drug: nab-paclitaxel
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: abraxane

Active Comparator: Phase II-Arm A:Gem,nab-paclitaxel,LDE225
Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose. Cycles repeated every 28 days.
Drug: LDE225-600mg

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.

Other Name: Sonidegib

Drug: Gemcitabine
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: gem

Drug: nab-paclitaxel
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: abraxane

Drug: LDE225-400mg
Phase I: oral LDE225 (Sonidegib), 400mg daily.
Other Name: Sonidegib

Drug: LDE225-800mg
Phase I: oral LDE225 (Sonidegib), 800mg daily.
Other Name: Sonidegib

Active Comparator: Phase II-Arm B:Gem,nab-paclitaxel
Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days.
Drug: Gemcitabine
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: gem

Drug: nab-paclitaxel
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: abraxane

Experimental: Phase I-Gem,nab-paclitaxel,LDE225-400mg
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), 400 mg daily.
Drug: Gemcitabine
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: gem

Drug: nab-paclitaxel
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: abraxane

Drug: LDE225-400mg
Phase I: oral LDE225 (Sonidegib), 400mg daily.
Other Name: Sonidegib

Experimental: Phase I-Gem,nab-paclitaxel,LDE225-800mg
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), 800 mg daily.
Drug: Gemcitabine
Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: gem

Drug: nab-paclitaxel
Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days.
Other Name: abraxane

Drug: LDE225-800mg
Phase I: oral LDE225 (Sonidegib), 800mg daily.
Other Name: Sonidegib




Primary Outcome Measures :
  1. 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 [ Time Frame: 5 years ]
    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).

  2. Phase II - Resection Rate of Two Preoperative Chemotherapy Regimens in Patients With Borderline Resectable PDA [ Time Frame: 5 years ]
    Number of participants with borderline resectable pancreatic adenocarcinoma (PDA) who undergo resection after therapy


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 5 years ]
    Number of months alive from cycle 1, Day 1 until 5 years post-intervention or death, whichever comes first.

  2. Overall Tumor Response as Determined by Number of Participants With Complete or Partial Response [ Time Frame: 5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Sexually active males should agree to use a barrier form of contraception, even if they have had a vasectomy, during the study and for 6 months after stopping LDE225. Males should not donate sperm during treatment, and for up to six months after last dose. Sexually active females of child bearing potential agree to using highly effective contraception during study and for 20 months after final dose of LDE225.
  • Agree not to donate blood products for 12 months after stopping LDE225.
  • Willing to have two biopsies while on treatment for correlative studies.

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 LDE225. 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 LDE225.
  • Patients with neuromuscular disorders.
  • Patients with impaired cardiac function.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01431794


Locations
Layout table for location information
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21205
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Novartis Pharmaceuticals
Viragh Foundation
Investigators
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Principal Investigator: Ana De Jesus-Acosta, MD Sidney Kimmel Comprehensive Cancer Center JHMI
  Study Documents (Full-Text)

Documents provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT01431794    
Other Study ID Numbers: J1130
NA_00047491 ( Other Identifier: JHMIRB )
First Posted: September 12, 2011    Key Record Dates
Results First Posted: June 25, 2019
Last Update Posted: January 22, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Pancreatic ductal adenocarcinoma (PDA)Neoplasms
LDE225
nab-paclitaxel
abraxane
gemcitabine
neoadjuvant
cytotoxic
hedgehog inhibitor
stromal cells
resectable PDA
Pancreatic Diseases
Carcinoma
Sonidegib
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs