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

A Phase I Trial Testing TH-302, a Tumor-selective Hypoxia-Activated Cytotoxic Prodrug, in Combination With Preoperative Chemoradiotherapy in Patients With Distal Esophageal and Esophago-gastric Junction Adenocarcinoma

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.

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