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

Esophageal Cancer Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02598687
• Other study ID #: 14-27-03/09
• Status: Withdrawn
• Phase: Phase 1
• First received: May 29, 2015
• Last updated: April 20, 2016
• Start date: December 2015
• Est. completion date: April 2016

Study information

• Verified date: April 2016
• Source: Maastricht Radiation Oncology
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Esophageal Cancer
• Esophageal Neoplasms

Intervention

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
• 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

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Maastricht Radiation Oncology	Threshold Pharmaceuticals, Zuyderland Medical Centre

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicity (DLT )	To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)	within 30days postoperative	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Local recurrence rate	Presence of anti-tumor activity measured by local recurrence rate	within 30 days after surgery	No
Secondary	distance recurrence rate	Presence of anti-tumor activity measured by distance recurrence rate	within 30 days after surgery	No
Secondary	Progression free survival	Presence of anti-tumor activity measured by progression free survival	within 30 days after surgery	No
Secondary	overall survival	Presence of anti-tumor activity measured by overall survival	within 30 days after surgery	No
Secondary	metabolic response	Presence of anti-tumor activity measured by metabolic response one month after treatment	within 30 days after surgery	No