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

NCT02906800 | Unknown Phase 1 DMC

• 2 other identifiers: P1504012015-003076-78
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Head and Neck Cancer

Keywords

cisplatin; head and neck cancer; digoxin

Outcome Measures

Primary Outcomes (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

  18 weeks

Secondary Outcomes (7)

• Clinical response after chemotherapy by fibroscopy (tumor seize)

  At 18 weeks

• Radiological response after chemotherapy

  At 18 weeks

• Biological efficacy: monitored by analysis of T cells recruitment

  At 18 weeks

• Biological efficacy: monitored by analysis of subpopulations of T cells

  At 18 weeks

• Biological efficacy: expression of IFN gamma assessed by quantitative RT-PCR assay

  At 18 weeks

Study Arms (1)

DIGHANC

EXPERIMENTAL

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

Interventions

Digoxin DRUG

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).

Also known as: Digoxine

DIGHANC

Eligibility Criteria

• Age: 19 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Cancer Research and Personalized Medicine (Carpem): collaborator
• Laboratoire d'excellence en immuno-oncologie (Labex): collaborator

Study Sites (1)

Hopital Europeen Georges Pompidou

Paris, Île-de-France Region, 75015, France

RECRUITING

MeSH Terms

Conditions

Head and Neck Neoplasms

Interventions

Digoxin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Officials

• Stephane HANS, MD, PH

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stephane HANS, MD, PH

CONTACT

stephane.hans@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2016
• First Posted: September 20, 2016
• Study Start: January 1, 2017
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: October 19, 2017

Record last verified: 2017-10

Locations

FR (1)