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

Ruben T H M Larue, Lien Van De Voorde, Maaike Berbée, Wouter J C van Elmpt, Ludwig J Dubois, Kranthi M Panth, Sarah G J A Peeters, Ann Claessens, Wendy M J Schreurs, Marius Nap, Fabiënne A R M Warmerdam, Frans L G Erdkamp, Meindert N Sosef, Philippe Lambin, Ruben T H M Larue, Lien Van De Voorde, Maaike Berbée, Wouter J C van Elmpt, Ludwig J Dubois, Kranthi M Panth, Sarah G J A Peeters, Ann Claessens, Wendy M J Schreurs, Marius Nap, Fabiënne A R M Warmerdam, Frans L G Erdkamp, Meindert N Sosef, Philippe Lambin

Abstract

Background: Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer.

Methods/design: A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer (18)F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice. Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on (18)F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival.

Discussion: This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs.

Trial registration: ClinicalTrials.gov Identifier: NCT02598687 .

Keywords: Dose limiting toxicity; Evofosfamide; Hypoxia imaging; Neoadjuvant chemoradiotherapy; Oesophageal cancer; Oesophagectomy; Window-of-opportunity trial.

Figures

Fig. 1
Fig. 1
Evofosfamide decreases the hypoxic fraction in a Rhabdomyosarcoma rat model. PET-scans with hypoxia tracer 18F-HX4 were made before (day 0) and after (day 4) administering evofosfamide for four consecutive days at a dose of 25 mg/kg
Fig. 2
Fig. 2
Flowcharts summarizing the 3 + 3 dose escalating study design. In the first cohort of patients evofosfamide will be administered at a dose of 120 mg/m2. Depending on the observed toxicity, we will escalate to dose level 2, or de-escalate to dose level -1. In further dose levels we can only escalate to the next dose (up to 340 mg/m2) or stop due to dose limiting toxicity
Fig. 3
Fig. 3
Study treatment schedule. Prior to the start of the standard CROSS treatment, patients will receive additional 18F-HX4 scans before and after the first dose of evofosfamide

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