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Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer (NEOPACHI-001)

Primary Purpose

Pancreatic Adenocarcinoma Resectable

Status
Unknown status
Phase
Early Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
gemcitabine
Vismodegib
Neoadjuvant chemotherapy
Sponsored by
Jean-Luc Van Laethem
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pancreatic Adenocarcinoma Resectable focused on measuring Pancreas, Cancer, Hedgehog inhibitor, Neoadjuvant chemotherapy, Dynamic imaging

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histo(cyto)logically proven ductal pancreatic adenocarcinoma
  • Resectable or potentially resectable tumor; resectability assessed during a multidisciplinary meeting with expert surgeon and radiologist
  • First line chemotherapy
  • Age > 18 years
  • WHO performance status (PS) grade 0 or 1;
  • Absolute neutrophil count > 1.5 x 10 9 / L, platelets > 100 x 10 9/ L, creatinine clearance (Cockcroft and Gault formula) > 60 ml/min, haemoglobin level > 10 g/dl (transfusions authorized), bilirubin<1.5 g/dl;
  • Optimal biliary drainage;
  • Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation of who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum or urine pregnancy test prior to treatment. All WCBP, all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study;
  • Signed written informed consent.

Exclusion Criteria:

  • Locally advanced non resectable or metastatic pancreatic adenocarcinoma
  • Previous anticancer therapy for the pancreatic adenocarcinoma
  • Biliary obstruction without endoscopic biliary drainage
  • Any contre-indication for surgery
  • Prior malignancy (except non-melanoma skin cancer, and in situ carcinoma of the uterine cervix treated with a curative intent and any other tumor in complete remission with a disease-free interval > 3 years)
  • Uncontrolled congestive heart failure or angina pectoris, myocardial infarction within 1 year prior to study entry, uncontrolled hypertension (systolic pressure > 160 mm or diastolic pressure > 100 mm under well conducted antihypertensive treatment), QT prolongation
  • Major uncontrolled infection
  • Severe hepatic impairment
  • Any medical, psychological, or social condition, which, in the opinion of the investigator, could hamper patient's compliance to the study protocol and/or assessment/interpretation of the data
  • Pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods
  • Patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study;Subject previously enrolled into this study.

Sites / Locations

  • Antwerp University Hospital (UZA)
  • Erasme University Hospital (ULB)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Gemcitabine+Vismodegib

Arm Description

Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery

Outcomes

Primary Outcome Measures

"Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.

Secondary Outcome Measures

Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.
Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).

Full Information

First Posted
October 17, 2012
Last Updated
October 22, 2012
Sponsor
Jean-Luc Van Laethem
Collaborators
Roche Pharma AG
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1. Study Identification

Unique Protocol Identification Number
NCT01713218
Brief Title
Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer
Acronym
NEOPACHI-001
Official Title
Evaluation of Tumoral Perfusion Modification by Dynamic Imaging After Neoadjuvant Chemotherapy Combining Gemcitabine and a Hedgehog Inhibitor (Vismodegib) in Patients With Resectable Pancreatic Adenocarcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
October 2012
Overall Recruitment Status
Unknown status
Study Start Date
December 2012 (undefined)
Primary Completion Date
June 2014 (Anticipated)
Study Completion Date
December 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jean-Luc Van Laethem
Collaborators
Roche Pharma AG

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all human cancers and is considered as a sanctuary, resistant to most of the drugs used. Identification of new molecular targets involved in its pathogenesis is urgently needed and required both proper and innovative efficacy assessment. This proof-of-concept trial is studying the "dynamic" tumor response after the administration of a short course (4 weeks) neoadjuvant combination of gemcitabine and a Hedgehog inhibitor (Vismodegib) before surgery in patients with operable pancreatic cancer.
Detailed Description
Pancreatic cancer is characterized by a high stromal density and is a hypoperfused tumor, precluding cytotoxics delivery to the epithelial tumoral compartment. There is thus a rationale for combining chemotherapy and antistromal drugs like Hedgehog inhibitors. Targeting the resectable primary tumor offers an appropriate setting to (1) evaluate and monitor early treatment effects on the tumor, (2) correlate dynamic imaging changes (perfusion and diffusion coefficient) to pre- and post-therapeutic tissue changes, (3) identify specific predictive biomarkers for the drugs used (i.e. gemcitabine transporters and Hedgehog pathway genes and proteins) and (4) assess if this early "dynamic and biomolecular response" can predict treatment benefit and patient outcome.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Adenocarcinoma Resectable
Keywords
Pancreas, Cancer, Hedgehog inhibitor, Neoadjuvant chemotherapy, Dynamic imaging

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Gemcitabine+Vismodegib
Arm Type
Experimental
Arm Description
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
Intervention Type
Drug
Intervention Name(s)
gemcitabine
Other Intervention Name(s)
GEMZAR
Intervention Description
Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4
Intervention Type
Drug
Intervention Name(s)
Vismodegib
Other Intervention Name(s)
GDC-0449
Intervention Description
150 mg capsule, oral, once daily
Intervention Type
Procedure
Intervention Name(s)
Neoadjuvant chemotherapy
Intervention Description
Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery
Primary Outcome Measure Information:
Title
"Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
Description
In order to detect changes in the tumor microenvironment and to monitor treatment efficacy, Dynamic Contrast-Enhanced-Magnetic Resonance Imaging (DCE-MRI) and Diffusion Weighted-Magnetic Resonance Imaging (DW-MRI) constitute tools more and more used. The acquired data can be analyzed using a pharmacokinetic model to obtain quantitative parameters relative to tissue perfusion and vascular permeability (Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space; Apparent Diffusion Coefficient as a surrogate marker of tissue cellularity). DCE/DW-MRI will be achieved weekly before each neoadjuvant chemotherapy treatment and before surgery. Each patient will be his/her own control by comparing serial imaging results with those of the baseline MRI.
Time Frame
4 weeks (duration of the neoadjuvant chemotherapy).
Secondary Outcome Measure Information:
Title
Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.
Description
Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).
Time Frame
End of study follow-up (up to 2 years).
Other Pre-specified Outcome Measures:
Title
Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time Frame
4 weeks (duration of the neoadjuvant chemotherapy).
Title
Effect of treatment on selected biomarkers in tumor resection specimens.
Description
The objective is to identify within pre-therapeutic samples and surgical specimens several specific biomarkers involved (1) in the Hedgehog signalling pathway (GLI1, Sonic Hedgehog, Patched, Smoothened immunohistochemical patterns protein expression) and predicting response to anti-Hh therapy, (2) in the metabolization of gemcitabine (human equilibrative nucleoside transporter 1, deoxycytidine kinase) and predicting response to gemcitabine therapy, and (3) in the relative contribution of both anti-Hh therapy and gemcitabine therapy.
Time Frame
4 weeks (duration of the neoadjuvant chemotherapy).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histo(cyto)logically proven ductal pancreatic adenocarcinoma Resectable or potentially resectable tumor; resectability assessed during a multidisciplinary meeting with expert surgeon and radiologist First line chemotherapy Age > 18 years WHO performance status (PS) grade 0 or 1; Absolute neutrophil count > 1.5 x 10 9 / L, platelets > 100 x 10 9/ L, creatinine clearance (Cockcroft and Gault formula) > 60 ml/min, haemoglobin level > 10 g/dl (transfusions authorized), bilirubin<1.5 g/dl; Optimal biliary drainage; Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation of who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum or urine pregnancy test prior to treatment. All WCBP, all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study; Signed written informed consent. Exclusion Criteria: Locally advanced non resectable or metastatic pancreatic adenocarcinoma Previous anticancer therapy for the pancreatic adenocarcinoma Biliary obstruction without endoscopic biliary drainage Any contre-indication for surgery Prior malignancy (except non-melanoma skin cancer, and in situ carcinoma of the uterine cervix treated with a curative intent and any other tumor in complete remission with a disease-free interval > 3 years) Uncontrolled congestive heart failure or angina pectoris, myocardial infarction within 1 year prior to study entry, uncontrolled hypertension (systolic pressure > 160 mm or diastolic pressure > 100 mm under well conducted antihypertensive treatment), QT prolongation Major uncontrolled infection Severe hepatic impairment Any medical, psychological, or social condition, which, in the opinion of the investigator, could hamper patient's compliance to the study protocol and/or assessment/interpretation of the data Pregnant or lactating women, or patients of both genders with procreative potential not using adequate contraceptive methods Patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study;Subject previously enrolled into this study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-Luc Van Laethem, MD, PhD
Email
jl.vanlaethem@erasme.ulb.ac.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Luc Van Laethem, MD, PhD
Organizational Affiliation
Erasme University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Antwerp University Hospital (UZA)
City
Edegem
State/Province
Antwerpen
ZIP/Postal Code
2650
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marc Peeters, MD,PhD
Email
marc.peeters@uza.be
First Name & Middle Initial & Last Name & Degree
Marc Peeters, MD, PhD
Facility Name
Erasme University Hospital (ULB)
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Luc Van Laethem, MD, PhD
Email
jl.vanlaethem@erasme.ulb.ac.be
First Name & Middle Initial & Last Name & Degree
Jean-Luc Van Laethem, MD, PhD
First Name & Middle Initial & Last Name & Degree
Raphaël Maréchal, MD, PhD
First Name & Middle Initial & Last Name & Degree
Anne Demols, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer

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