Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma

Study Overview
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Brief Summary
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Classic and endemic Kaposi's sarcoma (KS) are lymph angio proliferations associated with human herpes virus 8 (HHV8) which treatment is poorly codified. Chemotherapies give at best 30-60% of transient responses. While interferon responses are frequent, this drug is often poorly tolerated in elderly patients. Therefore new therapies are needed. Classic KS represents an ideal model for evaluating new drugs since patients do not receive concomitant immunosuppressive regimens nor antiviral therapies. Hypoxia-inducible factor 1(HIF-1 alpha) is a major regulator of solid tumor growth and therefore a suitable target currently explored in many cancers. Moreover HIF-1 alpha enhances HHV-8 gene expression in KS and induces lytic replication cycle. Digoxin has anti cancer effect in vivo through HIF-alpha down regulation in several preclinical tumor models including KS. The identification of HIF-1 alpha as a key factor in HHV8 replication prompt us to explore inhibition of HIF-1 alpha by digoxin as a potential therapeutic approach for KS treatment it has and consequently may down regulate HHV-8 replication in KS. This latter approach is heightened by recent data suggesting that Digoxin has some efficacy in vitro against others human herpes virus i.e. Herpes simplex and Cytomegalovirus (8) (9) In this study the investigators shall evaluate the benefit and safety profile of digoxin in classic and endemic KS (serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years and between 0.5-0.8 ng/ml in patients older than 75 years The participants will take study drug digoxin, for a total of 6 cycles (4 weeks/cycle).

Official Title
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Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma

Conditions
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Kaposi' s Sarcoma, Classic Kaposi' s Sarcoma, Endemic Kaposi' s Sarcoma, Lymph Angio Proliferations

Intervention / Treatment
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* Drug: digoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years <à 80 years Classic or endemic histologically confirmed Kaposi's Sarcoma (KS) Progressive disease KS with more than 10 lesions or involving more than one limb segment or with involvement >3% body surface KS with at least 4 lesions ≥5mm Patients should have at least 2 others cutaneous tumor available for repeated pharmacodynamics evaluation At least 4 weeks wash out for all KS specific therapies including chemotherapy and immunotherapy Signed informed consent Exclusion Criteria: Symptomatic visceral lesions Eastern Cooperative Oncology Group ( ECOG) performance status > 1 Life expectancy of ≤ 6 months Patients already receiving digoxin hepatic dysfunction defined as serum bilirubin>25 µm/l, transaminases > 3.0 times the upper limit of normal (ULN) (5ULN in cases of liver metastases) bone marrow dysfunction defined as absolute neutrophil count<1500/mcl, platelets<150000/mcl or hemoglobin<8g/dL renal failure with creatinine clearance< 40ml/mn HIV positive, active infectious hepatitis, type A, B or C Uncontrolled systemic infection Pregnant or lactating women Presence of any of the following on electrocardiogram (ECG): atrial arrhythmias, including atrial fibrillation and flutter with Wolff-Parkinson-White syndrome; auricular ventricular (AV) block; heart rate < 60 beats/minute and > 100 beats/minute; ventricular fibrillation; ventricular tachycardia; premature ventricular contractions. History of or current cardiac arrythmia including sinus node disease, history of AV Block, accessory AV pathway (Wolff-Parkinson-White Syndrome), history myocardial infarction, any significant valvulopathy. Electrolyte imbalance (hypokalemia, hypo- or hypercalcemia, hypomagnesemia) Severe pulmonary disease and hypoxia Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, hypothyroidism or hyperthyroidism, which would, in the opinion of the investigator, make this protocol unreasonably hazardous. Major thoracic or abdominal surgery within the prior 3 weeks. GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis). Immunosuppressive regimen should not be allowed including corticosteroids Use of any prohibited concomitant medications: the calcium channel blockers diltiazem or verapamil; Class I and III cardiac arrhythmic agents (such as quinidine, amiodarone); beta-blockers (such as atenolol, metoprolol); indomethacin (Indocin); calcium carbonate antacids (e.g., Maalox, Tums, Rolaids); Calcium omeprazole; antidiarrheal adsorbents (kaolin and pectin); antibiotics P450 inhibitors clarithromycin, erythromycin telithromycin and other P450 inhibitors./such as Ritonavir) Persistent Grade >2 treatment-related toxicity from prior therapy History of any digoxin-related or drug induced anaphylactic reaction Use of any other investigational agent Patient without health insurance coverage Patient under guardianship Enrollment into a clinical trial within last 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Digoxin<br>All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years and between 0.5-0.8 ng/ml in patients older than 75 years | Drug: digoxin<br>* All patients will receive Digoxin without interruption. Doses can be modified individually to reach a serum drug concentration of 0.6 to 1.2 ng/ml for patients <75 years and between 0.5-0.8 ng/ml in patients older than 75 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tumor response | The primary endpoint will be tumor response, at 3 months. Assessed by AIDS Clinical Trials Group (ACTG) criteria ;Complete response (CR) will be defined as the absence of detectable residual disease lasting for at least 4 weeks; patients whose only remaining manifestation of KS are pigmented macules could be classified as having had a complete response if malignant cells are absent on biopsy of at least one lesion. Patients with visceral disease on entry who have complete resolution of cutaneous lesions as described above could be considered to have a CR only if no residual disease was detected on endoscopic or radiographic restaging. | at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response during the trial | Best overall response during the trial, defined by the best response recorded from the start of treatment until disease progression/recurrence or treatment interruption for any reason | at 6 months | 
| Response rate at 6 months |  | at 6 months | 
| number of lesions | number of lesions | at 3 months | 
| size of target lesions |  | at 3 months | 
| tumor infiltration of target lesions |  | at 3 months | 
| lymphedema | lymphedema (scale of 0 (absence)-3 (painful or oozing), circumference) | at 3 months | 
| Time to response |  | at 3 months | 
| Time to progression |  | at 3 months | 
| toxicity | Safety and tolerance aspects, they will be assessed in terms of drug toxicity evaluated by clinic and on laboratory parameters and scored according Common Terminology Criteria for Adverse Events v4.0 (CTCAE) | at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kaposi' s sarcoma, Digoxin