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, it was demonstrate 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 HMGB1
      resulting in activation of tumor immunity (Galluzzi L Nat Rev Drug Discov 2012). The
      Na/K-ATPase inhibitor, digoxin, favors ICD, when combined with cisplatin, a drug known not to
      induce ICD. In preclinical models, a synergy was observed between cisplatin and digoxin which
      led to a significant therapeutic improvement (Menger L Sci Transl Med 2012). 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.

      Endpoints:

      Primary: grade 3 or 4 clinical or biological toxicity (Adverse Events graded by National
      Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0)

      Secondary:

        -  Clinical/radiological efficacy monitored after 3 cycles of chemotherapy as assessed by
           Positron Emission Tomography-Scan (PET-Scan), Magnetic Resonance Imaging (MRI),
           (computerized tomography-Scan) CT-scan

        -  Progression Free Survival (PFS) (months)

        -  Biological efficacy monitored by:

             1. Analysis of the T cells recruitment in biopsies from HNSCC patients after therapy.
                The T cell recruitment will be considered as significant if T cells increase of at
                least 25% in post-therapeutic compared to pre-therapeutic biopsies.

             2. Analysis of subpopulations of T cells (CD8+T cells, regulatory T cells
                (CD4+CD25+Foxp3+ and gamma-delta T cells) in tumor biopsies by immunofluorescence
                analysis to show a potential higher ratio of effector/regulatory T cells after
                therapy as previously described (Badoual C et al Clin Cancer Res 2006).

             3. Expression of IFN and IL-17 assessed by quantitative RT-PCR assay (Taq Man) to look
                for a production of Interferon gamma (IFNgamma) by CD4+ and CD8+T cells and the
                presence of T cells producing IL-17 as observed in preclinical models, (Menger L
                Sci Transl Med 2012).

      Methodology: Pilot, single arm, open label, phase I/II study.

      Study conduct:

      Patients meeting all inclusion /exclusion criteria, will be given 3 cycles of the following
      regimen: 1) digoxin (0.25 mg/day) for a 7-day period (digitalization time) from Day 1 to Day
      7; 2) chemotherapy regimen TPF (Taxoter, Platin, 5-FU) protocol from Day 8 to D12 (continuous
      perfusion of fluorouracil for 120h, Cisplatin at Day 10 and Docetaxel at Day 11) administered
      in combination with digoxin 0.25 mg/day from Day 8 to Day 9; 3) a 15-day period off
      treatment.

      The digoxin dose will be adjusted to achieve a plasma concentration of 0.6-1.2 ng/ml
      according to current recommendations in heart failure patients (doses adapted to renal
      function, comorbidities, concomitant medications, age, and plasma concentration). The risk
      related to digoxin treatment will be minimized in our study since the duration of exposure to
      digoxin will be limited to 9 days every 3 weeks for 3 cycles (total duration of treatment 27
      days).

      Biopsies will be performed before the first digoxin administration and at the end of the 3rd
      cycle.

      Patients with unacceptable adverse events (e.g. patients with grade 3 or 4 toxicities not
      improving to < grade 1 despite drug hold for 2 weeks) will be withdrawn of the study.

      Patients with estimated glomerular filtration rate (estimated by the MDRD formula) decreasing
      below 60 ml/min/1.73m2 at any time after the TPF chemotherapy during the study will be
      withdrawn of the study.

      Patients will be managed jointly by an oncologist and a cardiologist at the Clinical
      Investigation Center or at the Oncology and safety and tolerability assessed at each cycle
      by:

      Physical examination including neurological and hearing testing, body weight, WHO performance
      status Cardiac status: echocardiogram at baseline and daily ECG at rest during each cycle of
      chemotherapy (from Day 8 to Day 12) and at Day 1 of each cycle and at inclusion.

      Plasma digoxin concentration and plasma electrolytes and creatinine (at inclusion, at day 1
      at cycles 2 and 3 and everyday during the TPF chemotherapy regimen of each cycle of
      chemotherapy).

      Regular reporting of adverse events (AEs) graded by NCI CTC version 4.0.

      An Independent Safety Committee will receive information at the end of the treatment period
      of each patient, and if a serious adverse event (SAE) occurs. A formal meeting will be held
      every 3 patients.

      Randomisation: none

      Duration of participation for each patient: 18 weeks including the inclusion protocol

      Length of the study: 28 months 1/2