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

This study has been terminated.
(lack of recruitement)
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01215578
First received: September 23, 2010
Last updated: October 29, 2014
Last verified: August 2014
  Purpose

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)

Condition Intervention Phase
Neuroendocrine Tumors
Pancreatic Neoplasms
Advanced Disease
Sunitinib
Drug: Sutent
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Predictive molecular markers of response to sunitinib [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • The antitumor activity of sunitinib [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    • 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 ] [ Designated as safety issue: Yes ]
    correlation between the concentration of sunitinib and its major active metabolite, SU012662, and objective response and /or toxicity.


Enrollment: 33
Study Start Date: October 2008
Estimated Study Completion Date: December 2014
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: patient treated
patient who receive sunitinib (SUTENT)
Drug: Sutent
sunitinib 37.5 mg/day (per os) for 6 months
Other Name: Sutent

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01215578

Locations
France
Hôpital Beaujon
Clichy, Hauts de Seine, France, 92110
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Eric Raymond, Professor Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01215578     History of Changes
Other Study ID Numbers: P070145, 2007-005628-34
Study First Received: September 23, 2010
Last Updated: October 29, 2014
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Adenoma, Islet Cell
Adenocarcinoma
Carcinoma
Adenoma
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Sunitinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

Additional relevant MeSH terms:
Endocrine Gland Neoplasms
Neoplasms
Neuroendocrine Tumors
Pancreatic Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Endocrine System Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Pancreatic Diseases
Angiogenesis Modulating Agents
Sunitinib
Angiogenesis Inhibitors
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014