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Trial record 56 of 827 for:    Advanced | Neuroendocrine Tumors

Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

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ClinicalTrials.gov Identifier: NCT02399215
Recruitment Status : Active, not recruiting
First Posted : March 26, 2015
Last Update Posted : April 1, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase II trial studies how well nintedanib works in treating patients with neuroendocrine tumors that have spread from where they started to nearby tissue or lymph nodes (locally advanced) or have spread from the primary site (place where they started) to other places in the body (metastatic). Nintedanib may stop the growth of tumor cells by slowing or stopping a certain type of receptor called vascular endothelial growth factor receptor (VEGFR) from attaching to its target. This may stop the growth of neuroendocrine tumors by blocking the growth of new blood vessels necessary for tumor growth.

Condition or disease Intervention/treatment Phase
Carcinoid Tumor Metastatic Carcinoid Tumor Neuroendocrine Neoplasm Other: Laboratory Biomarker Analysis Drug: Nintedanib Other: Pharmacological Study Other: Quality-of-Life Assessment Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess progression free survival (PFS), defined as the time interval from initiation of therapy, to its cessation for documentation of progressive disease (PD) or death.

SECONDARY OBJECTIVES:

I. To assess the clinical response (complete response + partial response) in all patients with measurable disease (using standard Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria).

II. To assess overall survival (OS) in all patients. III. Assess changes in quality of life (QOL) throughout treatment using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) - Gastrointestinal Neuroendocrine Tumors (NET) 21 (GI.NET21) questionnaire for carcinoid patients with gastrointestinal neuroendocrine tumors, in all patients who have filled out at least two QOL questionnaires and, will be reported by groups based on response (response, stable disease or progressive disease).

IV. Steady-state pharmacokinetics (PK) of nintedanib, biomarkers, regulatory T cell (Treg) and cytokine expression and growth factors will be analyzed for all patients and reported in groups based on response.

V. Gene mutations and copy number alterations analysis in the mammalian target of rapamycin (mTOR) pathway (will be performed only on the first 10 patients), protein expression of activation of protein kinase B (Akt) (as well as other downstream targets).

VI. Toxicity (graded using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) will be closely monitored and all toxicities will be tabulated.

OUTLINE:

Patients receive nintedanib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter Phase 2 Study of Nintedanib for Patients With Advanced Carcinoid Tumors
Actual Study Start Date : May 15, 2015
Estimated Primary Completion Date : July 1, 2019
Estimated Study Completion Date : July 1, 2020


Arm Intervention/treatment
Experimental: Treatment (nintedanib)
Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Nintedanib
Given PO
Other Names:
  • BIBF 1120
  • BIBF-1120
  • Intedanib
  • Multitargeted Tyrosine Kinase Inhibitor BIBF 1120
  • tyrosine kinase inhibitor BIBF 1120
  • Vargatef

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. PFS [ Time Frame: Time interval from initiation of therapy, to its cessation for documentation of PD or death, assessed up to 2 years ]
    Will be reported using standard Kaplan-Meier methods. Ninety-five percent confidence intervals for the median PFS will be calculated using Greenwood's formula. Additionally, a confidence interval for the 16-week PFS rate will be obtained using Jeffrey's prior method. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.


Secondary Outcome Measures :
  1. Change in QOL using the EORTC QLQ-GI.NET21 questionnaire [ Time Frame: Baseline to 30 days post-treatment ]
    Will be analyzed in all patients who have filled out at least two QOL questionnaires and reported in three groups based on response (response, stable disease or progressive disease). An exact 90% confidence interval will be given for the rate of improved QOL. QOL will be analyzed using the logistic regression to investigate the association with quantified variables, such as biomarker expression and gene mutation.

  2. Circulating marker levels (steady state PK, fibroblast growth factor [FGF] and fibroblast growth factor receptor [FGFR] and soluble vascular endothelial growth factor receptor 2 [sVEGFR2]) [ Time Frame: Baseline ]
    Dynamic contrast enhanced CT parameters will be reported and predictive value assessed using the PK/pharmacodynamics model previously developed by our group to explore association with PFS, clinical response, QOL and overall survival.

  3. Clinical response (complete response + partial response) measured using standard RECISTv1.1 criteria [ Time Frame: Up to 2 years ]
    Exact 90% confidence interval estimates using the Clopper-Pearson method will be given for the response rates.

  4. Median OS [ Time Frame: Up to 2 years ]
    Will be reported using standard Kaplan-Meier methods. Ninety-five percent confidence intervals for the median OS will be calculated using Greenwood's formula. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.

  5. Ratio of FGFR IIIb/IIIc and Ki-67 and microvessel density scores [ Time Frame: Baseline ]
    Scores will be obtained to investigate association with PFS, clinical response, QOL and survival.


Other Outcome Measures:
  1. Biomarker levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.

  2. Change in cytokine expression [ Time Frame: Baseline to 8 weeks ]
    Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment cytokine expression will be analyzed using permutation paired t-tests.

  3. Change in growth factors [ Time Frame: Baseline to 30 days post-treatment ]
    Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment growth factors will be analyzed using permutation paired t-tests.

  4. Gene mutations and copy number alterations [ Time Frame: Baseline ]
    Gene mutations and copy number alterations in the several pathways particularly mTOR pathway will be evaluated. Will be analyzed for all patients and correlated with clinical outcomes.

  5. Treg levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient must be on a stable dose of octreotide (Sandostatin®) long-acting release (LAR) or lanreotide for 3 months prior to study enrollment
  • Patient must have histologically or cytologically confirmed well differentiated or moderately differentiated (low grade or intermediate grade) neuroendocrine tumor that is locally advanced or metastatic and not of pancreatic origin
  • Measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI)
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Life expectancy greater than 3 months
  • Leukocytes >= 3,000/uL
  • Absolute neutrophil count >= 1,500/uL
  • Total bilirubin =< 2 mg/dL
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) and bilirubin =< ULN for patients without liver metastases
  • AST/ALT =< 2.5 x ULN and bilirubin =< ULN for patients with liver metastases
  • Patients with Gilbert syndrome and bilirubin < 2 x ULN and normal AST/ALT
  • Creatinine =< 1.5 mg/dl
  • Prior treatment will be permitted including surgery (>= 4 weeks), cytotoxic chemotherapy (maximum of 2 prior regimens); radiation, interferon, targeted growth factors (>= 4 weeks); and prior treatment with octreotide, will be allowed
  • Ability to swallow and retain oral medication
  • Participants of child-bearing potential (both male and female) must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; 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
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  • Archival tissue of carcinoid biopsy must be available

Exclusion Criteria:

  • Uncontrolled hypertension, unstable angina, New York Heart Association grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease (grade II or greater)
  • Presence of brain metastases
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, or anticipated need for major surgical procedure during the course of the study, or fine needle aspirations or core biopsies within 7 days prior to day 0
  • Significant proteinuria at baseline (>= 500 mg/24 hours [h])
  • Serious non-healing wound, ulcer or bone fracture
  • Evidence of bleeding diathesis or coagulopathy
  • Recent (=< 6 months) arterial thromboembolic events, including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction
  • Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma
  • Hepatic artery embolization or ablation of hepatic metastasis within 3 months of enrollment, prior peptide receptor radionuclide therapy (PRRT) within 4 months or any other cancer therapy within 4 weeks (as long as all toxicities are resolved)
  • Intolerance or hypersensitivity to octreotide
  • Severe or uncontrolled medical conditions
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or nursing female participants
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

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): NCT02399215


Locations
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United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Renuka Iyer Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT02399215     History of Changes
Other Study ID Numbers: I 259114
NCI-2015-00238 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 259114 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: March 26, 2015    Key Record Dates
Last Update Posted: April 1, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
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Neoplasms
Carcinoid Tumor
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Adenocarcinoma
Carcinoma
Nintedanib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action