Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients
Status:
Unknown status
Trial end date:
2019-05-01
Target enrollment:
Participant gender:
Summary
Introduction: Patients with primary unresectable advanced head and neck squamous cell
carcinomas (HNSCC) have a poor prognosis with a median survival of 22 months (Hauswald H
Radiat Oncol 2011). They are usually treated with induction chemotherapy followed by
radiochemotherapy or platinum-based concomitant radiochemotherapy. Most patients achieve an
objective clinical response contrasting with a high rate of local recurrence and distant
metastases in the year following radiochemotherapy (Argiris A Ann Oncol 2011). Improvement of
the efficacy of chemotherapy remains therefore a major clinical goal for this group of
patients. During the past years, the investigators demonstrated that some conventional
chemotherapeutics (anthracycline, oxaliplatin…) induce a type of "immunogenic" cell death
(ICD) characterized by the exposure of calreticulin on the tumor cell surface, the secretion
of ATP and the release of high-mobility group box 1 (HMGB1) resulting in activation of tumor
immunity (Galluzzi L Nat Rev Drug Discov 2012). The investigators recently showed that the
Na/K-ATPase inhibitor, digoxin, favors ICD, when combined with cisplatin, a drug known not to
induce ICD. In preclinical models, a synergy between cisplatin and digoxin which led to a
significant therapeutic improvement (Menger L Sci Transl Med 2012) has been observed. This
effect seems to be mediated by the immune system as the combined therapy induced intratumor T
cell infiltration producing cytokines (Menger L Sci Transl Med 2012).
Hypothesis: Based on our preclinical data, the hypothesis is that adding digoxin to the
conventional cisplatin based induction chemotherapy regimen in unresectable advanced HNSCC
will increase the efficacy of this therapy via the induction of anti-tumor immunity.
Objectives:
Main: the primary objective is to assess the clinical and biological safety of the
combination of digoxin to cisplatin-based chemotherapy.
Secondary: The secondary objectives are to investigate biological markers of efficacy by
analyzing the recruitment of functional T cells in tumour biopsies after treatment with the
combination of digoxin and chemotherapy.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Assistance Publique - Hôpitaux de Paris
Collaborators:
Cancer Research and Personalized Medicine (Carpem) Laboratoire d'excellence en immuno-oncologie (Labex) Laboratoire d’excellence en immuno-oncologie (Labex)