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

Phase 2

Completed

Conditions: Multiple Endocrine Neoplasia Type 1
Pancreatic Neuroendocrine Carcinoma

Interventions: Radiation: Computed Tomography Perfusion Imaging
Other: Laboratory Biomarker Analysis
Biological: Ziv-Aflibercept

Registration Number: NCT02101918

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ziv-aflibercept, perfusion CT)	Computed Tomography Perfusion Imaging	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.
Treatment (ziv-aflibercept, perfusion CT)	Laboratory Biomarker Analysis	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.
Treatment (ziv-aflibercept, perfusion CT)	Ziv-Aflibercept	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	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,

Secondary Outcome Measures

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

Trial Locations

Locations (3): Moffitt Cancer Center-International Plaza
🇺🇸
Tampa, Florida, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States