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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01431794
First received: July 19, 2011
Last updated: October 1, 2014
Last verified: October 2014
  Purpose

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. The objective is to assess tolerability and the resection rate of patients with borderline resectable pancreatic adenocarcinoma who use this treatment.


Condition Intervention Phase
Resectable Pancreatic Adenocarcinoma
Drug: LDE-225
Drug: Gemcitabine
Drug: nab-paclitaxel
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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.

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • 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. [ Time Frame: 5 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, nab-paclitaxel, 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.



Secondary Outcome Measures:
  • 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. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    • Overall survival from cycle one day 1

  • 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. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    • Objective tumor response (complete response, partial response) by RECIST 1.1 criteria


Estimated Enrollment: 52
Study Start Date: September 2011
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I, Arm A: gem, nab-paclitxel, and LDE225
Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.
Drug: LDE-225

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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: nab-paclitaxel

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days.

Other Name: abraxane
Active Comparator: Phase II, Arm A: gem, nab-paclitaxel, and LDE 225

Phase II:

Arm A: 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.

Arm B: 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: LDE-225

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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: nab-paclitaxel

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days.

Other Name: abraxane
Active Comparator: Phase II, Arm B: gemcitabine and nab-paclitaxel

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: 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: nab-paclitaxel

Phase I:

Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 every 28 days cycle in combination with oral LDE225 600 mg daily.

Phase II:

Arm A: 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.

Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days.

Other Name: abraxane

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:

1. Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in combination with escalating doses 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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 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. .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:

  • 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01431794

Contacts
Contact: Sheila Linden, RN 410-614-4397 slinden2@jhmi.edu
Contact: Thomas Brown, MS 410-502-5328 tbrown55@jhmi.edu

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21205
Contact: Sheila Linden, RN    410-614-4397    slinden2@jhmi.edu   
Contact: Thomas Brown, MS    410-502-5328    tbrown55@jhmi.edu   
Principal Investigator: Ana De Jesus-Acosta, MD         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Novartis
Investigators
Principal Investigator: Ana De Jesus-Acosta, MD Sidney Kimmel Comprehensive Cancer Center JHMI
  More Information

No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01431794     History of Changes
Other Study ID Numbers: J1130, NA_00047491
Study First Received: July 19, 2011
Last Updated: October 1, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
Pancreatic ductal adenocarcinoma (PDA)Neoplasms
LDE225
nab-paclitaxel
abraxane
gemcitabine
neoadjuvant
cytotoxic
hedgehog (Hh) inhibitors
stromal cells
resectable PDA
Pancreatic Diseases
Carcinoma

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Paclitaxel
Gemcitabine
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
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
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on October 02, 2014