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 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 15004015-C-0040
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuroendocrine Tumors; Neuroendocrine Carcinoma; Neuroendocrine Neoplasms; Carcinoma, Neuroendocrine; Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas

Keywords

MEN1; VHL; Neoplasm; NF1; mTOR

Outcome Measures

Primary Outcomes (1)

• Median Amount of Time Subject Survives Without Disease Progression After Treatment

  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.

  Up to approximately 2 years

Secondary Outcomes (4)

• Number of Participants With an Overall Response

  Every 3 months until disease progression, up to 12 months

• Overall Survival

  Up to approximately 4 years

• Median Survival Time (MST)

  Death, an average of 12 months follow up

• Number of Participants With Serious and Non-Serious Adverse Events

  Date treatment consent signed to date off study approximately 49 months and 9 days.

Study Arms (2)

1/ Arm 1 Sunitinib

EXPERIMENTAL

Sunitinib

Drug: Sunitinib

2/ Arm 2 Everolimus

EXPERIMENTAL

Everolimus

Drug: Everolimus

Interventions

Sunitinib DRUG

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

Also known as: SU11248

1/ Arm 1 Sunitinib

Everolimus DRUG

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

Also known as: Afinitor

2/ Arm 2 Everolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Progressive, histologically or cytologically diagnosed low or intermediate grade, neuroendocrine tumors confirmed by the Laboratory of Pathology, National Cancer Institute (NCI). Disease progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progression of disease or any new lesions seen on 68-Gallium DOTATATE within the 18 months prior to enrolment.
• Age greater than or equal 18 years, because the incidence and prevalence of metastatic pancreatic and gastrointestinal neuroendocrine tumors in the pediatric patient population is exceedingly rare (children are excluded from this study, but will be eligible for future pediatric trials).
• Patients must have measurable disease according to RECIST criteria on anatomic imaging studies (computed tomography (CT) scan or magnetic resonance imaging (MRI)).
• Willingness to undergo tumor biopsy if the patient does not have a known familial cancer syndrome (multiple endocrine neoplasia type 1 (MEN1), Von Hippel-Lindau (VHL) and neurofibromatosis type 1 (NF1)). Archival tissue available.
• Eastern Cooperative Oncology Group (ECOG) performance status \<2.
• Patients must have normal organ and bone marrow function as defined below:
• hemoglobin greater than or equal 9 g/dL \*
• leukocytes greater than or equal 3,000/mcL \*
• absolute neutrophil count greater than or equal 1,500/mcL \*
• platelets greater than or equal institutional lower limit of normal
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) less than or equal 2.5 times institutional upper limit of normal
• (less than or equal 5 times upper limit of normal (ULN) in patients with liver metastases)
• \- creatinine within normal institutional limits
• creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

You may not qualify if:

• Uncontrolled hypertension (\>150/100 mmHg).
• Prior external beam radiation therapy to the target lesion(s) within 1 months prior to enrollment
• Prior systemic chemotherapy or therapy with one of the investigational agents within 1 month prior to enrollment.
• Patients who had therapy with one of the investigational agents more than 1 month prior to enrollment in whom tumor genotyping show assignment to the same investigational agent.
• Patients who are receiving any other investigational agents.
• Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Sunitinib or Everolimus.
• Patients who have any severe and/or uncontrolled medical conditions such as:
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction less than or equal 6 months prior to start of Everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
• symptomatic congestive heart failure of New York heart Association Class III or IV
• active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease
• known severely impaired lung function
• Corrected QT interval (QTc) interval \> 450 msec for males or \> 470 msec for females
• active, bleeding diathesis;
• psychiatric illness/social situations that would preclude informed consent, limit compliance with study requirements

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (6)

• Gan HK, Seruga B, Knox JJ. Sunitinib in solid tumors. Expert Opin Investig Drugs. 2009 Jun;18(6):821-34. doi: 10.1517/13543780902980171.

  PMID: 19453268 BACKGROUND

• Tanaka C, O'Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, Raymond E, Zumstein-Mecker S, Stephan C, Boulay A, Hattenberger M, Thomas G, Lane HA. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol. 2008 Apr 1;26(10):1596-602. doi: 10.1200/JCO.2007.14.1127. Epub 2008 Mar 10.

  PMID: 18332467 BACKGROUND

• Khagi S, Saif MW. Neuroendocrine tumors: treatment updates. JOP. 2013 Jul 10;14(4):367-71. doi: 10.6092/1590-8577/1657.

  PMID: 23846929 BACKGROUND

• Neychev V, Steinberg SM, Cottle-Delisle C, Merkel R, Nilubol N, Yao J, Meltzer P, Pacak K, Marx S, Kebebew E. Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial. BMJ Open. 2015 May 19;5(5):e008248. doi: 10.1136/bmjopen-2015-008248.

  PMID: 25991462 RESULT

• Tirosh A, Killian JK, Zhu YJ, Petersen D, Walling J, Mor-Cohen R, Neychev V, Stevenson H, Keutgen XM, Patel D, Nilubol N, Meltzer P, Kebebew E. ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS. Endocr Pract. 2019 Jun;25(6):580-588. doi: 10.4158/EP-2018-0603. Epub 2019 Mar 13.

  PMID: 30865533 RESULT

• Neychev V, Sadowski SM, Zhu J, Allgaeuer M, Kilian K, Meltzer P, Kebebew E. Neuroendocrine Tumor of the Pancreas as a Manifestation of Cowden Syndrome: A Case Report. J Clin Endocrinol Metab. 2016 Feb;101(2):353-8. doi: 10.1210/jc.2015-3684. Epub 2015 Dec 17.

  PMID: 26678657 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Neoplasms

Interventions

Sunitinib; Everolimus

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Naris Nilubol
• Organization: National Cancer Institute

niluboln@nih.gov

240-760-6154

Study Officials

• Naris Nilubol, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National Cancer Institute

Study Record Dates

• First Submitted: December 11, 2014
• First Posted: December 12, 2014
• Study Start: April 8, 2015
• Primary Completion: May 22, 2019
• Study Completion: May 22, 2019
• Last Updated: September 9, 2020
• Results First Posted: September 9, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)