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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

This study is currently recruiting participants.
Verified August 23, 2017 by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02315625
First Posted: December 12, 2014
Last Update Posted: September 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
  Purpose

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:

<TAB>- Medical history

<TAB>- Physical exam

<TAB>- Scans

<TAB>- Blood, urine, and lab tests

  • The study team will see if participants should have surgery.
  • If yes, participants will:
  • Sign a separate consent
  • Have 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.

Condition Intervention Phase
Neuroendocrine Tumors Drug: Sunitinib Drug: Everolimus Procedure: Surgery Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Primary Outcome Measures:
  • Progress Free Survival [ Time Frame: Disease progression ]

Secondary Outcome Measures:
  • To determine overall response rate sum of complete response, partial [ Time Frame: Overall Response Rate ]
  • To explore whether the PFS in patients who undergo cytoreductive surgery with [ Time Frame: Disease Progression ]
  • To determine overall survival and median survival time (MST) [ Time Frame: Overall Survival ]
  • To evaluate any relationship between tumor genotype, treatment and PFS [ Time Frame: Disease Progression ]
  • Safety endpoints AEs, clinical laboratory evaluations, ECGs, physical [ Time Frame: Disease Progression ]

Estimated Enrollment: 120
Study Start Date: December 5, 2014
Estimated Study Completion Date: September 6, 2021
Estimated Primary Completion Date: September 7, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Surgery followed by tx with sutent till progression
Drug: Sunitinib
37.5 mg once daily will continue until progression
Procedure: Surgery
Cytoreductive surgery only on patients for whom it is indicated. Performed within 3 months of first dose of study drug.
Experimental: Arm 2
Surgery followed by tx with everolimus till progression
Drug: Everolimus

10 mg daily

  1. x 10 mg tablets or
  2. x 5 mg tablets or

4 x 2.5 mg tablets

Procedure: Surgery
Cytoreductive surgery only on patients for whom it is indicated. Performed within 3 months of first dose of study drug.

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 CDKN1B, and genes involved in the PI3K/AKT/mTOR signaling pathway, and/or overexpression of growth factors and their receptors such as VEGF, VEGFR, PDGF, and 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.
  • It is also unknown whether these treatments are beneficial for patients with advanced NETs who have had cytoreductive surgery.
  • The present proposal aims to determine if mutation targeting therapy with or without surgery 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 with or without surgical resection.

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:

  • Pilot Phase II open labeled clinical trial.
  • Patients will undergo surgical resection if medically indicated but not only for tumor tissue procurement.
  • Tumor biopsy for tumor genotyping will be performed if the patient is not a surgical candidate 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.
  • Patients with somatic/germline mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL will be treated with everolimus.
  • Patients with wildtype tumor will be treated with sunitinib.
  • 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.
  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Progressive, histologically or cytologically diagnosed low or intermediate grade, neuroendocrine tumors confirmed by the Laboratory of Pathology, NCI. Disease progression is defined according to RECIST criteria for progression of disease or any new lesions seen on 68-Gallium DOTATATE within the 18 months prior to enrolment.
  2. 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).
  3. Patients must have measurable disease according to RECIST criteria on anatomic imaging studies (CT scan or MRI).
  4. Willingness to undergo tumor biopsy if the patient does not have a known familial cancer syndrome (MEN1, VHL and NF1). Archival tissue, if available, can be used if fresh tumor biopsy is not an option.
  5. ECOG performance status <2 (Karnofsky >60%).
  6. 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
    • AST(SGOT)/ALT(SGPT) less than or equal 2.5 times institutional upper limit of normal

    (less than or equal 5 times ULN in patients with liver metastases)

    - creatinine within normal institutional limits

    OR

    • creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
    • INR less than or equal 2;

      • If a patient s bone marrow function falls below the indicated values and it is not thought to be related to prior treatments a hematology consult will be ordered. If Hematology deems the patients safe to proceed with treatment they will be allowed to enroll on study. In such cases, the patient s absolute neutrophil count must be greater than 1,000/mcl, hemoglobin must be greater than 7.5 g/dL and the platelet count must be > 75,000 mcL. Each patient will also be seen by a medical oncologist at each follow-up visit.
  7. Fasting serum cholesterol less than or equal 300 mg/dL OR less than or equal 7.75 mmol/L AND fasting triglycerides less than or equal 2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication;
  8. Women of childbearing potential (WOCBP)or partners of WOCBP participating in this study must agree to use highly effective contraception while on treatment and for at least 8 weeks after end of treatment, because the effects of sunitinib and everolimus on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    Highly effective contraception methods include combination of:

    1. Any two of the following:

      • Use of oral, injected or implanted hormonal methods of contraception or;
      • Placement of an intrauterine device (IUD) or intrauterine system (IUS);
      • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
    2. Total abstinence or;
    3. Male/female sterilization.

    Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

  9. Must have fully recovered from toxicities of any prior treatment with cytotoxic drugs, radiotherapy, surgery, or other anti-cancer modalities (returned to baseline status as noted before most recent treatment or less than or equal grade 1).
  10. Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  1. Uncontrolled hypertension (>150/100 mmHg).
  2. Prior external beam radiation therapy to the target lesion(s) within 1 months prior to enrollment
  3. Prior systemic chemotherapy or therapy with one of the investigational agents within 1 month prior to enrollment.
  4. 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.
  5. Patients who are receiving any other investigational agents.
  6. Patients who cannot undergo tumor biopsy and archival tumor tissue is unavailable.
  7. 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.
  8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib or everolimus.
  9. Patients who have any severe and/or uncontrolled medical conditions such as:

    1. 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
    2. symptomatic congestive heart failure of New York heart Association Class III or IV
    3. active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease
    4. known severely impaired lung function
    5. QTc interval > 450 msec for males or > 470 msec for females
    6. active, bleeding diathesis;
    7. psychiatric illness/social situations that would preclude informed consent, limit compliance with study requirements
  10. 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.
  11. Current treatment with therapeutic doses of Coumadin-derivative anticoagulants (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
  12. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with study agents.
  13. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome, or the inability to take oral medication
  14. Uncontrolled diabetes mellitus as defined by 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

  15. 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, BCG, yellow fever, varicella and TY21a typhoid vaccines
  16. Patients who are on chronic treatment with corticosteroids or other immunosuppressive agents (topical or inhaled corticosteroids are allowed)
  17. 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
  18. Patients who are taking medications that are strong inhibitors of 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
  19. Patients who have a history of another primary malignancyfrom 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 TS;
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02315625


Contacts
Contact: Roxanne E Merkel (240) 760-6058 ncieobinquiry@mail.nih.gov
Contact: Electron Kebebew, M.D. (240) 760-6153 kebebewe@mail.nih.gov

Locations
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Xavier Keutgen, MD    312-563-1557    xavier_keutgen@rush.edu   
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Electron Kebebew, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02315625     History of Changes
Other Study ID Numbers: 150040
15-C-0040
First Submitted: December 11, 2014
First Posted: December 12, 2014
Last Update Posted: September 13, 2017
Last Verified: August 23, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
MEN1
VHL
Neoplasm
NF1
mTOR

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neuroendocrine Tumors
Carcinoid Tumor
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms
Neoplasms, Nerve Tissue
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Sunitinib
Everolimus
Sirolimus
Pancrelipase
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Gastrointestinal Agents


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