AzTrials
AzTrials

Neuroendocrine TumorsPhase 2NCT02315625

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 2 study testing Sunitinib and Everolimus in people with Neuroendocrine Tumors and Neuroendocrine Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Sunitinib and Everolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
1 siteUnited States
Study dates
8 Apr 2015to 22 May 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

None listed.

Who cannot join

  • 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.
Show all 25Show fewer
  • 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
  • Pregnant or nursing patients will be excluded from the study, because the effects of Sunitinib and Everolimus on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Sunitinib or Everolimus, breastfeeding should be discontinued if the mother is treated with Sunitinib or Everolimus.
  • Current treatment with therapeutic doses of Coumadin-derivative anticoagulants (low dose Coumadin up to 2 mg by mouth (PO) daily for deep vein thrombosis prophylaxis is allowed).
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with study agents.
  • Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome, or the inability to take oral medication
  • Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HbA1c) >8% despite adequate therapy. Patients with a known history or diagnosis of diabetes mellitus who are on therapy and have had good blood sugar control may be included, even if the HbA1c is > 8% because this value can take up to 3-4 months to normalize
  • Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacille Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
  • Patients who are on chronic treatment with corticosteroids or other immunosuppressive agents (topical or inhaled corticosteroids are allowed)
  • Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
  • Patients who are taking medications that are strong inhibitors of cytochrome P450 AA4 (CYP3A4) or PgP and need to remain on these medications. For a current table of Substrates, Inhibitors and Inducers please access the following website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc es/DrugInteractionsLabeling/ucm093664.htm
  • Patients who have a history of another primary malignancy from which the patient has been disease free for < 3 years at the time of enrolment, with the exceptions of: a patient with a familial cancer syndrome-associated NETs including MEN1, VHL, NF-1, and tuberous sclerosis (TS);

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: 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

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.
Read more

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.
Read the 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.
Being tested
Sunitinib, Everolimus
Keywords
MEN1, VHL, Neoplasm, NF1, mTOR
Medical subject headings
Neuroendocrine Tumors, Carcinoma, Neuroendocrine, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SunitinibDrug

    Also called SU11248

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

  • EverolimusDrug

    Also called Afinitor

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

Study groups in NCT02315625
Study groupRoleWhat they receive
1/ Arm 1 SunitinibExperimentalSunitinib
Receives: Drug: Sunitinib
2/ Arm 2 EverolimusExperimentalEverolimus
Receives: Drug: Everolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to approximately 2 years

Secondary outcomes (4)

  1. Number of Participants With an Overall Response

    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.

    Measured: Every 3 months until disease progression, up to 12 months

  2. Overall Survival

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

    Measured: Up to approximately 4 years

  3. Median Survival Time (MST)

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

    Measured: Death, an average of 12 months follow up

  4. Number of Participants With Serious and Non-Serious Adverse Events

    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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Dec 2014 (estimated)
  2. Study start8 Apr 2015
  3. Primary completion22 May 2019
  4. Study completion22 May 2019

Why it stopped: Study closed due to poor accrual.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02315625
Sponsor's protocol ID
150040
Other IDs
15-C-0040
Status last verified
Aug 2020
First submitted
11 Dec 2014
Last updated
9 Sep 2020
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

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

    PubMed 19453268

  • 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.

    PubMed 18332467

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

    PubMed 23846929

  • 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.

    PubMed 25991462

  • 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.

    PubMed 30865533

  • 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.

    PubMed 26678657

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Sunitinib and Everolimus in people with Neuroendocrine Tumors and Neuroendocrine Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Amount of Time Subject Survives Without Disease Progression After Treatment (time frame: Up to approximately 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02315625, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2020.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in