Testing TH-302, in Combination With Preoperative Chemoradiotherapy, in Esophageal Cancer.

Overview

Open-label, single-center phase 1 study of an investigational agent TH-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels.

Rationale: Neoadjuvant chemoradiotherapy followed by surgery remains the standard of care for esophageal cancer patients. Both limited local response as well as distant metastases are a common cause of treatment failure. Combining TH-302 with chemo-radiotherapy may improve outcome by: * Direct cytotoxic effect of TH-302 on hypoxic cells of the primary tumor without enhancing normal tissue toxicity. * Increase the sensitivity of the primary tumor to chemo-radiotherapy by decreasing the hypoxic fraction. * A bystander cytotoxic effect of TH-302 on normoxic cells adjacent to hypoxic cells of the primary tumor. * A potential cytotoxic effect on micro-metastasis. Objective: Primary objective • To determine Maximum Tolerated Dose (MTD) of TH-302 combined with chemoradiotherapy (23 x 1.8 Gy in combination with Carboplatin and Paclitaxel) in patients with distal esophageal or esophago-gastric junction adenocarcinoma, and consequently find the recommended phase II dose (RP2D). Secondary objective * To explore the prognostic and predictive value on outcome of the repeated hypoxia PET/CT-scan at baseline and after administration of TH-302 (before start of RCT). * To determine presence of anti-tumor activity with TH-302 administration. * To explore the relationship between tumor hypoxia detected by the HX4 PET/CT-scans and serum biomarker expression: CAIX and Osteopontin expression. Study design: Open-label, single-center phase 1 study of an investigational agent TH-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels. Number of patients: 9 to18. For each of the 3 dose steps, 3 to 6 patients will be included.

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