Clinical trial NCT02212639: Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma
Official title: Phase II Multicentric Study of Digoxin Per os in Classic or Endemic Kaposi' s Sarcoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Kaposi' s Sarcoma
Classic Kaposi' s Sarcoma
Endemic Kaposi' s Sarcoma
Lymph Angio Proliferations
Keywords: Kaposi' s sarcoma
Digoxin
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2014-08-08
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility 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

Primary outcomes:
measure: tumor response
timeFrame: at 3 months
Secondary outcomes:
measure: Best overall response during the trial
timeFrame: at 6 months
measure: Response rate at 6 months
timeFrame: at 6 months
measure: number of lesions
timeFrame: at 3 months
measure: size of target lesions
timeFrame: at 3 months
measure: tumor infiltration of target lesions
timeFrame: at 3 months
measure: lymphedema
timeFrame: at 3 months
measure: Time to response
timeFrame: at 3 months
measure: Time to progression
timeFrame: at 3 months
measure: toxicity
timeFrame: at 6 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint-Louis Hospital
Study officials:
affiliation: APHP
name: celeste lebbe, MDPHD
role: PRINCIPAL_INVESTIGATOR
References: