Gastrinoma, Glucagonoma, Insulinoma, Metastatic Gastrointestinal Carcinoid Tumor, Neuroendocrine Tumor, Pancreatic Polypeptide Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma, WDHA Syndrome
Conditions
Brief summary
This phase II trial is studying how well sorafenib tosylate works in treating patients with progressive metastatic neuroendocrine tumors. Sorafenib tosylate 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.
Detailed description
PRIMARY OBJECTIVES: I. To determine the objective tumor response rate of BAY 43-9006 (sorafenib tosylate) in patients with advanced neuroendocrine tumors. SECONDARY OBJECTIVES: I. Adverse event rate(s). II. Progression free survival and time to progression. III. Improvement in circulating hormone levels. IV. Overall survival. OUTLINE: This is a multicenter study. Patients are grouped into 2 separate analysis Groups according to tumor type (Group A: Carcinoid; Group B: Islet cell/other well-differentiated tumor). Each Group was independently evaluated for all study endpoints. Patients receive oral sorafenib tosylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 2 years from study entry.
Interventions
DRUGsorafenib tosylate
400 mg given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Criteria: * Histologically confirmed neuroendocrine tumor: * Carcinoid tumor OR islet cell carcinoma/other well-differentiated tumor * No anaplastic or high-grade histology * Metastatic disease * Measurable disease * No thyroid carcinoma of any histology, thymoma, or pheochromocytoma/paraganglioma * No known brain metastases * Performance status: * Eastern Cooperative Oncology Group (ECOG) 0-2 * Life expectancy: * At least 24 weeks * Hematopoietic: * Absolute neutrophil count \>= 1,500/mm3 * Platelet count \>= 100,000/mm3 * No bleeding diathesis * Hepatic: * Bilirubin =\< 2 times upper limit of normal (ULN) * Aspartate aminotransferase (AST) =\< 3 times ULN (5 times ULN if liver metastases are present) * International normalized ratio (INR) normal * PTT normal * Renal: * Creatinine =\< 1.5 times ULN * Cardiovascular: No poorly controlled hypertension; No symptoms of congestive heart failure; No unstable angina pectoris; No cardiac arrhythmia * Gastrointestinal: * Able to swallow capsules intact * No gastrointestinal tract disease resulting in an inability to take oral medication (e.g., dysphagia) * No requirement for IV alimentation * No active peptic ulcer disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No ongoing or active infection * No psychiatric illness or social situation that would preclude study compliance * No other invasive malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * No other uncontrolled illness * At least 4 weeks since prior interferon * No more than 1 prior systemic chemotherapy regimen: Chemoembolization is not considered systemic chemotherapy * At least 4 weeks since prior chemoembolization * At least 3 weeks since prior radiotherapy * No prior procedures adversely affecting intestinal absorption * At least 4 weeks since prior hepatic artery embolization * No other prior systemic therapy * No other concurrent investigational treatment * No concurrent combination antiretroviral therapy for HIV-positive patients * No concurrent enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin) * No concurrent rifampin * No concurrent Hypericum perforatum (St. John's wort) * Prior or concurrent octreotide for symptomatic treatment allowed * No concurrent therapeutic anticoagulation: Concurrent prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices allowed provided requirements for INR or PTT are met * At least 4 weeks since prior major surgery * Recovered from all prior therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response Rate | Duration of Treatment (Up to 2 years) | Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients.\> \> Complete Response (CR) is defined as the disappearance of all target lesions.\> Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions;\> \> We report the percentage of patients with a confirmed response and a 95% confidence interval estimated by the Duffy and Santner method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity | Up to 2 years | For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The number of participants reporting a grade 3 or higher toxicity are reported. |
| Overall Survival | From registration to death (up to 2 years) | Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. |
| Progression Free Survival | Time from registration to progression or death (up to 2 years) | Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) as a 20% increase in the su of longest diameter of target lesions. Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Participants who were progression free were censored at the date of their most recent disease assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method. |
| Duration of Response | Time from response to progression (up to 2 years) | Duration of response (DOR) was defined as the time from attaining a response (PR or CR) to the date of progression. Participants without progression were censored at the date of their most recent disease assessment. The median DOR was estimated using simple summary statistics. |
Countries
United States
Participant flow
Recruitment details
Between June 21, 2005 and September 15, 2006, a total of 93 (51 carcinoid, 42 islet cell) patients initiated treatment on this study.
Pre-assignment details
One carcinoid patient canceled prior to treatment and was excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Patients With Carcinoid Tumors) Patients receive 400 mg oral sorafenib twice daily on days 1-28. | 51 |
| Group B (Islet Cell and Other Neuroendocrine Tumors) Patients receive 400 mg oral sorafenib twice daily on days 1-28. | 42 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Group A (Patients With Carcinoid Tumors) | Group B (Islet Cell and Other Neuroendocrine Tumors) | Total |
|---|---|---|---|
| Age, Continuous | 60 years | 56.5 years | 59 years |
| Region of Enrollment United States | 51 participants | 42 participants | 93 participants |
| Sex: Female, Male Female | 28 Participants | 21 Participants | 49 Participants |
| Sex: Female, Male Male | 23 Participants | 21 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 90 / 93 |
| serious Total, serious adverse events | 52 / 93 |
Outcome results
Primary
Confirmed Response Rate
Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients.\> \> Complete Response (CR) is defined as the disappearance of all target lesions.\> Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions;\> \> We report the percentage of patients with a confirmed response and a 95% confidence interval estimated by the Duffy and Santner method.
Time frame: Duration of Treatment (Up to 2 years)
Population: Nine of the 50 carcinoid patients and 6 of the 42 Islet cell patients did not continue treatment past cycle 1. Therefore, these patients were not evaluated on consecutive cycles and were excluded from this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Patients With Carcinoid Tumors) | Confirmed Response Rate | 10 percentage of participants |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Confirmed Response Rate | 14 percentage of participants |
Secondary
Duration of Response
Duration of response (DOR) was defined as the time from attaining a response (PR or CR) to the date of progression. Participants without progression were censored at the date of their most recent disease assessment. The median DOR was estimated using simple summary statistics.
Time frame: Time from response to progression (up to 2 years)
Population: There were 4 confirmed responses in Group A and 5 confirmed responses in Group B used in analyzing this endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Patients With Carcinoid Tumors) | Duration of Response | 6.7 months |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Duration of Response | 9.2 months |
Secondary
Overall Survival
Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.
Time frame: From registration to death (up to 2 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Patients With Carcinoid Tumors) | Overall Survival | 25.6 months |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Overall Survival | NA months |
Secondary
Progression Free Survival
Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) as a 20% increase in the su of longest diameter of target lesions. Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Participants who were progression free were censored at the date of their most recent disease assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method.
Time frame: Time from registration to progression or death (up to 2 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Patients With Carcinoid Tumors) | Progression Free Survival | 9.1 months |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Progression Free Survival | 12.7 months |
Secondary
Toxicity
For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The number of participants reporting a grade 3 or higher toxicity are reported.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Patients With Carcinoid Tumors) | Toxicity | Grade 3 Toxicity | 37 participants |
| Group A (Patients With Carcinoid Tumors) | Toxicity | Grade 4 or Grade 5 Toxicity | 5 participants |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Toxicity | Grade 3 Toxicity | 25 participants |
| Group B (Islet Cell and Other Neuroendocrine Tumors) | Toxicity | Grade 4 or Grade 5 Toxicity | 2 participants |