Multiple Endocrine Neoplasia Type 1, Pancreatic Neuroendocrine Carcinoma
Conditions
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.
Interventions
Undergo computed tomography perfusion imaging
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALZiv-Aflibercept
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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). |
| 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Participants Parameters | 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. |
| Change in BV | 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). |
| Tumor Perfusion Parameters at Time of Progression | Up to 1 year | — |
| Post-treatment Tumor Blood Flow (BF) | 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. |
| Post-treatment Change in BF | 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. |
| Post-treatment Change in BV | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept 6 mg /kg IV Aflibercept 6 mg /kg IV every 3 weeks. | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Aflibercept 6 mg /kg IV |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 60.3 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 22 |
| other Total, other adverse events | 21 / 22 |
| serious Total, serious adverse events | 4 / 22 |
Outcome results
Primary
Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
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,
Time frame: Through study completion an average of 19 months
Population: Eligible patients with baseline perfusion CT imaging. One patient from moffitt was a screen fail however 21 patients were evaluable for response and toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 6 mg /kg IV | Objective Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | 9.5 percentage of participants |
Secondary
Baseline Blood Volume (BV)
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).
Time frame: Baseline
Population: Due to low response rate data were not collected
Secondary
Baseline Permeability Surface (PS)
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).
Time frame: Baseline
Population: Due to low response rate data were not collected
Secondary
Progression Free Survival (PFS)
Calculated for all eligible participants using the Kaplan Meier method and reported with confidence interval.
Time frame: Through study completion an average of 19 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflibercept 6 mg /kg IV | Progression Free Survival (PFS) | 10.4 months |
Other Pre-specified
Change in BV
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).
Time frame: Baseline to 4 weeks after treatment
Population: Due to the low response rate, data for blood volume were not collected
Other Pre-specified
Change in Participants Parameters
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.
Time frame: Baseline to 4 weeks after treatment
Population: Response rate was too low to power a valid analysis.
Other Pre-specified
Post-treatment Change in BF
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.
Time frame: Baseline to 4 weeks after treatment
Population: Response rate was too low to power a valid analysis.
Other Pre-specified
Post-treatment Change in BV
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.
Time frame: Baseline to 4 weeks after treatment
Population: Response rate was too low to power a valid analysis.
Other Pre-specified
Post-treatment Tumor Blood Flow (BF)
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.
Time frame: 4 weeks after treatment
Population: Response rate was too low to power a valid analysis.
Other Pre-specified
Tumor Perfusion Parameters at Time of Progression
Time frame: Up to 1 year
Population: No patients underwent perfusion CT at time of progression, no analysis could not be performed.