Ziv-Aflibercept in Treating and Computed Tomography Perfusion Imaging in Predicting Response in Patients With Pancreatic Neuroendocrine Tumors That Are Metastatic or Cannot Be Removed by Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02101918
First received: March 28, 2014
Last updated: October 17, 2014
Last verified: October 2014
  Purpose

This phase II trial studies ziv-aflibercept in treating and perfusion computed tomography perfusion imaging in predicting response in patients with pancreatic neuroendocrine tumors that have spread to other parts of the body or cannot be removed by surgery. Ziv-aflibercept may stop the growth of tumor cells by blocking blood flow to the tumor. Diagnostic procedures, such as computed tomography perfusion, imaging may help measure a patient's response to ziv-aflibercept treatment.


Condition Intervention Phase
Gastrinoma
Glucagonoma
Insulinoma
Pancreatic Polypeptide Tumor
Recurrent Islet Cell Carcinoma
Somatostatinoma
Biological: ziv-aflibercept
Radiation: computed tomography perfusion imaging
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Perfusion CT as Predictive Biomarker in a Phase II Study of Ziv-Aflibercept in Patients With Advanced Pancreatic Neuroendocrine Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective response rate according to RECIST 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    90% exact confidence interval will be constructed for the overall group and for all the marker subgroups respectively. Fisher's exact test will be applied to test the equal response rates between the two groups with a one-sided 5% type I error rate.


Secondary Outcome Measures:
  • PFS [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Calculated for all eligible patients using the Kaplan Meier method and reported with confidence interval.

  • Baseline BV [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The relationship between response rate and baseline BV will be evaluated. In addition to hypothesis testing using externally generated cut-points, refinement of optimal cut points in baseline BV separating responders and non-responders will be performed. Receiver operating characteristic (ROC) curves will be generated. Response rates of perfusion CT (pCT) subgroups defined by these cut-points will be compared using chi-square test. Response profiles of pCT subgroups defined by these cut-points will be compared using non-parametric test (Wilcoxon rank sum test).

  • Baseline PS [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The relationship between response rate and baseline PS will be evaluated. In addition to hypothesis testing using externally generated cut-points, refinement of optimal cut points in baseline PS separating responders and non-responders will be performed. ROC curves will be generated. Response rates of pCT subgroups defined by these cut-points will be compared using chi-square test. Response profiles of pCT subgroups defined by these cut-points will be compared using non-parametric test (Wilcoxon rank sum test).


Other Outcome Measures:
  • Change in BV [ Time Frame: Baseline to 4 weeks after treatment ] [ Designated as safety issue: No ]
    Median will be used as cut point for correlation of post-treatment changes in BV expressed as relative change from baseline with response. Response rates will be compared using chi-square test or Fisher's exact test whenever appropriate. Response profiles will be compared using non-parametric test (Wilcoxon rank sum test).

  • Post-treatment tumor BF [ Time Frame: 4 weeks after treatment ] [ Designated as safety issue: No ]
    Median will be used as cut point for correlation of post-treatment tumor BF (absolute measurement) with response. Response rates will be compared using chi-square test or Fisher's exact test whenever appropriate. Response rates will be compared using chi-square test or Fisher's exact test whenever appropriate.

  • Post-treatment change in BF [ Time Frame: Baseline to 4 weeks after treatment ] [ Designated as safety issue: No ]
    Continuous parameters in relative change in pCT parameters will be plotted against best relative change in sum of tumor diameters from RECIST 1.1 tumor measurements. Pearson correlation will be used to test statistical significance. Non-parametric test will be used if appropriate.

  • Post-treatment change in BV [ Time Frame: Baseline to 4 weeks after treatment ] [ Designated as safety issue: No ]
    Continuous parameters in relative change in pCT parameters will be plotted against best relative change in sum of tumor diameters from RECIST 1.1 tumor measurements. Pearson correlation will be used to test statistical significance. Non-parametric test will be used if appropriate.

  • Change in patient parameters [ Time Frame: Baseline to 4 weeks after treatment ] [ Designated as safety issue: No ]
    The effect of ziv-aflibercept therapy on post-treatment BF, BV, mean transit time, and PS will be determined. Descriptive statistics of pre and post treatment values will be given. Distribution of pre and post treatment values will be graphed. Treatment induced change in values will be compared using paired-t test. Non-parametric test will be used if appropriate.

  • Tumor perfusion parameters at time of progression [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Summary statistics will be given to describe change from baseline and change from post treatment pCT. Differences will be compared using paired-t test. Non-parametric test will be used if appropriate.


Estimated Enrollment: 60
Study Start Date: June 2014
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (ziv-aflibercept, perfusion CT)
Patients receive ziv-aflibercept IV over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography perfusion imaging at baseline, day 21 of course 1, and at time of progression.
Biological: ziv-aflibercept
Given IV
Other Names:
  • aflibercept
  • vascular endothelial growth factor trap
  • VEGF Trap
  • Zaltrap
Radiation: computed tomography perfusion imaging
Undergo computed tomography perfusion imaging
Other Names:
  • computed tomography perfusion
  • CT perfusion
  • CTP
  • perfusion computed tomography
  • perfusion CT
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Estimate the objective response rate (RR) of ziv-aflibercept among patients with advanced pancreatic neuroendocrine tumors (NET)s according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

II. Test the following hypotheses: that baseline perfusion computed tomography (CT) parameters can predict which patients with advanced pancreatic neuroendocrine tumors (pNETs) will respond to treatment with ziv-aflibercept.

SECONDARY OBJECTIVES:

I. Estimate progression free survival (PFS) duration among patients treated with ziv-aflibercept.

II. Evaluate the relationship between response rate and baseline blood volume (BV) and between response rate and baseline permeability surface (PS).

TERTIARY OBJECTIVES:

I. Determine whether post-treatment changes in BV expressed as relative change from baseline correlate with response to ziv-aflibercept.

II. Determine whether post-treatment tumor blood flow (BF) (absolute measurement) correlates with response to ziv-aflibercept.

III. Determine whether post-treatment changes in BF and, BV, expressed as relative change from baseline, correlate with relative change in sum of tumor diameters (RECIST 1.1 measurements).

IV. Determine the effect of ziv-aflibercept therapy on post-treatment BF, BV, mean transit time (MTT), and PS at 4 weeks after treatment.

V. Evaluate the changes in tumor perfusion parameters at time of progression.

OUTLINE:

Patients receive ziv-aflibercept intravenously (IV) over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography perfusion imaging at baseline, day 21 of course 1, and at time of progression.

After completion of study treatment, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed low or intermediate grade pancreatic NET; patients with neuroendocrine tumors associated with menin (MEN1) syndrome will be eligible
  • Patients must have unresectable or metastatic disease
  • Patients must have at least one measurable site of disease according to RECIST 1.1 that has not been previously irradiated
  • Patients must have at least one lesion suitable for perfusion CT; the lesion should be greater than or equal to 3 cm in size in the cranial caudal direction
  • Patient must have no contraindication for CT with iodinated contrast
  • Patients who are on a somatostatin analogue for control of hormonal syndromes must be on a stable dose (no change in mg dose of long acting octreotide or lanreotide, changes in dosing interval of +/- 1 week is allowed) for 2 months prior to date of study entry
  • Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to date of study entry; women who have had menses within the past 2 years, who have not had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy are considered to be of child-bearing potential; patients with elevated human chorionic gonadotropin (hCG) at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal ultrasound
  • Up to two prior lines of systemic anti-neoplastic therapy are allowed; for purpose of this criterion, somatostatin analogues will not be counted toward lines of systemic anti-neoplastic therapy and prior vascular endothelial growth factor (VEGF) inhibitor will not be allowed
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Urine protein:creatinine ratio =< 1.0 OR 24-hour urine protein =< 500 mg (24-hour total urine protein only need be obtained if urine protein:creatinine ratio < 1.0)
  • Patients must have prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 X the upper limit of normal
  • Patients must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or 90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is permitted prior to study entry
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior chemotherapy to the time of randomization; less than 42 days elapsed from prior major surgery to the time of randomization
  • Adverse events (with exception of alopecia, peripheral sensory neuropathy and those listed in specific exclusion criteria) from any prior anti cancer therapy of grade > 1 (National Cancer Institute Common terminology Criteria [NCI CTCAE] version [v.]3.0) at the time of randomization
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 2
  • History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease
  • Other prior malignancy; adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or any other cancer from which the patient has been disease free for > 5 years are allowed
  • Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization
  • Any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack
  • Any of the following within 3 months prior to randomization: grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event
  • Occurrence of deep vein thrombosis within 4 weeks, prior to randomization
  • Acquired immuno deficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment
  • Any severe acute or chronic medical condition, which could impair the ability of the patient to participate to the study or to interfere with interpretation of study results
  • Pregnant or breast feeding women; positive pregnancy test (serum or urine beta-human chorionic gonadotropin [HCG]) for women of reproductive potential
  • Patient with reproductive potential (female and male) who do not agree to use an accepted effective method of contraception (hormonal or barrier methods, abstinence) during the study treatment period and for at least 3 months following completion of study treatment; for female patient enrolled, the following methods of contraception are acceptable: oral contraceptives accompanied by the use of a second method of contraception, or intra uterine device (IUD) or women who are surgically sterile, or women who are post -menopausal or other reasons have no chance of becoming pregnant
  • Absence of signed and dated Institutional Review Board-approved patient informed consent from prior to enrollment in the study
  • EXCLUSION CRITERIA RELATED TO ZIV-AFLIBERCEPT
  • Urine protein-creatinine ratio (UPCR ) > 1 urinalysis or total urine protein > 500 mg/24 hours (h)
  • Serum creatinine > 1.5 x upper limit of normal (ULN); if creatinine 1.0-1.5 x ULN, creatinine clearance, calculated according to Cockcroft-Gault formula, < 60 ml/min will exclude the patient
  • History of uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg while simultaneous diastolic blood pressure > 100 mmHg, or systolic blood pressure > 180 mmHg when diastolic blood pressure < 90 mmHg, on at least 2 repeated determinations on separate days within 3 months prior to study enrollment
  • Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of- therapeutic range INR (> 3) within the 4 weeks prior to study entry
  • Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. INR > 1.5 without vitamin K antagonist therapy), non-healing wound
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02101918

Locations
United States, Florida
Moffitt Cancer Center Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Jonathan R. Strosberg    813-745-3636    Jonathan.strosberg@moffitt.org   
Principal Investigator: Jonathan R. Strosberg         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: James C. Yao    713-792-2828    jyao@mdanderson.org   
Principal Investigator: James C. Yao         
Sponsors and Collaborators
Investigators
Principal Investigator: James Yao M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02101918     History of Changes
Other Study ID Numbers: NCI-2014-00642, NCI-2014-00642, 2013-0954, 9604, P30CA016672, N01CM00039
Study First Received: March 28, 2014
Last Updated: October 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Insulinoma
Adenoma, Islet Cell
Carcinoma, Islet Cell
Gastrinoma
Glucagonoma
Neuroendocrine Tumors
Somatostatinoma
Adenocarcinoma
Adenoma
Carcinoma
Carcinoma, Neuroendocrine
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Pancreatic Diseases
Pancreatic Neoplasms
Endothelial Growth Factors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 29, 2014