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

Phase 2

Terminated

Conditions: Neuroendocrine Tumors
Neuroendocrine Neoplasms
Carcinoma, Neuroendocrine
Neuroendocrine Carcinoma
Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas

Interventions: Drug: Sunitinib
Drug: Everolimus

Registration Number: NCT02315625

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 16

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
1/ Arm 1 Sunitinib	Sunitinib	Sunitinib
2/ Arm 2 Everolimus	Everolimus	Everolimus

Primary Outcome Measures

Name	Time	Method
Median Amount of Time Subject Survives Without Disease Progression After Treatment	Up to approximately 2 years	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious and Non-Serious Adverse Events	Date treatment consent signed to date off study approximately 49 months and 9 days.	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.
Overall Survival	Up to approximately 4 years	Overall survival is defined as the time from treatment start date until date of death or date last known alive following therapy.
Median Survival Time (MST)	Death, an average of 12 months follow up	MST is the amount of time a subject survives after therapy.
Number of Participants With an Overall Response	Every 3 months until disease progression, up to 12 months	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.