Official Title: “A Randomized, Placebo-controlled Phase II Trial Investigating SUNITINIB Versus Placebo in Patients With Chemorefractory Advanced Adenocarcinoma of the Stomach or Lower Esophagus Treated With Chemotherapy FOLFIRI”

This trial will be conducted to evaluate the efficacy, safety and tolerability of SUNITINIB as add-on therapy with a widely used second-line palliative FOLFIRI chemotherapy in patients with chemo-refractory advanced or metastatic adenocarcinoma of stomach or lower esophagus (mGC).

There is a clear scientific rationale for the use of Sunitinib to treat patients with mGC.

Despite recent therapeutic advances, the median overall survival (OS) in patients with mG is still ≤ 12 months. Therefore, newer agents with novel mechanisms of action are desperately needed for treatment of these patients.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2011

In parallel to the efforts in front-line therapy, second-line protocols like irinotecan-based regimens have been established in clinical trials for those patients. As many patients are still in good performance status and present with low tumor burden after failure of first-line chemotherapy, they clearly benefit from second-line treatment.

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.

The safety and efficacy of Sunitinib as single agent for the treatment of mGC has been determined and support the proposed clinical study with FOLFIRI in combination with Sunitinib in the treatment of patients with mGC.

Patients included in this trial suffer from advanced or metastatic adenocarcinoma of stomach or lower esophagus. They have failed to respond at least to one standard palliative first-line therapy (based on docetaxel and/or cisplatin plus 5-FU). Irinotecan/FA/5-FU can be determined as one established second-line treatment to be available for these patients.

Taken together, treatment of those patients with Sunitinib combined with standard chemotherapy FOLFIRI offers the chance to benefit from a new innovative therapy with acceptable side effects.

Intervention(s) in this Clinical Trial

• Drug: Sunitinib
  • Sunitinib will be orally administered at 25 mg once daily (in the morning without regards to meals) for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks.
• Drug: Placebo
  • Placebo will be orally administered once daily (in the morning without regards to meals) for 4 consecutive weeks followed by a 2-week rest period to comprise a complete cycle of 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Sunitinib
  • 25 mg (2 capsules of 12.5 mg) for oral administration
• Placebo Comparator: Placebo
  • 2 capsules for oral administration

Primary Measures

• The primary endpoint is the Progression-free survival (PFS) according to RECIST V1.1.
  • Time Frame: After first and second cycle, then after every second cycles or if clinically indicated until progress of disease
    Safety Issue?: No

Secondary Measures

• Objective response rate (CR + PR) according to RECIST
  • Time Frame: After first and second cycle, then after every second cycles (i.e. after fourth, sixth, eighth cycle etc.) or if clinically indicated until progress of disease
    Safety Issue?: No
• Safety and tolerability
  • Time Frame: one yaer
    Safety Issue?: Yes

Inclusion Criteria:

• Signed and dated informed consent before the start of specific protocol procedures
• Histological proven gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction or lower esophagus
• Failure of any prior palliative chemotherapy (docetaxel and/or platinum-based chemotherapy); but patient has not previously received FOLFIRI treatment
• Measurable metastatic disease according to the RECIST criteria patients aged 18 years and older
• Karnofski index 100 - 70 %
• Life expectancy > 12 weeks
• Adequate hematological, hepatic and renal functions
• At least 3 weeks from previous docetaxel- and/or platinum-based chemotherapy
• Recovery from side effects of any prior therapy (except oxaliplatin induced neuropathy)

Exclusion Criteria:

• History of another primary malignancy >3 years, with the exception of non-melanoma skin cancer and in situ carcinoma of the uterine cervix
• Any prior palliative radiotherapy
• Concurrent treatment with any other anti-cancer therapy
• Prior treatment with a VEGF, VEGFR or RTK inhibitor, or prior enrolment on this study
• Known allergic/hypersensitivity reaction to any of the components of the treatment
• Treatment with potent CYP3A4 inhibitor within 7 days of Sunitinib/placebo dosing or with potent CYP3A4 inducer within 12 days of Sunitinib/placebo dosing
• Other serious illness or medical conditions within the last 12 months prior to study drug administration: Unstable cardiac disease despite treatment; myocardial infarction within 12 months prior to study entry; congestive heart failure NYHA grade 3 and 4; Hypertension that cannot be controlled by medication ; ongoing cardiac dysrhythmias of NCI CTCAE grade >2, atrial fibrillation of any grade, or QTc interval
• >450 msec for males or >470 msec for females; History of significant neurologic or psychiatric disorders including dementia or seizures; Active uncontrolled infection;
• History of clinically significant bleeding within the past 6 months, including hemoptysis or haematuria, or underlying coagulopathy; Active disseminated intravascular coagulation; Deep vein thrombosis, or other significant thromboembolic event; Cerebrovascular accident including transient ischemic attack; Pulmonary embolus; Bowel obstruction or chronic diarrhoea, history or presence of inflammatory enteropathy or extensive intestinal resection; History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrolment, unless affected area has been removed surgically
• Known deficit in DPD
• Hypercalcemia not controlled by bisphosphonates
• Contraindications to the use of atropine
• Current treatment with therapeutic doses of anticoagulant medication (low dose warfarin or equivalent up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed)
• Pregnant or lactating women; female patients who are pregnant or lactating or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 3 months after discontinuing study treatment
• Known drug abuse/alcohol abuse
• Current, recent, or planned participation in an experimental treatment drug study other than this protocol
• Major surgical procedure, open biopsy or significant traumatic injury within 4 weeks before starting treatment; anticipation of need for major surgical procedure (e.g.
• impending bowel obstruction) during the course of the study
• History of other medical or psychiatric condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the patient at high risk from treatment complications

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Johannes Gutenberg University Mainz

Overall Clinical Trial Officials and Contacts

Markus Moehler, MD Principal Investigator Johannes Gutenberg University Mainz, 1. Med. Klinik  

Overall Contact: Markus Moehler, MD 0049-6131-1768 moehler@1-med.klinik.uni-mainz.de

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01020630

Study ID Number: 2009-02-SUN-Case

ClinicalTrials.gov Identifier: NCT01020630

Health Authority: Germany: Federal Institute for Drugs and Medical Devices