Barrett Esophagus, Gastric Adenocarcinoma
Conditions
Keywords
Adenocarcinoma of esophagogastric junction, Adenocarcinoma of lower esophagus (Barrett carcinoma)
Brief summary
This trial will be conducted to evaluate the efficacy, safety, and tolerability of sunitinib (sunitinib-malate) as a second-line palliative therapy in metastatic gastric cancer. Despite the efforts in front-line therapy, second-line protocols have not yet been established in randomized clinical trials for those patients. Although many patients are still in good performance status and present with low tumor burden after failure of first-line chemotherapy, they may clearly benefit from second-line treatment. Increasingly more metachronic metastatic patients are urging for new platinum-free therapeutic options due to the fast-growing use of (neo-) adjuvant platin-based protocols. So far, only sparse data on chemotherapy are available after failure of platin-based protocols. Nearly only irinotecan-containing combinations have properly been analyzed, and produced excellent response rates and survival times of up to 30% and 7.6 months, respectively. However, irinotecan has not been approved yet for this indication. In addition, as irinotecan-containing regimens have been submitted for approval for first-line therapy, second-line regimens in irinotecan-refractory patients have not been evaluated in any trial. Thus, there is an urgent need to establish new second-line treatment options for both, cisplatinum- or irinotecan-combination refractory patients with advanced or metastatic gastric cancer. Sunitinib inhibits the receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, specifically the VEGFR, PDGFR, KIT, FLT-3, and RET. The VEGF pathway has been shown to be a significant factor in metastatic gastric cancer. In gastric carcinoma cells, VEGF ligands and its receptors are definitely involved in the process of tumor progression. KDR and FLT-1 are expressed widely and VEGF stimulated KDR-positive tumor cell growth directly. The ligand VEGF-C has also been shown to be involved in progression of human gastric carcinoma, particularly via lymphangiogenesis. In addition, peritoneal metastases of some cancers such as gastric cancers were largely dependent on VEGF. Therefore, patients with chemo-refractory metastatic gastric cancer might benefit from VEGFR inhibitory therapy with sunitinib.
Interventions
DRUGSunitinib-Malate
Capsules of 50, 25 or 12,5 mg. Dosage 50 mg, 37.5 mg or 25 mg once daily until progression of disease or untolerable side effects
Sponsors
Pfizer
Johannes Gutenberg University Mainz
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent of the patient before the start of specific protocol procedures * Histologically proven adenocarcinoma of stomach, esophagogastric junction or lower esophagus (Barrett carcinoma) * Measurable metastatic disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). If locally recurrent disease, it must be associated with at least one measurable lymph node (\> 20 mm by computed tomography \[CT\] scan or \> 10 mm with spiral CT). * Failure of prior palliative chemotherapy/chemotherapies (at least one irinotecan- or cisplatin-based). Failure is defined either by progression of disease or by significant toxicity that precludes further treatment. * At least 3 weeks from previous chemotherapy at first dose of trial drug * Resolution of all acute toxic side effects of prior therapy or surgical procedures to grade ≤ 1 National Cancer Institute-Common Toxicity Criteria (NCI-CTC) (except for the laboratory values) * Adequate organ function as defined by the following criteria: * Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase \[SGOT\]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy * Total serum bilirubin ≤ 1.5 x ULN * Absolute neutrophil count (ANC) ≥1500/microL * Platelets ≥ 100,000/microL * Hemoglobin ≥ 8.0 g/dL without support of growth factors (previous administration of erythrocyte concentrate is allowed) * Serum calcium ≤ 12.0 mg/dL * Serum creatinine ≤ 2.0 x ULN * Lipase/amylase ≤ 2.5 x ULN * All other laboratory values specified in the protocol (white blood cell count, white blood cell differential, alkaline phosphatase, sodium, potassium, creatinine clearance): resolution of all side effects of prior therapy or surgical procedure to grade \< 3 NCI-CTC * At least 4 weeks from any major surgery (at first dose of trial drug) * Karnofsky Performance Status (KPS) ≥ 70 * Life expectancy \> 12 weeks * Patients must be able to swallow sunitinib capsules * Patients who understand the nature of the trial and are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures * Female patients who are capable of bearing children must have a negative pregnancy test result (serum or urine) at trial entry. All women included in the trial must be surgically sterile or postmenopausal or agree to employ adequate birth control measures for the duration of the trial and six months post-dosing. Male patients must be surgically sterile or must agree to use effective contraception during the trial and six months post-dosing.
Exclusion criteria
* Tumor type other than adenocarcinoma (e.g., leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion. * Patients with known brain or leptomeningeal metastasis * Intake of non-permitted concomitant drugs. (The coordinating investigator should be contacted to discuss the individual case.) * Concomitant treatment with antiarrhythmics and drugs with dysrhythmic potential (i.e., terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide) * Administration of potent CYP34A inhibitors during or within 7 days before start of sunitinib-treatment (e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir, grapefruit juice) * Administration of potent CYP3A4 inducers during or within 12 days before start of sunitinib-treatment (e.g. dexamethasone, rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John´s wort, efavirenz, tipranavir) * Ongoing treatment with therapeutic doses of anticoagulants such as Coumadin or heparins. (However, low dose Coumadin up to 2 mg by mouth \[PO\] daily for deep vein thrombosis prophylaxis is allowed.) * Any other medicinal anticancer therapy during treatment phase except treatment with non-conventional therapies (e.g. herbs or acupuncture) and vitamins/mineral supplements, provided that they do not interfere with the trial endpoint, in the opinion of the investigator * Concurrent systemic immune therapy, chemo- or hormone therapy * Concomitant or within a 4-week period administration (from first dose of trial drug) of any other experimental drug under investigation (except for irinotecan and cetuximab) and participation in another clinical trial * Any prior radiotherapy of target lesions * Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (\> hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis * Current history of chronic diarrhoea * Active disseminated intravascular coagulation, or patients prone to thromboembolism * Any of the following events (in any grade) prior to starting the trial treatment: * myocardial infarction * severe/unstable angina * coronary/peripheral artery bypass graft * congestive heart failure * cerebrovascular accident or transient ischemic attack * pulmonary embolism * Known history of QT interval prolongation, ongoing QT prolongation (\> 450 msec for males or \> 470 msec for females), any cardiac ventricular dysrhythmias, atrial fibrillation of any grade * Hypertension that cannot be controlled by medications (\> 150/100 mmHg despite optimal medical therapy) * Known human immunodeficiency virus (HIV) infection * Active uncontrolled infection * Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with trial participation or trial drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into the trial * Pregnant or lactating women * Known allergic/hypersensitivity reaction to any of the components of the treatment; or known drug abuse/alcohol abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | one year | The primary endpoint is the ORR within the first 6 treatment cycles, defined as the percentage of participants with a confirmed reduction in tumor size fulfilling the criteria for complete or partial response (CR or PR) according to RECIST. CR=disappearance of all target lesions, PR=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | one year | OS is defined as the time from the first dose of trial medication to date of death due to any cause. |
| One-Year Survival | one year | One-year survival is defined as the percentage of participants surviving for at least one year after first dose of trial medication. |
| Progression-Free Survival (PFS) | one year | PFS is defined as the time from first dose of trial medication to first documentation of objective tumor progression or to death due to any cause, whichever occurs first. |
| Safety and Tolerability: Serious Adverse Events | one year | The number of participants with at least one Serious Adverse Event was measured. |
| Safety and Tolerability: Adverse Events in ≥10% of Patients | one year | — |
| Adverse Events | one year | The number of participants with at least one adverse event was measured. |
Countries
Germany
Participant flow
Recruitment details
First patient in (FPI): 15.02.2007 Last patient out (LPO): 20.08.2009
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib open-label and uncontrolled treatment cycle 4+2: Sunitinib capsules for oral administration (50mg daily for 4 weeks and 2 weeks rest) | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 38 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Trial prematurely closed | 4 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Sunitinib |
|---|---|
| Age Continuous | 59 years FULL_RANGE 12.07 |
| Grading of adenocarcinoma 1 | 0 Participants |
| Grading of adenocarcinoma 2 | 19 Participants |
| Grading of adenocarcinoma 3 | 26 Participants |
| Grading of adenocarcinoma 4 | 2 Participants |
| Grading of adenocarcinoma Missing | 5 Participants |
| Karnofsky Performance Status (KPS) 10% | 0 Participants |
| Karnofsky Performance Status (KPS) 100% | 17 Participants |
| Karnofsky Performance Status (KPS) 20% | 0 Participants |
| Karnofsky Performance Status (KPS) 30% | 0 Participants |
| Karnofsky Performance Status (KPS) 40% | 0 Participants |
| Karnofsky Performance Status (KPS) 50% | 0 Participants |
| Karnofsky Performance Status (KPS) 60% | 0 Participants |
| Karnofsky Performance Status (KPS) 70% | 2 Participants |
| Karnofsky Performance Status (KPS) 80% | 18 Participants |
| Karnofsky Performance Status (KPS) 90% | 15 Participants |
| Karnofsky Performance Status (KPS) Missing | 0 Participants |
| Localisation of adenocarcinoma Gastroesophageal junction | 12 Participants |
| Localisation of adenocarcinoma Lower esophagus | 5 Participants |
| Localisation of adenocarcinoma Missing | 0 Participants |
| Localisation of adenocarcinoma Stomach | 36 Participants |
| Localisation of non-target lesions Bone | 1 Participants |
| Localisation of non-target lesions Liver | 15 Participants |
| Localisation of non-target lesions Lung | 4 Participants |
| Localisation of non-target lesions Lymph node mediastinum | 3 Participants |
| Localisation of non-target lesions Lymph node paraaortal caudal | 3 Participants |
| Localisation of non-target lesions Lymph node truncus coeliacus | 4 Participants |
| Localisation of non-target lesions Missing | 9 Participants |
| Localisation of non-target lesions No non-target lesions | 9 Participants |
| Localisation of non-target lesions Other | 9 Participants |
| Localisation of non-target lesions Peritoneum | 3 Participants |
| Localisation of non-target lesions Primary tumor | 1 Participants |
| Localisation of target lesions Liver | 28 Participants |
| Localisation of target lesions Lung | 8 Participants |
| Localisation of target lesions Lymph node mediastinum | 11 Participants |
| Localisation of target lesions Lymph node paraaortal caudal | 9 Participants |
| Localisation of target lesions Lymph node spleen/pancreas | 3 Participants |
| Localisation of target lesions Lymph node truncus coeliacus | 10 Participants |
| Localisation of target lesions Missing | 0 Participants |
| Localisation of target lesions Other | 14 Participants |
| Localisation of target lesions Peritoneum | 2 Participants |
| Localisation of target lesions Primary tumor | 3 Participants |
| Localisation of target lesions Soft tissue | 5 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 40 Participants |
| Total size of target lesions | 62 mm |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 52 |
| serious Total, serious adverse events | 0 / 52 |
Outcome results
Primary
Objective Response Rate (ORR)
The primary endpoint is the ORR within the first 6 treatment cycles, defined as the percentage of participants with a confirmed reduction in tumor size fulfilling the criteria for complete or partial response (CR or PR) according to RECIST. CR=disappearance of all target lesions, PR=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions
Time frame: one year
Population: Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | Objective Response Rate (ORR) | 3.92 Participants (%) |
Secondary
Adverse Events
The number of participants with at least one adverse event was measured.
Time frame: one year
Population: Safety population comprises all patients registered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | Adverse Events | 52 Participants |
Secondary
One-Year Survival
One-year survival is defined as the percentage of participants surviving for at least one year after first dose of trial medication.
Time frame: one year
Population: Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | One-Year Survival | 23.7 Participants (%) |
Secondary
Overall Survival (OS)
OS is defined as the time from the first dose of trial medication to date of death due to any cause.
Time frame: one year
Population: Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib | Overall Survival (OS) | 177 Days |
Secondary
Progression-Free Survival (PFS)
PFS is defined as the time from first dose of trial medication to first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
Time frame: one year
Population: Intention-to-treat (ITT) population comprises all patients registered, except one patient whose tumor diagnosis was not confirmed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib | Progression-Free Survival (PFS) | 39 Days |
Secondary
Safety and Tolerability: Adverse Events in ≥10% of Patients
Time frame: one year
Population: Safety population comprises all patients registered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Fatigue | 19 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Nausea | 16 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Mucosal inflammation | 9 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Anorexia | 9 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Vomiting | 8 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Diarrhoea | 8 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Dysgeusia | 6 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Headache | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Paraesthesia | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Cough | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Abdominal pain | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Palmar-plantar erythrodysaesthesia syndrome | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Blood bilirubin increased | 5 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Leukopenia | 11 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Thrombocytopenia | 11 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Neutropenia | 8 Participants |
| Sunitinib | Safety and Tolerability: Adverse Events in ≥10% of Patients | Anaemia | 7 Participants |
Secondary
Safety and Tolerability: Serious Adverse Events
The number of participants with at least one Serious Adverse Event was measured.
Time frame: one year
Population: Safety population comprises all patients registered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | Safety and Tolerability: Serious Adverse Events | 26 Participants |