Trial | NCT02598687  Report issue

Title

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

  • Phase

    Phase 1

  • Study Type

    Interventional

  • Status

    Withdrawn

  • Study Participants

    0
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.
Study Started
Dec 31
2015
Primary Completion
Apr 30
2016
Study Completion
Apr 30
2016
Last Update
Apr 21
2016
Estimate

Drug TH-302

TH-302 day 4 (pre-treatment) and weekly during chemo-radiotherapy (CRT)

Other HX4 scan

HX 4 scan day 1 and day 8

Drug Carboplatin

2mg/ml/min

Drug Paclitaxel

50 mg/m2

Radiation Radiotherapy

23 x 1.8 Gy

Procedure surgery

minimally invasive transhiatal approach including a one-field node dissection or transthoracic approach with a two-field lymph node dissection

treatment Other

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

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
No Results Posted