Efficacy and Safety of Sunitinib in Metastatic Gastric Cancer

An Open-label, Multicenter Phase II Trial of Sunitinib for Patients With Chemo-refractory Metastatic Gastric Cancer

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.

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