Clinical trial NCT01713218: Effect on Tumor Perfusion of a Chemotherapy Combining Gemcitabine and Vismodegib Before Surgery in Pancreatic Cancer
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
Overall status: UNKNOWN
Phase: EARLY_PHASE1
Conditions: Pancreatic Adenocarcinoma Resectable
Keywords: Pancreas
Cancer
Hedgehog inhibitor
Neoadjuvant chemotherapy
Dynamic imaging
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2012-10-24
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: "Dynamic" tumor response rate as defined by a 20% modification of tumoral perfusion and cellular density parameters.
timeFrame: 4 weeks (duration of the neoadjuvant chemotherapy).
Secondary outcomes:
measure: Number of participants with adverse events as assessed by National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0.
timeFrame: End of study follow-up (up to 2 years).
Other outcomes:
measure: Tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
timeFrame: 4 weeks (duration of the neoadjuvant chemotherapy).
measure: Effect of treatment on selected biomarkers in tumor resection specimens.
timeFrame: 4 weeks (duration of the neoadjuvant chemotherapy).
Locations:
city: Edegem
country: Belgium
facility: Antwerp University Hospital (UZA)
state: Antwerpen
city: Brussels
country: Belgium
facility: Erasme University Hospital (ULB)
Study officials:
affiliation: Erasme University Hospital
name: Jean-Luc Van Laethem, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: