Neoplasms

All Conditions

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Carcinoma

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neurofibromatoses

Neurofibromatosis 1

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Adenocarcinoma

Neuroendocrine Tumor

Neurofibromatosis

Neurofibromatosis Type 1

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Anti-Infective Agents

Everolimus

Sunitinib

Pancrelipase

Pancreatin

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

37.5 mg once daily will continue until progression or unacceptable treatment-related toxicity

10 mg daily will continue until progression or unacceptable treatment-related toxicity

Naris Nilubol, M.D.

Background:

- Neuroendocrine tumors (NETs) come from cells of the hormonal and nervous systems. Some people have surgery to shrink the tumor. Sometimes the tumors come back. Researchers think that treatment with drugs based on knowing the defective gene might give better results.

Objective:

- To see if drugs selected based on the defective gene result in better tumor response. The drugs are Sunitinib and Everolimus.

Eligibility:

- People age 18 and older with an advanced low- or intermediate-grade gastrointestinal or pancreatic neuroendocrine tumor.

Design:

* Participants will be screened with:
* Medical history
* Physical exam
* Scans
* Blood, urine, and lab tests
* The study team will see if participants should have surgery.
* If yes, participants will:
* Sign a separate consent
* Have computed tomography (CT) scan before and after surgery
* Have as much of the tumor removed as possible. A small piece will be tested for mutation type.
* If no, participants will have a small piece of tumor removed for the testing.
* If the surgery might cure them, the participant will leave the study. The other participants will be assigned to take either Sunitinib or Everolimus.
* Participants will take their drug by mouth once a day. They will keep a medicine diary. Some will keep track of their blood pressure at least weekly.
* Screening tests may be repeated at study visits. Participants also may have their heart evaluated.
* About 30 days after the last day of their study drug, participants will have a follow-up visit that repeats the screening tests.
* Participants will be contacted every 3 months after this visit.

Background:

* Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and heterogeneous group of neoplasms with unique tumor biology, natural history, and clinical management issues.
* Most NETs are sporadic, but they can be part of familial cancer syndromes such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1) or Von Hippel-Lindau (VHL) syndrome.
* Well-differentiated, low or intermediate grade NETs have a heterogeneous natural history.
* Surgery is the only curative treatment option in patients with localized early stage NETs.
* The optimal management strategy for patients with advanced NETs is unknown.
* The majority of NETs have somatic mutations in MEN1 and cyclin dependent kinase inhibitor 1B (CDKN1B), and genes involved in the phosphatidylinositol-3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway, and/or overexpression of growth factors and their receptors such as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor (PDGF), and platelet-derived growth factor receptors (PDGFR) that can be targeted for therapy.
* Survival in patients with NETs and somatic mutations is better than patients with wild type NETs.
* Sunitinib (multi-tyrosine kinase inhibitor) and Everolimus (mTOR signaling pathway inhibitor) are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic pancreatic NETs.
* However, mutation targeted therapy with Sunitinib or Everolimus has not been studied in this patient population.
* The present proposal aims to determine if mutation targeting therapy for patients with advanced low- or intermediate grade NETs is more effective than historically expected results.

Objectives:

-To determine the progression-free survival in patients with NETs of the gastrointestinal tract and pancreas treated with Sunitinib or Everolimus based on tumor genotyping.

Eligibility:

-Patients with:

* progressive, histologically or cytologically diagnosed low or intermediate grade locally advanced or metastatic NETs.
* Age greater than or equal to 18 years

Design:

* Phase II open labeled clinical trial.
* Tumor biopsy for tumor genotyping will be performed if the patient does not have archival tissue available and does not have MEN1, VHL or NF1.
* Patients with somatic or germline mutations in MEN1/PDGFR/KIT/FMS-like tyrosine kinase-3 will be treated with Sunitinib. (Arm 1)
* Patients with somatic/germline mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL will be treated with Everolimus. (Arm 2)
* Patients with wildtype tumor will be treated with Sunitinib. (Arm 1)
* Patients who have disease-progression on either Sunitinib or Everolimus will cross-over to the other drug.
* Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal.
* Up to 120 patients will be accrued to the study. It is anticipated that 20-30 patients per year may enroll into this trial; thus accrual may be completed in 4-5 years.

Study of Mutation-Targeted Therapy With Sunitinib or Everolimus in People With Advanced Low- or Intermediate-Grade Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas With or Without Cytoreductive Surgery

A Phase II Trial of Mutation-Targeted Therapy With Sunitinib or Everolimus in Patients With Advanced Low-or Intermediate Grade Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas With or Without Cytoreductive Surgery

Median amount of time subject survives without disease progression after treatment. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

Overall response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) is defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD). Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD) (e.g. appearance of one or more new lesions), taking as reference the smallest sum of diameters while on study.

Overall survival is defined as the time from treatment start date until date of death or date last known alive following therapy.

MST is the amount of time a subject survives after therapy.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

National Cancer Institute

Participants who received Sunitinib in period 1 or 2.

Participants who received Everolimus in period 1 or 2.

In Period 1 participants received Sunitinib 37.5 mg once daily until progression or unacceptable treatment-related toxicity. In Period 2 participants received Everolimus 10 mg daily until progression or unacceptable treatment-related toxicity.

Sunitinib Followed by Everolimus

In Period 1 participants received Everolimus 10 mg daily until progression or unacceptable treatment-related toxicity. In Period 2 participants received Sunitinib 37.5 mg once daily until progression or unacceptable treatment-related toxicity.

Everolimus Followed by Sunitinib

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Naris Nilubol

Participants who received Sunitinib first, followed by Everolimus.

Sunitinib First, Everolimus Second

Participants who received Everolimus first, followed by Sunitinib.

Everolimus First, Sunitinib Second

The data in this outcome measure is reported per sequence as pre-specified in the protocol.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Mutation-Targeted Therapy With Sunitinib or Everolimus in People With Advanced Low- or Intermediate-Grade Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas With or Without Cytoreductive Surgery	NCT02315625	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Carcinoma, Neur... Neuroendocrine ...	Sunitinib Everolimus	18 Years -	National Institutes of Health Clinical Center (CC)
Study of Mutation-Targeted Therapy With Sunitinib or Everolimus in People With Advanced Low- or Intermediate-Grade Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas With or Without Cytoreductive Surgery	NCT02315625	Neuroendocrine ... Neuroendocrine ... Neuroendocrine ... Carcinoma, Neur... Neuroendocrine ...	Sunitinib Everolimus	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for neuroendocrine tumors of the gastrointestinal tract and pancreas