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Trial record 56 of 837 for:    Advanced | Neuroendocrine Tumors

Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

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

Tracking Information
First Submitted Date  ICMJE March 13, 2015
First Posted Date  ICMJE March 26, 2015
Last Update Posted Date July 26, 2019
Actual Study Start Date  ICMJE May 15, 2015
Estimated Primary Completion Date September 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 2, 2015)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 20, 2015)
PFS reported using standard Kaplan-Meier methods [ 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.
Change History Complete list of historical versions of study NCT02399215 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 2, 2015)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 20, 2015)
  • 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.
  • Median OS reported using standard Kaplan-Meier methods [ 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.
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures
 (submitted: June 2, 2015)
  • Biomarker levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.
  • 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.
  • 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.
  • 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.
  • Treg levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.
Original Other Pre-specified Outcome Measures
 (submitted: March 20, 2015)
  • 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 and reported as a single value for each group.
  • Biomarker levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.
  • Treg levels [ Time Frame: Baseline ]
    Will be analyzed for all patients and reported in groups based on response.
  • Change in cytokine expression analyzed using permutation paired t-tests. [ 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.
  • Change in growth factors analyzed using permutation paired t-tests. [ 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.
 
Descriptive Information
Brief Title  ICMJE Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors
Official Title  ICMJE Multicenter Phase 2 Study of Nintedanib for Patients With Advanced Carcinoid Tumors
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Carcinoid Tumor
  • Metastatic Carcinoid Tumor
  • Neuroendocrine Neoplasm
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Drug: Nintedanib
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 20, 2015)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2020
Estimated Primary Completion Date September 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02399215
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Renuka Iyer Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP