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Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma (KADIG 01)

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ClinicalTrials.gov Identifier: NCT02212639
Recruitment Status : Recruiting
First Posted : August 8, 2014
Last Update Posted : July 23, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Kaposi' s Sarcoma Classic Kaposi' s Sarcoma Endemic Kaposi' s Sarcoma Lymph Angio Proliferations Drug: digoxin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma
Study Start Date : September 2014
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Digoxin

Arm Intervention/treatment
Experimental: Digoxin
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
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




Primary Outcome Measures :
  1. tumor response [ Time Frame: at 3 months ]
    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.


Secondary Outcome Measures :
  1. Best overall response during the trial [ Time Frame: at 6 months ]
    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

  2. Response rate at 6 months [ Time Frame: at 6 months ]
  3. number of lesions [ Time Frame: at 3 months ]
    number of lesions

  4. size of target lesions [ Time Frame: at 3 months ]
  5. tumor infiltration of target lesions [ Time Frame: at 3 months ]
  6. lymphedema [ Time Frame: at 3 months ]
    lymphedema (scale of 0 (absence)-3 (painful or oozing), circumference)

  7. Time to response [ Time Frame: at 3 months ]
  8. Time to progression [ Time Frame: at 3 months ]
  9. toxicity [ Time Frame: at 6 months ]
    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)



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT02212639


Contacts
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Contact: Céleste Céleste, MD PHD +33 1 42494679 celeste.lebbe@sls.aphp.fr
Contact: matthieu resche-rigon, MD PHD +33 1 42 49 97 42 matthieu.resche-rigon@paris7.jussieu.fr

Locations
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France
Saint-Louis Hospital Recruiting
Paris, France, 75010
Contact: Celeste Lebbe, MD PHD    + 33 142494679    celeste.lebbe@sls.aphp.fr   
Principal Investigator: celeste lebbe, MD-PHD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: celeste lebbe, MDPHD APHP

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02212639     History of Changes
Other Study ID Numbers: P130944
2014-001741-24 ( EudraCT Number )
First Posted: August 8, 2014    Key Record Dates
Last Update Posted: July 23, 2018
Last Verified: July 2018
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Kaposi' s sarcoma
Digoxin
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Digoxin
Anti-Arrhythmia Agents
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs