Carcinoid Tumor
Conditions
Keywords
progressive advanced carcinoid tumors, advanced, unresectable, metastatic, cancerous tumors, neuroendocrine, digestive tract, lungs, renal, ovarian, thymic, hepatic
Brief summary
The main purpose of this study is to see whether Axitinib will help prolong the time that the patient's carcinoid tumors remain stable, and to examine their treatment response through testing. Researchers also want to find out if Axitinib is safe and tolerable.
Detailed description
This is a bi-institutional, prospective phase II, open-label study. The target population is comprised of adult patients with histologically confirmed unresectable or metastatic carcinoid tumors. Carcinoid tumors are defined as well to moderately differentiated neuroendocrine tumors of the digestive tract and lungs. Patients with metastatic carcinoid tumors of unknown primary as well as rare primaries (renal, ovarian, thymic, hepatic) will also be eligible. Patients will be drawn from two institutions Moffitt Cancer Center (MCC) and The University of California, San Francisco (UCSF).
Interventions
DRUGAxitinib
Axitinib Administration as outlined in Arm description
Sponsors
National Comprehensive Cancer Network
Pfizer
H. Lee Moffitt Cancer Center and Research Institute
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
* Locally unresectable or metastatic well-and moderately-differentiated (low- or intermediate- grade) neuroendocrine tumors of the aerodigestive tract (e.g. foregut, midgut, and hindgut) and unknown primary site as well as rare primary sites (renal, ovarian, thymic, hepatic); Otherwise known as typical or atypical carcinoid tumors * Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria * Functional or nonfunctional tumors allowed * Evidence of progressive disease within 12 months of study entry * Adequate hepatic function: total bilirubin ≤1.5 x upper limit of normal (ULN)mg/dl; aspartic transaminase (AST) ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases) * Adequate renal function: serum creatinine ≤ 1.5 x ULN * Adequate bone marrow function: absolute neutrophil count ≥ 1,500/mm³; platelets ≥75,000/mm³ * Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x ULN (unless patients receiving coumadin anticoagulation in which case a stable international normalization ration (INR) of 2-3 is required). * Urine protein \<2+proteinuria (or \<2 g proteinuria /24 hr) * Prior somatostatin-analog therapy required in patients with midgut carcinoid tumors * Minimum 4 weeks since completion of prior treatment (investigational or other). Prior treatment with chemotherapy, radiotherapy, hepatic artery embolization, surgery or other therapeutic agents is allowed. * Treatment related toxicity should have returned to baseline and/or ≤grade 1 prior to study treatment. * Prior or concurrent therapy with somatostatin analogs is permitted for the control of hormone-mediated symptoms, provided patient has been on a stable dose for at least 2 months and progressive disease on somatostatin analogs (SSTa) has been documented * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to treatment. * Ability to sign informed consent * Willingness and ability to comply with scheduled visits, laboratory tests and other study procedures
Exclusion criteria
* Poorly differentiated, high-grade (e.g. small cell or large cell) neuroendocrine carcinomas are excluded. * Pancreatic neuroendocrine tumors (NETs), paragangliomas, pheochromocytomas and medullary thyroid cancers are excluded. * Adenocarcinoid tumors and goblet cell carcinoid tumors are excluded. * Prior antiangiogenic therapy with a dedicated vascular endothelial growth factor (VEGF) pathway inhibitor * Clinically apparent central nervous system metastases * Any of the following within 12 months prior to study: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack * Deep venous thrombosis or pulmonary embolism within 6 months of study * Major surgery 4 weeks prior to enrollment * Inability to take oral medication or prior surgical procedures affecting absorption (including total gastric resection) * Active gastrointestinal bleeding, if transfusion dependent * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days * History of pulmonary hemorrhage or evidence of significant hemoptysis * History of serious non-healing wound, ulcer, or bone fracture within the past 28 days * Pre-existing thyroid abnormality allowed provided thyroid function can be controlled with medication. * Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, etc.) * Current use or anticipated need for treatment with drugs that are known inducers of CYP3AR or CYP1A2 (i.e carbamazepine, dexamethasone, omeprazole, phenobarbital, phenytoin, rifampin, St. John's Wart, etc.) * Uncontrolled serious medical or psychiatric illness. Patients with a currently active second malignancy other than non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pathological tumor-2 (pT2) with Gleason Score ≤ 6 and postoperative prostatic specific antigen (PSA) \< 0.5 ng/mL), or other adequately treated carcinoma-in-situ are ineligible. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for ≥3 years. * Pregnant or lactating women, or adults of reproductive potential who are not using effective birth-control methods. * Prior antitumor therapy within 4 weeks of enrollment (with exception of somatostatin analogs) * Liver-directed therapy within 2 months of enrollment. Prior treatment with radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial embolization (with or without chemotherapy) or cryotherapy/ablation is allowed if these therapies did not affect the areas of measurable disease being used for this protocol or if progressive disease can be documented in the previously treated area. * Recent infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection) * Uncontrolled hypertension (blood-pressure \>140/90). Patient with baseline hypertension may be eligible after initiation of antihypertensive therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Progression Free Survival (PFS) | 12 Months | Progression-free survival rate at 12 months. PFS: determined as the time from administration of the initial dose of axitinib until objective tumor progression using Response Evaluation Criteria In Solid Tumors (RECIST), or death. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Stable Disease (SD): Neither sufficient shrinkage to qualify for Partial Response (PR) nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Median Progression Free Survival | Up to 36 Months | Post follow-up progression free survival at time of analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate | 12 Months | Tumor response rate using RECIST. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| 24 Month Overall Survival (OS) Rate | 24 months | Overall survival by Kaplan Meier, determined from the time of drug administration to death from any cause. The effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis. |
| Time to Treatment Failure | 12 Months | Time to Treatment Failure: Time from administration of the initial dose of axitinib until study discontinuation for any reason (e.g., disease progression, toxicity, death, withdrawal of consent). |
| Occurrence of Possibly Related Adverse Events (AEs) | 12 Months | Grade 2 through 4 toxicities considered at least possibly related to treatment. Percentage of participants affected per category. Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology and blood chemistry parameters and regular physical examinations. Adverse events will be evaluated continuously throughout the study. Safety and tolerability will be assessed according to the National Institute of Health/National Cancer Institute (NIH/NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) available at: http://ctep.cancer.gov/protocolDevelopment/electronic\_applications/ctc.htm. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida and the UCSF Comprehensive Cancer Center, University of California, San Francisco, California, from October 2011 through January 2014.
Participants by arm
| Arm | Count |
|---|---|
| Axitinib Administration The investigational drug used in this study is axitinib, and is available as tablets. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Early withdrawal due to toxicity | 8 |
Baseline characteristics
| Characteristic | Axitinib Administration |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 64 years |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 12 / 30 |
Outcome results
Primary
Median Progression Free Survival
Post follow-up progression free survival at time of analysis.
Time frame: Up to 36 Months
Population: All participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Axitinib Administration | Median Progression Free Survival | 26.7 months |
Primary
Rate of Progression Free Survival (PFS)
Progression-free survival rate at 12 months. PFS: determined as the time from administration of the initial dose of axitinib until objective tumor progression using Response Evaluation Criteria In Solid Tumors (RECIST), or death. Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Stable Disease (SD): Neither sufficient shrinkage to qualify for Partial Response (PR) nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: 12 Months
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Axitinib Administration | Rate of Progression Free Survival (PFS) | 74.5 percentage of participants |
Secondary
24 Month Overall Survival (OS) Rate
Overall survival by Kaplan Meier, determined from the time of drug administration to death from any cause. The effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis.
Time frame: 24 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Axitinib Administration | 24 Month Overall Survival (OS) Rate | 74.3 percentage of participants |
Secondary
Occurrence of Possibly Related Adverse Events (AEs)
Grade 2 through 4 toxicities considered at least possibly related to treatment. Percentage of participants affected per category. Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, the regular monitoring of hematology and blood chemistry parameters and regular physical examinations. Adverse events will be evaluated continuously throughout the study. Safety and tolerability will be assessed according to the National Institute of Health/National Cancer Institute (NIH/NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) available at: http://ctep.cancer.gov/protocolDevelopment/electronic\_applications/ctc.htm.
Time frame: 12 Months
Population: All participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Dehydration | 10 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Hypertension | 87 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Abdominal pain | 17 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Diarrhea | 17 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Nausea | 13 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Vomiting | 7 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Mucositis | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Oral pain | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Headache | 20 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Confusion | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Insomnia | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Syncope | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Anxiety | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Intracranial hemorrhage | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Fatigue | 27 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Weight loss | 6 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Anorexia | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Myalgia | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Hypothyroidism | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Increased transaminases | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Increased alkaline phosphatase | 10 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Increased gamma-glutamyl transferase | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Urinary tract infection | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Right ventricular dysfunction | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Pain in extremity | 3 percentage of participants |
| Axitinib Administration | Occurrence of Possibly Related Adverse Events (AEs) | Hand-foot syndrome | 2 percentage of participants |
Secondary
Time to Treatment Failure
Time to Treatment Failure: Time from administration of the initial dose of axitinib until study discontinuation for any reason (e.g., disease progression, toxicity, death, withdrawal of consent).
Time frame: 12 Months
Population: All participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Axitinib Administration | Time to Treatment Failure | 9.6 months |
Secondary
Tumor Response Rate
Tumor response rate using RECIST. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 12 Months
Population: All participants evaluable at time of analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Axitinib Administration | Tumor Response Rate | Partial response | 1 Participants |
| Axitinib Administration | Tumor Response Rate | Stable disease | 21 Participants |