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

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.

Study Overview

• Status: Withdrawn
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: TH-302; Other: HX4 scan; Drug: Carboplatin; Drug: Paclitaxel; Radiation: Radiotherapy; Procedure: surgery

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.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT )	To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)	within 30days postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Local recurrence rate	Presence of anti-tumor activity measured by local recurrence rate	within 30 days after surgery
distance recurrence rate	Presence of anti-tumor activity measured by distance recurrence rate	within 30 days after surgery
Progression free survival	Presence of anti-tumor activity measured by progression free survival	within 30 days after surgery
overall survival	Presence of anti-tumor activity measured by overall survival	within 30 days after surgery
metabolic response	Presence of anti-tumor activity measured by metabolic response one month after treatment	within 30 days after surgery

Collaborators and Investigators

• Sponsor: Maastricht Radiation Oncology
• Collaborators: Threshold Pharmaceuticals; Zuyderland Medical Centre
• Investigators: Principal Investigator: Philippe Lambin, MD, PhD, MUMC+, dept Radiotherapy

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: May 29, 2015
• First Submitted That Met QC Criteria: November 5, 2015
• First Posted (Estimate): November 6, 2015

Study Record Updates

• Last Update Posted (Estimate): April 21, 2016
• Last Update Submitted That Met QC Criteria: April 20, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: 14-27-03/09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED