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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: TH-302
* Other: HX4 scan
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiotherapy
* Procedure: surgery


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: treatment<br>treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy | Drug: TH-302<br>* TH-302 day 4 (pre-treatment) and weekly during chemo-radiotherapy (CRT)<br>Other: HX4 scan<br>* HX 4 scan day 1 and day 8<br>Drug: Carboplatin<br>* 2mg/ml/min<br>Drug: Paclitaxel<br>* 50 mg/m2<br>Radiation: Radiotherapy<br>* 23 x 1.8 Gy<br>Procedure: surgery<br>* minimally invasive transhiatal approach including a one-field node dissection or transthoracic approach with a two-field lymph node dissection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT ) | To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) | within 30days postoperative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hypoxia response in tumor | Presence of hypoxia response based on hypoxia imaging (HX4) at baseline and first administration of TH-302 (before chemoradiotherapy). | day 4 and day 8 | 
| rate of pathological Complete Remission (pCR) | Presence of anti-tumor activity measured by the rate of pathological Complete Remission (pCR) | within 30 days after surgery | 
| histopathologic negative circumferential resection margin (CRM) rate | Presence of anti-tumor activity measured by histopathologic negative circumferential resection margin (CRM) rate. | within 30 days after surgery | 
| Local recurrence rate | Presence of anti-tumor activity measured by local recurrence rate | within 30 days after surgery | 
| distance recurrence rate | Presence of anti-tumor activity measured by distance recurrence rate | within 30 days after surgery | 
| Progression free survival | Presence of anti-tumor activity measured by progression free survival | within 30 days after surgery | 
| overall survival | Presence of anti-tumor activity measured by overall survival | within 30 days after surgery | 
| metabolic response | Presence of anti-tumor activity measured by metabolic response one month after treatment | within 30 days after surgery |