Efficacy and Safety of Sunitinib in Metastatic Gastric Cancer
Condition: Gastric Adenocarcinoma; Barrett Esophagus
MeSH terms: Adenocarcinoma; Barrett Esophagus
Intervention: Sunitinib-Malate
Intervention description: 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
Intervention MeSH terms: Sunitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Adenocarcinoma of esophagogastric junction; Adenocarcinoma of lower esophagus (Barrett carcinoma)

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.
    

Eligibility criteria:

        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