Sorafenib Trial in Advanced and/or Recurrent Gastric Adenocarcinoma: Treatment Evaluation: STARGATE

A Randomized Phase II Study of Capecitabine and Cisplatin (XP) +/- Sorafenib (Nexavar®) in Patients With Advanced Gastric Cancer

This study investigates the efficacy and safety profiles of sorafenib in combination of capecitabine and cisplatin, one of standard chemotherapy regimens in patients with advanced gastric cancer.

Inclusion Criteria:

1. Age 18-75

2. Histological or cytological documentation of gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.;

3. Metastatic gastric adenocarcinoma or metastatic gastroesophageal junction adenocarcinoma, initially diagnosed or recurrent.

4. Measurable disease according to Response Evaluation Criteria in Solid Tumors

5. ECOG Performance Status of 0 or 1

6. Life expectancy of at least 3 months

7. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:

   • Hemoglobin ≥ 9.0 g / dl
   • Absolute neutrophil count (ANC) ≥1,500 / mm3
   • Platelet count ≥ 100,000 / mm3
   • Total bilirubin < 1.5 x upper limit of normal
   • ALT and AST < 2.5 x upper limit of normal (< 5 x ULN for patients with liver involvement of their cancer)
   • International normalized ratio of PT (PT-INR) / PTT < 1.5 x ULN

8. Creatinine Clearance ≥ 60 ml / min (based on Cockcroft and Gault formula)

9. Ability to understand and willingness to sign a written informed consent. Signed informed consent must be obtained prior to any study specific procedures

Exclusion Criteria:

1. Patients with local-regional gastric or gastroesophageal adenocarcinoma (no para-aortic nodes or visceral structure-invading primary [T4]) who can potentially become candidates for surgery with curative intent following systemic therapy

2. History of cardiac disease:

   • Congestive heart failure >NYHA class 2; unstable angina (angina symptoms present at rest), new-onset angina (began within last three months prior to randomization) or myocardial infarction within six months prior to randomization;
   • Ventricular arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted);
   • Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg) despite optimal medical management

3. Past or concurrent history of neoplasm < 5 years prior to start of study treatment other than gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix uteri or superficial bladder tumors [Ta noninvasive tumor (Ta), carcinoma in situ (Tis) and T1 (tumor invades lamina propria)]

4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization

5. Evidence of gastrointestinal perforation or bowel obstruction during the screening period

6. Evidence or history of bleeding diathesis or coagulopathy

7. Non-healing wound, ulcer, or bone fracture

8. History of gastrointestinal bleeding > grade 1 CTCAE version 4.0 within 4 weeks prior to randomization

9. History of any other bleeding > grade 2 according to CTCAE version 4.0 within 4 weeks prior to randomization

10. Known psychiatric and neurological disorders including known peripheral or autonomous neuropathy or hearing impairment > grade 1 according to CTCAE version 4.0

    • However, if the patient already has known irreversible grade 4 hearing loss (>90 decibels (dB) bilaterally) at baseline, he or she is eligible at the investigator's discretion

11. Pregnant or lactating women, women of childbearing potential not employing adequate contraception [Women of childbearing potential must have a negative serum pregnancy test performed within seven days prior to the start of treatment. Of note, both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and four weeks after the completion of trial or 6 months after last dose of cisplatin (whichever is greater). The definition of effective contraception will be based on the clinical judgment of the principal investigator or a designated associate.]

12. Evidence of infection (> grade 2 )

13. History of HIV infection or chronic / active hepatitis B or C

14. Evidence of brain metastasis. Patients with unexplained neurological symptoms will undergo a CT scan or MRI of the brain to exclude metastases.

15. Seizure disorder requiring treatment with medications that affect CYP 3A4

16. History of organ allograft

17. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes or excipients in the formulation given during the course of this trial

18. Any condition that is unstable or could jeopardize the safety of the patient and his / her compliance in the study

19. Inability to swallow or retain oral medications

20. Any malabsorption condition that the investigator deems would jeopardize the absorption or pharmacokinetics of the study medication

21. Uncorrected dehydration

22. Known dihydropyrimidine dehydrogenase deficiency

23. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

24. Evidence of thrombotic or embolic disease, including cerebrovascular accident, transient ischemic attacks, or pulmonary embolus within the past 6 months

25. Any tumor with characteristics that the investigator deems unsuitable for potentially cytoreductive therapy due to likelihood of severe bleeding or perforation such as ulcerations or hemorrhage. Excluded therapies and medications

26. Prior or concomitant systemic anticancer therapy including cytotoxic therapy, targeted agents, or experimental therapy for gastric cancer. However, (neo)-adjuvant cytotoxic therapy is permitted if the last dose was administered > 6 months (12 months for platinum based therapy) before start of study medication in this study.

27. Radiotherapy prior to or during the study (palliative radiotherapy will be allowed as described in the 'prior and concomitant therapy section',4.3.7)

28. Use of biologic response modifiers, such as granulocyte G-CSF, within 3 weeks of study entry and during the study.

29. Investigational drug therapy outside of this trial during or within 4 weeks prior to randomization

30. Previous exposure to a Ras pathway inhibitor such MEK or Raf inhibitors or any farnesyl transferase inhibitors

31. Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids

    • Low dose warfarin (1 mg p.o. q.d.) is permitted if the international normalized ratio is < 1.5
    • Low-dose aspirin is permitted (≤ 100 mg daily)
    • Prophylactic doses of heparin are permitted
    • For patients on warfarin, the INR will be measured prior to initiation of sorafenib, and patients will be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes as infrequent bleeding or elevations in the INR have been reported in some patients taking warfarin while on sorafenib therapy.