Clinical trial NCT02598687: Testing TH-302, in Combination With Preoperative Chemoradiotherapy, in Esophageal Cancer.
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Esophageal Cancer
Lead sponsor: Maastricht Radiation Oncology
Sponsor class: OTHER
Collaborators: name: Threshold Pharmaceuticals
name: Zuyderland Medical Centre
First posted: 2015-11-06
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Dose Limiting Toxicity (DLT )
timeFrame: within 30days postoperative
Secondary outcomes:
measure: hypoxia response in tumor
timeFrame: day 4 and day 8
measure: rate of pathological Complete Remission (pCR)
timeFrame: within 30 days after surgery
measure: histopathologic negative circumferential resection margin (CRM) rate
timeFrame: within 30 days after surgery
measure: Local recurrence rate
timeFrame: within 30 days after surgery
measure: distance recurrence rate
timeFrame: within 30 days after surgery
measure: Progression free survival
timeFrame: within 30 days after surgery
measure: overall survival
timeFrame: within 30 days after surgery
measure: metabolic response
timeFrame: within 30 days after surgery
Other outcomes:
Locations:
Study officials:
affiliation: MUMC+, dept Radiotherapy
name: Philippe Lambin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Larue RT, Van De Voorde L, Berbee M, van Elmpt WJ, Dubois LJ, Panth KM, Peeters SG, Claessens A, Schreurs WM, Nap M, Warmerdam FA, Erdkamp FL, Sosef MN, Lambin P. A phase 1 'window-of-opportunity' trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients. BMC Cancer. 2016 Aug 17;16:644. doi: 10.1186/s12885-016-2709-z.