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

March 18, 2020 updated by: National Cancer Institute (NCI)

Perfusion CT as Predictive Biomarker in a Phase II Study of Ziv-Aflibercept in Patients With Advanced Pancreatic Neuroendocrine Tumors

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.

Study Overview

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 blood flow (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 60-120 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.

Study Type

Interventional

Enrollment (Actual)

22

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Florida
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
      • Tampa, Florida, United States, 33607
        • Moffitt Cancer Center-International Plaza
    • Texas
      • Houston, Texas, United States, 77030
        • M D Anderson Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed low or intermediate grade pancreatic NET; patients with neuroendocrine tumors associated with multiple endocrine neoplasia type 1 (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
  • Any number of prior lines of systemic anti-neoplastic therapy are allowed; treatment with =< 1 prior VEGF inhibitor will 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.]4.0)
  • 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 study entry
  • Any of the following within 6 months prior to study entry: 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 study entry: 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 study entry
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (ziv-aflibercept, perfusion CT)
Patients receive ziv-aflibercept IV over 60-120 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.
Correlative studies
Given IV
Other Names:
  • Eylea
  • vascular endothelial growth factor trap
  • VEGF Trap
  • Zaltrap
  • AVE0005
  • VEGF Trap R1R2
  • VEGF-Trap
  • AFLIBERCEPT
Undergo computed tomography perfusion imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame: Through study completion an average of 19 months
90% exact confidence interval was constructed for the overall group. Per Response EvaluationCriteria In SolidTumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR+PR,
Through study completion an average of 19 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: Through study completion an average of 19 months
Calculated for all eligible participants using the Kaplan Meier method and reported with confidence interval.
Through study completion an average of 19 months
Baseline Blood Volume (BV)
Time Frame: Baseline
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 computed tomography (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
Baseline Permeability Surface (PS)
Time Frame: Baseline
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).
Baseline

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in BV
Time Frame: Baseline to 4 weeks after treatment
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).
Baseline to 4 weeks after treatment
Post-treatment Tumor Blood Flow (BF)
Time Frame: 4 weeks after treatment
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.
4 weeks after treatment
Post-treatment Change in BF
Time Frame: Baseline to 4 weeks after treatment
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.
Baseline to 4 weeks after treatment
Post-treatment Change in BV
Time Frame: Baseline to 4 weeks after treatment
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.
Baseline to 4 weeks after treatment
Change in Participants Parameters
Time Frame: Baseline to 4 weeks after treatment
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.
Baseline to 4 weeks after treatment
Tumor Perfusion Parameters at Time of Progression
Time Frame: Up to 1 year
Up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Daniel Halperin, M.D. Anderson Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 18, 2014

Primary Completion (Actual)

January 31, 2018

Study Completion (Actual)

January 31, 2018

Study Registration Dates

First Submitted

March 28, 2014

First Submitted That Met QC Criteria

March 28, 2014

First Posted (Estimate)

April 2, 2014

Study Record Updates

Last Update Posted (Actual)

March 23, 2020

Last Update Submitted That Met QC Criteria

March 18, 2020

Last Verified

March 1, 2020

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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