Testing TH-302, in Combination With Preoperative Chemoradiotherapy, in Esophageal Cancer.
- Conditions
- Esophageal Cancer
- Interventions
- Other: HX4 scanRadiation: RadiotherapyProcedure: surgery
- Registration Number
- NCT02598687
- Lead Sponsor
- Maastricht Radiation Oncology
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
-
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
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Willing and able to comply with the study prescriptions
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No history of prior thoracic radiotherapy
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No severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
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Women should not be pregnant or lactating
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No known infection with HIV, hepatitis B or C or any other active infection
-
Normal ECG with careful evaluation of QT/QTc
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Have given written informed consent before patient registration
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description treatment TH-302 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 treatment HX4 scan 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 treatment Paclitaxel 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 treatment Radiotherapy 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 treatment surgery 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 treatment Carboplatin 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
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicity (DLT ) within 30days postoperative To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)
- Secondary Outcome Measures
Name Time Method overall survival within 30 days after surgery Presence of anti-tumor activity measured by overall survival
hypoxia response in tumor day 4 and day 8 Presence of hypoxia response based on hypoxia imaging (HX4) at baseline and first administration of TH-302 (before chemoradiotherapy).
rate of pathological Complete Remission (pCR) within 30 days after surgery Presence of anti-tumor activity measured by the rate of pathological Complete Remission (pCR)
histopathologic negative circumferential resection margin (CRM) rate within 30 days after surgery Presence of anti-tumor activity measured by histopathologic negative circumferential resection margin (CRM) rate.
Local recurrence rate within 30 days after surgery Presence of anti-tumor activity measured by local recurrence rate
distance recurrence rate within 30 days after surgery Presence of anti-tumor activity measured by distance recurrence rate
Progression free survival within 30 days after surgery Presence of anti-tumor activity measured by progression free survival
metabolic response within 30 days after surgery Presence of anti-tumor activity measured by metabolic response one month after treatment