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

Sponsor

Jean-Luc Van Laethem (Other)

Overall Status

Unknown status

CT.gov ID

NCT01713218

Collaborator

Roche Pharma AG (Industry)

Enrollment

Locations

Arm

Duration (Months)

10.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Adenocarcinoma Resectable	Drug: gemcitabine Drug: Vismodegib Procedure: Neoadjuvant chemotherapy	Early Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Study Start Date :

Dec 1, 2012

Anticipated Primary Completion Date :

Jun 1, 2014

Anticipated Study Completion Date :

Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
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 Names: GEMZAR Drug: Vismodegib 150 mg capsule, oral, once daily Other Names: GDC-0449 Procedure: Neoadjuvant chemotherapy Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery

Arm

Intervention/Treatment

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 Names:

GEMZAR

Drug: Vismodegib

150 mg capsule, oral, once daily

Other Names:

GDC-0449

Procedure: Neoadjuvant chemotherapy

Combination of gemcitabine and Vismodegib during a window interval (4 weeks) before surgery

Outcome Measures

Primary Outcome Measures

"Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters. [4 weeks (duration of the neoadjuvant chemotherapy).]
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. [End of study follow-up (up to 2 years).]
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. [4 weeks (duration of the neoadjuvant chemotherapy).]
Effect of treatment on selected biomarkers in tumor resection specimens. [4 weeks (duration of the neoadjuvant chemotherapy).]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.