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Trial record 19 of 1321 for:    Recruiting, Not yet recruiting, Available Studies | "Head and Neck Neoplasms"

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

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ClinicalTrials.gov Identifier: NCT02906800
Recruitment Status : Recruiting
First Posted : September 20, 2016
Last Update Posted : October 19, 2017
Sponsor:
Collaborators:
Cancer Research and Personalized Medicine (Carpem)
Laboratoire d’excellence en immuno-oncologie (Labex)
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief 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.


Condition or disease Intervention/treatment Phase
Head and Neck Cancer Drug: Digoxin Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Potentiation of Cisplatin-based Chemotherapy by Digoxin in Advanced Unresectable Head and Neck Cancer Patients
Actual Study Start Date : January 2017
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: DIGHANC
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 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.
Drug: Digoxin
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).
Other Name: Digoxine




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Clinical response after chemotherapy by fibroscopy (tumor seize) [ Time Frame: At 18 weeks ]
  2. Radiological response after chemotherapy [ Time Frame: At 18 weeks ]
    Measured by TDM, MRI and TEP-Scan (tumor seize, criteria RECIST (Response Evaluation Criteria In Solid Tumours)

  3. Biological efficacy: monitored by analysis of T cells recruitment [ Time Frame: At 18 weeks ]
    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

  4. Biological efficacy: monitored by analysis of subpopulations of T cells [ Time Frame: At 18 weeks ]
    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).

  5. Biological efficacy: expression of IFN gamma assessed by quantitative RT-PCR assay [ Time Frame: At 18 weeks ]
  6. Biological efficacy: expression of IL-17 assessed by quantitative RT-PCR assay [ Time Frame: At 18 weeks ]
  7. 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 ]
    Death or recurrence (clinical and/or radiological analysis)



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Ages Eligible for Study:   19 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02906800


Contacts
Contact: Stephane HANS, MD, PH stephane.hans@aphp.fr

Locations
France
Hopital Europeen Georges Pompidou Recruiting
Paris, Île-de-France, France, 75015
Contact: Stephane Hans, MD       stephane.hans@aphp.fr   
Principal Investigator: Stephane Hans, MD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Cancer Research and Personalized Medicine (Carpem)
Laboratoire d’excellence en immuno-oncologie (Labex)
Investigators
Principal Investigator: Stephane HANS, MD, PH Assistance Publique - Hôpitaux de Paris

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02906800     History of Changes
Other Study ID Numbers: P150401
2015-003076-78 ( EudraCT Number )
First Posted: September 20, 2016    Key Record Dates
Last Update Posted: October 19, 2017
Last Verified: October 2017

Keywords provided by Assistance Publique - Hôpitaux de Paris:
cisplatin
head and neck cancer
digoxin

Additional relevant MeSH terms:
Head and Neck Neoplasms
Neoplasms by Site
Neoplasms
Cisplatin
Digoxin
Antineoplastic Agents
Anti-Arrhythmia Agents
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs