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

NCT ID: NCT02598687

Last Updated: 2016-04-21

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2016-04-30

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.

Conditions

Esophageal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

treatment

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

Group Type: OTHER

TH-302

Intervention Type: DRUG

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

HX4 scan

Intervention Type: OTHER

HX 4 scan day 1 and day 8

Carboplatin

Intervention Type: DRUG

2mg/ml/min

Paclitaxel

Intervention Type: DRUG

50 mg/m2

Radiotherapy

Intervention Type: RADIATION

23 x 1.8 Gy

surgery

Intervention Type: PROCEDURE

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

Interventions

TH-302

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

Intervention Type: DRUG

HX4 scan

HX 4 scan day 1 and day 8

Intervention Type: OTHER

Carboplatin

2mg/ml/min

Intervention Type: DRUG

Paclitaxel

50 mg/m2

Intervention Type: DRUG

Radiotherapy

23 x 1.8 Gy

Intervention Type: RADIATION

surgery

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

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Threshold Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Zuyderland Medical Centre

OTHER

Sponsor Role: collaborator

Maastricht Radiation Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe Lambin, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

MUMC+, dept Radiotherapy

References

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.

Reference Type: DERIVED

PMID: 27535748 (View on PubMed)

Other Identifiers

14-27-03/09

Identifier Type: -

Identifier Source: org_study_id