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

Pancreatic Adenocarcinoma Resectable Clinical Trial

— 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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01713218
• Other study ID #: 2012-003516-31
• Status: Not yet recruiting
• Phase: Phase 0
• First received: October 17, 2012
• Last updated: October 22, 2012
• Start date: December 2012
• Est. completion date: December 2016

Study information

• Verified date: October 2012
• Source: Erasme University Hospital
• Contact: Jean-Luc Van Laethem, MD, PhD
• Email: jl.vanlaethem[@]erasme.ulb.ac.be
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 21
• Est. completion date: December 2016
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Adenocarcinoma Resectable
• Pancreatic Neoplasms

Intervention

Drug:
• gemcitabine
Administrated intravenously at a dose of 1000 mg/m2 over 30 minutes weekly, week 1 to 4
• Vismodegib
150 mg capsule, oral, once daily

Procedure:
• Neoadjuvant chemotherapy
Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery

Locations

Country	Name	City	State
Belgium	Erasme University Hospital (ULB)	Brussels
Belgium	Antwerp University Hospital (UZA)	Edegem	Antwerpen

Sponsors (2)

Lead Sponsor	Collaborator
Jean-Luc Van Laethem	Roche Pharma AG

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.		4 weeks (duration of the neoadjuvant chemotherapy).	No
Other	Effect of treatment on selected biomarkers in tumor resection specimens.	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.	4 weeks (duration of the neoadjuvant chemotherapy).	No
Primary	"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.	4 weeks (duration of the neoadjuvant chemotherapy).	No
Secondary	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).	End of study follow-up (up to 2 years).	Yes