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

NCT02212639 | Unknown Phase 2

• 2 other identifiers: P1309442014-001741-24
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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).

Conditions

Kaposi' s Sarcoma; Classic Kaposi' s Sarcoma; Endemic Kaposi' s Sarcoma; Lymph Angio Proliferations

Keywords

Kaposi' s sarcoma; Digoxin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Best overall response during the trial

  at 6 months

• Response rate at 6 months

  at 6 months

• number of lesions

  at 3 months

• size of target lesions

  at 3 months

• tumor infiltration of target lesions

  at 3 months

Study Arms (1)

Digoxin

EXPERIMENTAL

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

Interventions

digoxin DRUG

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

Digoxin

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Saint-Louis Hospital

Paris, 75010, France

RECRUITING

MeSH Terms

Interventions

Digoxin

Intervention Hierarchy (Ancestors)

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

Study Officials

• celeste lebbe, MDPHD

  APHP

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Céleste Céleste, MD PHD

CONTACT

+33 1 42494679; celeste.lebbe@sls.aphp.fr

matthieu resche-rigon, MD PHD

CONTACT

+33 1 42 49 97 42; matthieu.resche-rigon@paris7.jussieu.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2014
• First Posted: August 8, 2014
• Study Start: September 1, 2014
• Primary Completion: January 1, 2019
• Study Completion: September 1, 2019
• Last Updated: July 23, 2018

Record last verified: 2018-07

Locations

FR (1)