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Predictive Biomarkers of Response to Sunitinib in the Treatment of Poorly-differentiated NEURO-Endocrine Tumors (NET)

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ClinicalTrials.gov Identifier: NCT01215578
Recruitment Status : Terminated (lack of recruitement)
First Posted : October 6, 2010
Last Update Posted : April 30, 2015
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE September 23, 2010
First Posted Date  ICMJE October 6, 2010
Last Update Posted Date April 30, 2015
Study Start Date  ICMJE October 2008
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 5, 2010)
Predictive molecular markers of response to sunitinib [ Time Frame: 1 year ]
to assess the correlation between the expression of biomarkers and CT scan response. Patients are considered as responders when objective response (Partial or complete response) is showed on CT scan.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01215578 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 5, 2010)
  • The antitumor activity of sunitinib [ Time Frame: 1 year ]
    • Objective response according to RECIST criteria (Time Frame: duration of study Safety issue: No).
    • Overall Survival (Time Frame: 6 months. Safety issue: No).
    • Progression-free survival (PFS)
    • Correlation between overall survival, PFS and tumor necrosis assessed on CT scan
  • Residual concentration [ Time Frame: 2 months ]
    correlation between the concentration of sunitinib and its major active metabolite, SU012662, and objective response and /or toxicity.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Predictive Biomarkers of Response to Sunitinib in the Treatment of Poorly-differentiated NEURO-Endocrine Tumors
Official Title  ICMJE A Multicenter Phase II Open Study Coupled With a Translational Assessment of Biomarkers Predictive of Response to Sunitinib in Patients With Poorly-differentiated Advanced/Inoperable NEURO-Endocrine Tumors.
Brief Summary

The purpose of this study is to identify predictive molecular markers of response to continuous daily sunitinib at dose of 37.5 mg used in patients with poorly-differentiated Advanced/Inoperable NEURO-Endocrine Tumors.

Hypothesis:

  • To distinguish molecular markers based on their expression at the initial biopsy, their detection by proteomic analysis and demonstrating that tumor or vascular cells are straightaway sensitive to sunitinib (markers sensitivity).
  • The presence of these markers at the initial biopsy predict the sensitivity to sunitinib(Positive predictive value of markers)
Detailed Description

Neuroendocrine tumors (NET) are rare malignancies (1-2% of digestive cancers); and there is, in recent years, a slow but steady increase in their incidence. Despite the joint efforts of several research groups, which led to the new WHO classification (2002), the natural history of the disease remains heterogene and the resistance to conventional cytotoxic treatment remains the common denominator of these tumors.

Indeed, the prognosis of patients with metastatic disease remains poor despite numerous treatments (including: IFN, DTIC, 5-FU, doxorubicin, somatostatin analogues, etc.).

None of which showed a benefit in terms of survival. The main therapeutic objective is still to get a palliative effect on the symptoms and / or limit a few months tumor progression.

There are many publications showing that angiogenesis is one of the major mechanisms of tumor progression in TNE. But the multiple signaling pathways involved, the existence of alternative routes and their relationship to apoptosis inducing molecules remain unknown. Sunitinib is a new molecule in the family of tyrosine kinase inhibitors targeting multiple receptors which VEGFR, KIT, PDGF-R, FLT3 and RET. Since 2006 year, Sunitinib has been approved to treat advanced kidney cancer also called advanced renal cell carcinoma (a typically chemoresistant disease for which there was no active treatment available).

Many retrospective studies in patients showing that the TNE overexpress one or more targets of sunitinib. In Phase I trial, an antitumor activity has been identified in neuroendocrine tumors. In a phase II trial including 100 patients with well-differentiated TNE and carcinoids, sunitinib is associated with a response rate of 10%, and 82% of clinical benefit in the form of tumor stability.

Currently, an international randomised phase III trial initiated in well differentiated forms, but no studies are underway for poorly-differentiated TNE.

All of this suggests that sunitinib could represent an important therapeutic option for moderate, or poorly differentiated inoperable TNE and needs to be explored in this pathology by identifying predictive biomarkers of response.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Neuroendocrine Tumors
  • Pancreatic Neoplasms
  • Advanced Disease
  • Sunitinib
Intervention  ICMJE Drug: Sutent
sunitinib 37.5 mg/day (per os) for 6 months
Study Arms  ICMJE Experimental: patient treated
patient who receive sunitinib (SUTENT)
Intervention: Drug: Sutent
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 29, 2014)
33
Original Estimated Enrollment  ICMJE
 (submitted: October 5, 2010)
70
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Digestive NET histopathologically proven, poorly-differentiated
  • Inoperable/advanced NET (Tumor relapse inoperable or metastatic with no surgical indication).
  • Tumor samples should be made available for analysis(diagnostic biopsy, surgical specimen)
  • measurable disease defined by at least one lesion wich can be measured by at least one dimension :

    • equal or superior to 20 mm ( by conventional methods )
    • equal or superior to 10 mm (by spiral scan within 28 days before the beginning of the treatment)
  • Performance status WHO ≤ 2.
  • Adequate organ function :

    • hematology (absolute neutrophil count equal or superior to 1,5 x 10*9/l , platelet equal or superior to 100 x 10*9/l),
    • clearance of creatinine equal or superior to 60 ml/min),
    • AST/ALT ≤ 5 N, PAL ≤ 5 N, total bilirubin ≤ 2N.
  • the selected women must be post-menopausal woman or surgically castrated or have to accept an effective contraception for the duration of the treatment and 3 month after.Women who are old enough to procreate must have a negative pregnancy test within the 72 hours of the beginning of the treatment.They must not be pregnant or to breastfeed.the selected men and theirs partners must be sterile or use an effective contraception for the duration of the treatment and 3 month after.

Exclusion Criteria:

  • Hypersensitivity to sunitinib.
  • Contraindication to sunitinib, including uncontrolled hypertension, medical history of cerebrovascular accident, unstable cardiac pathology despite optimal medical therapy (myocardial infarction within the 6 months prior to study drug administration, severe/unstable angina ), active hemorrhagic syndrome or concomitant treatment with anticoagulants.
  • Any severe acute or chronic co-morbid that may compromise to comply with study participation: uncontrolled infection, symptomatic congestive heart failure, liver disturbance, chronic renal failure, active gastro-duodenal ulcer (nonexhaustive list).
  • Known brain metastases.
  • Diagnosis of any second malignancy within the last 3 years, except for basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri
  • Current treatment on another clinical trial.
  • Prior treatment with an investigational agent within 4 weeks.
  • Prior treatment with intravenous biphosphonates
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01215578
Other Study ID Numbers  ICMJE P070145
2007-005628-34 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Eric Raymond, Professor Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date April 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP