Clinical Trials /

Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients

NCT02906800

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients
  • Official Title: Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: P150401
  • SECONDARY ID: 2015-003076-78
  • NCT ID: NCT02906800

Conditions

  • Head and Neck Cancer

Interventions

DrugSynonymsArms
DigoxinDigoxineDIGHANC

Purpose

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.

Detailed Description

      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
    

Trial Arms

NameTypeDescriptionInterventions
DIGHANCExperimentalPatients 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 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.
  • Digoxin

Eligibility Criteria

        Inclusion Criteria:

          -  Patients of both sexes, with primary unresectable, advanced (stage III-IV) HNSCC to be
             treated by cisplatin-based chemotherapy.

          -  Life expectancy > 12 months.

          -  Age > 18 and < 70

          -  WHO PS : 0-2

          -  Signed informed consent

          -  creatinine clearance : MDRD > 60ml/min/1,73m2

          -  Affiliation to the French Social Security Health Care plan

        Exclusion Criteria:

          -  Difficulties planned for the 6 month follow up during the study period

          -  Swallowing disorder preventing digoxin treatment

          -  Severe aortic stenosis or idiopathic hypertrophic subaortic stenosis at the
             pretreatment echocardiography.

          -  Hypertrophic or dilated or restrictive cardiomyopathy at the pretreatment
             echocardiography

          -  Severe cardiac condition contraindicating the use of digoxin (Constrictive
             pericarditis, acute cor pulmonale, myocarditis…)

          -  Acute Myocardial infarction within the past 3 months

          -  Severe ventricular arrhythmias on ECG at rest including frequent ventricular
             extrasystoles, ventricular tachycardia/fibrillation

          -  Second and third degree atrio-ventricular block or sick sinus syndrome on resting ECG
             without pacemaker

          -  Wolf Parkinson White syndrome on ECG at rest

          -  Renal insufficiency (estimated glomerular filtration rate by the MDRD formula < 60
             ml/min/1.73m2)

          -  Liver insufficiency (Child-Pugh grades B and C)

          -  Severe uncorrected electrolyte disturbances (hypercalcemia, hypokaliemia,
             hypomagnesemia…)

          -  Known hypersensitivity reaction to digoxin

          -  Compelling indication for continuous use of digoxin

          -  Use of drugs contraindicated with oral digoxin (Midodrine, calcium salt, millepertuis,
             sultopride, phenytoin, yellow fever vaccine, live attenuated vaccine)

          -  Absence of effective contraception methods for men and women during the study and 6
             months after the end of the study

          -  Pregnancy and breastfeeding at inclusion, during the study and 6 months after the end
             of the study

          -  HPV positive tumors (These tumors are associated with very good response to
             chemotherapy alone)

          -  History of another cancer which treatment is ongoing
      
Maximum Eligible Age:69 Years
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Appearance of the grade 3 or 4 (Adverse Events graded by NCI CTC version 4.0) clinical or biological toxicity of the combination of digoxin to cisplatin-based chemotherapy during the study
Time Frame:18 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Clinical response after chemotherapy by fibroscopy (tumor seize)
Time Frame:At 18 weeks
Safety Issue:
Description:
Measure:Radiological response after chemotherapy
Time Frame:At 18 weeks
Safety Issue:
Description:Measured by TDM, MRI and TEP-Scan (tumor seize, criteria RECIST (Response Evaluation Criteria In Solid Tumours)
Measure:Biological efficacy: monitored by analysis of T cells recruitment
Time Frame:At 18 weeks
Safety Issue:
Description: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
Measure:Biological efficacy: monitored by analysis of subpopulations of T cells
Time Frame:At 18 weeks
Safety Issue:
Description: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).
Measure:Biological efficacy: expression of IFN gamma assessed by quantitative RT-PCR assay
Time Frame:At 18 weeks
Safety Issue:
Description:
Measure:Biological efficacy: expression of IL-17 assessed by quantitative RT-PCR assay
Time Frame:At 18 weeks
Safety Issue:
Description:
Measure:Progression Free Survival (PFS): Death or recurrence (clinical and/or radiological analysis)
Time Frame:10 days after each cycle of chemotherapy and two weeks after the end of the third cycle of chemotherapy
Safety Issue:
Description:Death or recurrence (clinical and/or radiological analysis)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

Trial Keywords

  • cisplatin
  • head and neck cancer
  • digoxin

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