Gastrointestinal Carcinoid Tumor, Islet Cell Tumor, Neoplastic Syndrome
Conditions
Keywords
localized gastrointestinal carcinoid tumor, recurrent gastrointestinal carcinoid tumor, metastatic gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor, gastrinoma, insulinoma, WDHA syndrome, glucagonoma, pancreatic polypeptide tumor, somatostatinoma, recurrent islet cell carcinoma, neuroendocrine tumor
Brief summary
RATIONALE: AMG 706 and octreotide may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well AMG 706 and octreotide work in treating patients with low-grade neuroendocrine tumors.
Detailed description
OBJECTIVES: Primary * Determine the 4-month progression-free survival (PFS) of patients with low-grade neuroendocrine tumors treated with AMG 706 and octreotide acetate. Secondary * Determine the response rate and overall survival of patients treated with these drugs. * Determine the toxicity and tolerability of AMG 706 in these patients. * Determine the effect of AMG 706 on tumor perfusion by functional computerized tomography (CT) scan. * Determine the effect of AMG 706 on tumor markers (e.g., chromogranin A, 5-hydroxyindoleacetic acid, and gastrin) specific for neuroendocrine tumors. * Determine the effect of AMG 706 on serum vascular endothelial growth factor (VEGF) levels. * Determine the expression of VEGF, VEGF receptor-2 (VEGFR-2), chromogranin A, human achaete-scute homolog-1 (hASH1), and Notch1 markers of neuroendocrine tumors. OUTLINE: This is a multicenter study. Patients receive oral AMG 706 and octreotide acetate intramuscularly once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Plasma samples are collected at baseline, periodically during study treatment, and at 4 weeks after the completion of study treatment. Samples are used to determine plasma VEGF levels. Gene expression of downstream markers of Raf kinase expression (raf, MEK, and ERK) as well as hASH1 and Notch1 are evaluated at baseline. Tumor tissue collected at diagnosis or prior surgery is examined by reverse transcriptase-polymerase chain reaction assay. Contrast CT scans are conducted at baseline, day 2 of course 1, and week 8 to assess tumor perfusion. After the completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.
Interventions
DRUGAMG 706
AMG 706 was administered on a flat scale of mg/day and not by weight or body surface area (BSA). AMG 706 was provided as a 25 mg tablet; the daily dose was 125 mg administered as five 25 mg tablets in the AM. AMG 706 was taken daily without breaks in treatment
DRUGoctreotide
One dose consisted of octreotide-LAR 30 mg administered IM on day 1 of each cycle. The first octreotide-LAR injection would correspond with the first day of AMG 706 and then on day 1 of subsequent cycles.
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
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
* Histologically confirmed low-grade neuroendocrine neoplasm * Measurable disease * Radiographic evidence of disease progression after any prior systemic therapy, chemoembolization, bland embolization, or observation, defined by either of the following: * Appearance of a new lesion * At least 20% increase in the longest diameter of any previously documented lesion or in the sum of the longest diameters of multiple lesions * Tissue block from original diagnostic or surgical specimen required * Concurrent stable-dose octreotide acetate required * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Negative pregnancy test * Fertile patients must use effective contraception * Must be able to receive a contrast-enhanced CT scan * Absolute neutrophil count ≥ 1,000/mm³ * Platelet count ≥ 75,000/mm³ * Hemoglobin level ≥ 8.0 g/dL * Bilirubin ≤ 2.0 times upper limit of normal (ULN) * Aspartate aminotransferase (AST) ≤ 3 times ULN (5 times ULN if liver metastases are present) * Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal as evaluated by echocardiography or multigated acquisition (MUGA) scan * No history of uncontrolled hypertension (resting blood pressure \> 150/90 mm Hg) * Antihypertensive medications allowed if patients is stable on their current dose * One prior systemic chemotherapy regimen for low-grade neuroendocrine neoplasm allowed * Chemoembolization is not considered systemic chemotherapy * At least 4 weeks since prior major surgery, chemotherapy, radiation therapy, other systemic therapy, or local liver therapy
Exclusion criteria
* Prior procedures that would adversely affect intestinal absorption * Prior anti-vascular endothelial growth factors * Concurrent chemotherapy or radiation therapy * History of the following within the past 12 months: * New York Heart Association class III or IV congestive heart failure * Unstable angina pectoris * Myocardial infarction * Symptomatic cardiac arrhythmia * Cerebrovascular accident or transient ischemic attack * Arterial or venous thrombosis * Known history of allergic reactions to AMG 706 or derivatives or to octreotide acetate injections * Gastrointestinal tract disease resulting in an inability to take oral medication (i.e., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, bowel obstruction, or inability to swallow tablets) * Pregnant or nursing * Small cell lung cancer, medullary thyroid cancer, paraganglioma, or pheochromocytoma * Requirement for intravenous alimentation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Four-month Progression-free Survival Rate | assessed every 4 weeks while on treatment and at three months post-treatment for participants treated for one cycle, up to month four | Four-month progression-free survival (PFS) rate is defined as number of patients who are still progression free at 4 months after study entry divided by number of eligible and treated patients enrolled to the study. Progression is evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years | Overall survival (OS) is defined as the time from registration until death (event), or censored at last date known alive. OS was estimated using the Kaplan-Meier method , with 95% confidence intervals calculated using Greenwood's formula |
| Objective Response Rate | assessed every 8 weeks while on treatment, and frequency of tumor measurements during follow-up were determined by the treating physician, assessed up to 5 years | Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by the total number of analyzable patients. CR is defined as complete disappearance of all tumor lesions, and partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. |
Countries
United States
Participant flow
Recruitment details
This study was activated on September 16, 2008, accrued its first patient on November 7, 2008, and closed on March 18, 2010 with 46 patients registered to the study from 10 ECOG-ACRIN affiliated institutions.
Participants by arm
| Arm | Count |
|---|---|
| AMG 706+Octreotide Patients receive oral AMG 706 and octreotide acetate intramuscularly once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
AMG 706: AMG 706 was administered on a flat scale of mg/day and not by weight or body surface area (BSA). AMG 706 was provided as a 25 mg tablet; the daily dose was 125 mg administered as five 25 mg tablets in the AM. AMG 706 was taken daily without breaks in treatment.
octreotide: One dose consisted of octreotide-LAR 30 mg administered IM on day 1 of each cycle. The first octreotide-LAR injection would correspond with the first day of AMG 706 and then on day 1 of subsequent cycles. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Alternative therapy | 1 |
| Overall Study | Death | 1 |
| Overall Study | Ineligible | 1 |
| Overall Study | Lack of Efficacy | 23 |
| Overall Study | Never started therapy | 1 |
| Overall Study | Other | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | AMG 706+Octreotide |
|---|---|
| Age, Continuous | 65 years |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 43 / 45 |
| serious Total, serious adverse events | 26 / 45 |
Outcome results
Primary
Four-month Progression-free Survival Rate
Four-month progression-free survival (PFS) rate is defined as number of patients who are still progression free at 4 months after study entry divided by number of eligible and treated patients enrolled to the study. Progression is evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), or unequivocal progression of existing non-target lesions.
Time frame: assessed every 4 weeks while on treatment and at three months post-treatment for participants treated for one cycle, up to month four
Population: The analysis population includes all 44 eligible and treated patients. But 2 patients did not have disease assessment after study entry and are excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG 706+Octreotide | Four-month Progression-free Survival Rate | 78.5 percentage of participants |
Comparison: The null hypothesis is that the 4-month progression free survival rate is 20%. Alternatively, AMG 706 will be considered worthy of further study if its true progression-free survival rate is 40% or better at 4 months (alternative hypothesis).p-value: <0.001one sample binomial test
Secondary
Objective Response Rate
Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by the total number of analyzable patients. CR is defined as complete disappearance of all tumor lesions, and partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.
Time frame: assessed every 8 weeks while on treatment, and frequency of tumor measurements during follow-up were determined by the treating physician, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG 706+Octreotide | Objective Response Rate | 13.6 percentage of participants |
Secondary
Overall Survival
Overall survival (OS) is defined as the time from registration until death (event), or censored at last date known alive. OS was estimated using the Kaplan-Meier method , with 95% confidence intervals calculated using Greenwood's formula
Time frame: assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years
Population: All eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMG 706+Octreotide | Overall Survival | 27.5 months |