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

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.

Eligibility Criteria:
Inclusion Criteria:

* Histologically proven adenocarcinoma of the esophagus
* Age \>18 years
* UICC T2-4 N0-2 M0, potentially resectable disease
* Patient discussed at tumour board (multidisciplinary team meeting)
* No evident tumor invasion in nearby regions like aorta or trachea
* WHO performance status 0-2
* Less than 10 % weight loss in the past 6 months
* Laboratory requirements within 7 days prior to enrollment (start chemoradiotherapy):
* Haematology:

  * haemoglobin \>10g/dl
  * absolute neutrophils ≥ 1.5 x 109/L
  * platelets ≥ 100x109/L
* Biochemistry:

  * bilirubin within institutional normal limits
  * AST(SGOT)/ALT (SGPT) ≤ 2.5 institutional upper limit
  * Creatinine clearance ≥ 60 ml/min
* Willing and able to comply with the study prescriptions
* No history of prior thoracic radiotherapy
* No severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
* Women should not be pregnant or lactating
* No known infection with HIV, hepatitis B or C or any other active infection
* Normal ECG with careful evaluation of QT/QTc
* Have given written informed consent before patient registration

Exclusion Criteria:

* Recent (\< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
* Patients with difficult peripheral intravenous access
* History of prior thoracic radiotherapy
* severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
* Women who are pregnant or lactating
* Known infection with HIV, hepatitis B or C or any other active infection