Esophageal Cancer
Conditions
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.
Interventions
DRUGTH-302
TH-302 day 4 (pre-treatment) and weekly during chemo-radiotherapy (CRT)
OTHERHX4 scan
HX 4 scan day 1 and day 8
DRUGCarboplatin
2mg/ml/min
DRUGPaclitaxel
50 mg/m2
RADIATIONRadiotherapy
23 x 1.8 Gy
PROCEDUREsurgery
minimally invasive transhiatal approach including a one-field node dissection or transthoracic approach with a two-field lymph node dissection
Sponsors
Threshold Pharmaceuticals
Zuyderland Medical Centre
Maastricht Radiation Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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). |
| Progression free survival | within 30 days after surgery | Presence of anti-tumor activity measured by progression free survival |
| overall survival | within 30 days after surgery | Presence of anti-tumor activity measured by overall survival |
| metabolic response | within 30 days after surgery | Presence of anti-tumor activity measured by metabolic response one month after treatment |
| distance recurrence rate | within 30 days after surgery | Presence of anti-tumor activity measured by distance recurrence rate |
Outcome results
None listed