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KX-ORAX-005 Oraxol in combination with Ramucirumab for Gastric, Gastro-esophageal or Esophageal Cancer

Background

Gastric cancer is the fourth most common cause cancer-related death in the world, and it remains difficult to cure, primary because patients present with advanced disease. Early gastric cancer has no associated symptoms, however some patients with incidental complaints are diagnosed with early gastric cancer. Most symptoms reflect advanced disease. The most common cause of gastric cancer is infection by the bacterium helicobacter pylori, which accounts for more than 60% if case. Most of time, gastric cancer develops in stage over year. Diagnosis is usually by biopsy done during endoscopy.

Esophageal cancer is a highly aggressive malignancy and was the eighth most common cancer. Esophageal cancer is arising from the esophagus. Symptom often include difficulty in swallowing and weight loss. The prevalence rate vary widely among countries with about half of all case occurring in China. It is three times more common in men than woman.

Unmet Medical Needs

Currently, several therapies are used for gastric cancer and esophageal cancer, including some combination of surgery, radiation therapy, target drug, and chemotherapy. If treated late, outcomes are often poor with a less than 10% five years survival rate for gastric cancer and 20~25 % for esophageal cancer. Paclitaxel is a useful drug against a wide range of solid cancer. Mechanism of action is through tubulin-binding, causing stabilization of the microtubule assembly, ultimately leading to mitotic arrest and apoptosis. The most common dosage is intravenous (IV) paclitaxel with 80mg/m2 weekly. IV paclitaxel could reduce cancer-related symptom and prolong survival. Weekly infusions of paclitaxel have gained wide popularity because of the favorable toxicity profile allowing dose intensification. However, IV administration of paclitaxel is inconvenient to patients and associated with significant and unpredictable side effects. Hospitalization, medical and nursing assistance and infusion equipment are required for IV administration of paclitaxel. Implement of artificial blood vessel are also uncomfortable.

Oral administration of paclitaxel is convenient and practical for patients, oral administration enables the development of chronic treatment schedules, resulting in sustained plasma concentrations above a pharmacologically. Effective blood concentrations of paclitaxel and duration can predict clinical outcomes. Unfortunately, paclitaxel has very low level of oral bioavailability, at less than 10%. This poor bioavailability level results from limited aqueous solubility and dissolution affinity for the intestinal and liver cytochrome P450 metabolic enzymes and the multidrug efflux pump p-glycoprotein, which is present abundantly in the gastrointestinal tract.

Incentive of The Tria

Oraxol is an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel p-glycoprotein inhibitor, to enhance the oral absorption of paclitaxel in cancer patients. In this study, the maximum tolerated dose and pharmacokinetics of Oraxol in combination with ramucirumab will be evaluated in adult patients with histologically or cytologically confirmed diagnosis of advanced stage gastric, gastro-esophageal, or esophageal adenocarcinoma with disease progression on or after prior fluoropyrimidine or platinum containing chemotherapy, in who, ramucirumab and paclitaxel are reasonable treatment.