Gastrinoma, Glucagonoma, Insulinoma, Metastatic Gastrointestinal Carcinoid Tumor, Pancreatic Polypeptide Tumor, Pulmonary Carcinoid Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma
Conditions
Brief summary
This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that have spread from the primary site (place where it started) to other places in the body. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To assess progression-free survival (PFS) in advanced/metastatic in patients with carcinoid or pancreatic islet cell tumors. SECONDARY OBJECTIVES: I. To assess overall survival and response rate in advanced/metastatic poor prognosis in patients with carcinoid or pancreatic islet cell tumors. II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors. OUTLINE: Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.
Interventions
DRUGregorafenib
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Southern California
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
* Advanced metastatic, progressing carcinoid or pancreatic islet cell cancers * No prior targeted treatment (tx) or anti-angiogenic therapy; patients may have received one line of prior therapy with octreotide, locoregional therapy; continuation of concurrent octreotide is allowed; patients will be maintained on octreotide (sandostatin) for the duration of their treatment * Life expectancy of at least 12 weeks (3 months) * Subjects must be able to understand and be willing to sign the written informed consent form (ICF); a signed ICF must be appropriately obtained prior to the conduct of any trial-specific procedure * All acute toxic effects of any prior treatment have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)4.0 grade 1 or less at the time of signing the informed consent form (ICF); exceptions to this include alopecia * Total bilirubin =\< 1.5 x the upper limits of normal (ULN) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer) * Alkaline phosphastase limit =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer) * Lipase =\< 1.5 x the ULN * Amylase =\< 1.5 x the ULN * Serum creatinine =\< 1.5 x the ULN * International normalized ratio (INR)/ partial thromboplastin time (PTT) \< 1.5 x ULN; (subjects who are treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring \[day 5 of cycle 1 and day 1 of each cycle\] is mandatory) will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care) * Platelet count \>= 100,000 /mm\^3 * Hemoglobin (Hb) \>= 9 g/dL * Absolute neutrophil count (ANC) \>= 1,500/mm\^3; blood transfusion to meet the inclusion criteria will not be allowed * Glomerular filtration rate (GFR) \>= 30 ml/min/1.73 m\^2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test; the definition of adequate contraception will be based on the judgement of the investigator * Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate * Subject must be able to swallow and retain oral medication * Southwest Oncology Group (SWOG) performance status 0-1 * Patients must have measurable disease
Exclusion criteria
* Previous assignment to treatment during this study; subjects permanently withdrawn from study participation will not be allowed to re-enter study * Uncontrolled hypertension (systolic pressure \> 140 mm Hg or diastolic pressure \> 90 mm Hg \[NCI-CTCAE v4.0\] on repeated measurement) despite optimal medical management * Active or clinically significant cardiac disease including: * Congestive heart failure - New York Heart Association (NYHA) \> class II * Active coronary artery disease * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization * Evidence or history of bleeding diathesis or coagulopathy * Any hemorrhage or bleeding event \>= NCI-CTCAE grade 3 within 4 weeks prior to start of study medication * Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment * Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from carcinoid or pancreatic islet cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed; all cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form) * Patients with pheochromocytoma * Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy * Ongoing infection \> grade 2 NCI-CTCAE v4.0 * Presence of a non-healing wound, non-healing ulcer, or bone fracture * Renal failure requiring hemo-or peritoneal dialysis * Dehydration grade \>= 1 NCI-CTCAE v4.0 * Patients with seizure disorder requiring medication * Persistent proteinuria \>= grade 3 NCI-CTCAE v4.0 (\> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample) * Interstitial lung disease with ongoing signs and symptoms at the time of informed consent * Pleural effusion or ascites that causes respiratory compromise (\>= NCI-CTCAE version 4.0 grade 2 dyspnea) * History of organ allograft (including corneal transplant) * Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial * Any malabsorption condition * Women who are pregnant or breast-feeding * Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation * Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results * Patients with known brain metastases should be excluded from this clinical trial * History of allergic reactions attributed to compounds of similar chemical or biologic composition to regorafenib or other agents used in study * Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Excluded therapies and medications, previous and concomitant * Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib) * Prior use of regorafenib * Concurrent use of chemotherapy, radiotherapy or another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry (signing of the ICF) * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication * Use of any herbal remedy (e.g. St. John's wort \[Hypericum perforatum\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS | Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months | Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee | Up to 4 years | Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given. |
| Overall Survival | From start of treatment until death due to any cause, assessed up to 4 years | The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves. |
| Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Up to 4 years | Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis | Up to 4 years | The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons. |
Countries
United States
Participant flow
Recruitment details
The study began recruiting in August 2016 and ended in January 2019. All subjects were seen and treated either at USC Norris Comprehensive Cancer Center or at LAC+USC Medical Center.
Pre-assignment details
There were no pre-assignment criteria. All subjects were given the same treatment.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Regorafenib) Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
regorafenib: Given PO
laboratory biomarker analysis: Correlative studies | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Treatment (Regorafenib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 3 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 |
Outcome results
Primary
PFS
Two parallel Simon's 2-stage phase II trials will be conducted to evaluate the efficacy of regorafenib in patients with advanced carcinoid (cohort A) or pancreatic islet cell tumors (cohort B). Will be summarized as a proportion of patients who are alive and progression-free among all patients in the primary data analysis set. The 95% confidence intervals (CIs) will be calculated using the Wilson method. Will be analyzed using Kaplan-Meier (KM) curves. The median PFS and 95% CIs will be calculated. The probability of 6-month PFS will be estimated from the KM curve too.
Time frame: Time from start of treatment to time of progression or death on study whichever comes first, assessed at 6 months
Population: No analysis done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.
Secondary
Incidence of Adverse Events, Assessed According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Toxicity profile will be summarized by attribution: regorafenib-related and all reported, course: course 1 and all courses, type, and grade: grade 1-2, 3-4, and 5.
Time frame: Up to 4 years
Population: Data not collected
Secondary
Overall Survival
The 95% CIs will be calculated using the Wilson method. Will be analyzed using KM curves.
Time frame: From start of treatment until death due to any cause, assessed up to 4 years
Population: Due to insufficient accrual (only 3 accrued), no analysis was performed.
Secondary
Tumor Response Rate, Evaluated Using the New International Criteria Proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee
Will be calculated as a proportion of patients who have either a complete or partial response among all patients in the primary data analysis set. The 95% CIs will be given.
Time frame: Up to 4 years
Population: No analysis was done. Only 3 subjects were enrolled out of accrual goal of 24 subjects.
Other Pre-specified
Biomarkers Such as Messenger Ribonucleic Acid (mRNA) Levels or Germline Variations of Genes Related to Angiogenesis
The associations between biomarkers and clinical outcomes (6-month PFS, response, PFS, and overall survival) will be analyzed in univariate analysis first using appropriate methods. Multivariable analyses will be conducted to evaluate the independent effect of a marker on clinical outcome. All tests will be two-sided at a significance level of 0.05. P values will be adjusted for multiple comparisons.
Time frame: Up to 4 years
Population: Analysis not done. Only 3 subjects were enrolled out of the accrual goal of subjects.