A Study of ARQ 197 Versus Investigator's Choice of Second-Line Chemotherapy in Patients With Locally Advanced or Metastatic Gastric Cancer Who Have Progressive Neoplastic Disease Following Treatment With One Prior Chemotherapy Regimen

This will be a multi-center, open-label randomized phase 2 study designed to evaluate the PFS of ARQ 197 versus investigator's choice of second-line chemotherapy in patients with unresectable (locally advanced or metastatic) gastric carcinoma who have progressive neoplastic disease following treatment with a prior regimen consisting of at least two of the drugs 5-FU, cisplatin and docetaxel. Patients will be randomized to ARQ 197 arm or investigator's choice arm in a 1:1 ratio. The study will also evaluate other efficacy and safety parameters including ORR, OS and adverse events in the two treatment arms.

Patients assigned to the investigator's choice arm may receive any one of the following:

• Oxaliplatin 85 mg/m2 i.v. every two weeks (each cycle = 4 weeks)
• Capecitabine 1250 mg/m2 p.o. twice daily for 14 days followed by 7 days of no therapy every 3 weeks (each cycle = 3 weeks)
• Irinotecan 125 mg/m2 i.v. weekly for 4 weeks followed by 2 weeks of no therapy every 6 weeks (each cycle = 6 weeks) Treatment will continue unless one of the treatment discontinuation criteria is met. Dose reductions should occur based on the current labels for each of the investigator choice agents.

Patients randomly assigned to the ARQ arm will receive 120 mg of ARQ 197 twice daily (240 mg/day) throughout the treatment period. The treatment of ARQ 197 can be continued until unacceptable toxicity, documented progression of disease, or another discontinuation criterion is met. A cycle of ARQ 197 treatment will be defined as 21 days and cycles may be repeated every 3 weeks (21 days) based on toxicity and response.

The assigned treatment should continue until unacceptable toxicity, disease progression (clinical or radiological) or another discontinuation criterion is met.

Tumor evaluations: Tumor evaluations will be performed at 6-week or 8-week intervals. Tumor response will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).

Progression-free survival: The time of disease progression-free will be calculated from date of randomization until disease progression per RECIST or death due to any cause. Patients who are alive and progression free will be censored at the date of their last tumor evaluation.

Overall response rate: The ORR will be calculated for the intent to treat patient population as the number of patients with a confirmed complete response or partial response divided by the number of randomized patients.

Overall survival: Overall survival time will be calculated from the date of randomization until death due to any cause.

Safety assessments: Data on vital signs, physical examination, adverse events, serum chemistry, hematological laboratory tests, and electrocardiograms will be collected.

Based on the data for irinotecan, it is estimated that the median PFS in the second-line chemotherapy arm will be 4 months. In order to demonstrate an improvement in median PFS to 5.5 months (37.5% improvement, hazard ratio of 0.73) based on a two-sided log rang test, 338 patients (169 per arm) will be required, assuming an 18 month enrollment and a 12 month follow-up, an alpha of 0.05 and 90% power. The sample size assumes a 10% loss to follow-up rate.

A futility analysis will be performed when 33% of the events required for the final analysis have occurred by an Independent Data Monitoring Committee. The futility boundary will be described in the full statistical analysis plan for the study.