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

This study is not yet open for participant recruitment.
Verified October 2012 by Erasme University Hospital
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Jean-Luc Van Laethem, Erasme University Hospital
ClinicalTrials.gov Identifier:
NCT01713218
First received: October 17, 2012
Last updated: October 22, 2012
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Pancreatic Adenocarcinoma Resectable
Drug: gemcitabine
Drug: Vismodegib
Procedure: Neoadjuvant chemotherapy
Phase 0

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Erasme University Hospital:

Primary Outcome Measures:
  • "Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
    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. [ Time Frame: End of study follow-up (up to 2 years). ] [ Designated as safety issue: Yes ]
    Number of participants with (serious) adverse events will be considered as a measure of safety of the whole therapeutic sequence (gemcitabine + Hedgehog inhibitor+ surgery).


Other Outcome Measures:
  • Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
  • Effect of treatment on selected biomarkers in tumor resection specimens. [ Time Frame: 4 weeks (duration of the neoadjuvant chemotherapy). ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 21
Study Start Date: December 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gemcitabine+Vismodegib
Neoadjuvant chemotherapy combining gemcitabine and Vismodegib during 4 weeks before surgery
Drug: gemcitabine
Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4
Other Name: GEMZAR
Drug: Vismodegib
150 mg capsule, oral, once daily
Other Name: GDC-0449
Procedure: Neoadjuvant chemotherapy
Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01713218

Contacts
Contact: Jean-Luc Van Laethem, MD, PhD jl.vanlaethem@erasme.ulb.ac.be

Locations
Belgium
Antwerp University Hospital (UZA) Not yet recruiting
Edegem, Antwerpen, Belgium, 2650
Contact: Marc Peeters, MD,PhD       marc.peeters@uza.be   
Principal Investigator: Marc Peeters, MD, PhD         
Erasme University Hospital (ULB) Not yet recruiting
Brussels, Belgium, 1070
Contact: Jean-Luc Van Laethem, MD, PhD       jl.vanlaethem@erasme.ulb.ac.be   
Principal Investigator: Jean-Luc Van Laethem, MD, PhD         
Sub-Investigator: Raphaël Maréchal, MD, PhD         
Sub-Investigator: Anne Demols, MD, PhD         
Sponsors and Collaborators
Jean-Luc Van Laethem
Roche Pharma AG
Investigators
Principal Investigator: Jean-Luc Van Laethem, MD, PhD Erasme University Hospital
  More Information

No publications provided

Responsible Party: Jean-Luc Van Laethem, MD, PhD, Erasme University Hospital
ClinicalTrials.gov Identifier: NCT01713218     History of Changes
Other Study ID Numbers: 2012-003516-31
Study First Received: October 17, 2012
Last Updated: October 22, 2012
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Erasme University Hospital:
Pancreas
Cancer
Hedgehog inhibitor
Neoadjuvant chemotherapy
Dynamic imaging

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on April 16, 2014