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Everolimus safety and efficacy for renal angiomyolipomas associated with tuberous sclerosis complex: a Spanish expanded access trial

View Article: PubMed Central - PubMed

ABSTRACT

Background: Renal angiomyolipomas (AML) are usual manifestations of tuberous sclerosis complex (TSC) that may cause aneurism-related haemorrhages and renal impairment. Everolimus has emerged as an alternative to surgery/embolization. We provide further insight into everolimus safety and efficacy for TSC-related AML.

Methods: This was a Spanish expanded access trial including patients aged ≥18 years with TSC-related AML. They received 10 mg everolimus once daily until AML progression, unacceptable toxicity, death/withdrawal, commercialisation for TSC-related AML, or 1 year after first patient enrolment. The primary outcome was dose-limiting safety according to grade 3/4 adverse events, serious adverse events, or adverse events leading to treatment modification. Secondary outcomes included overall safety and efficacy.

Results: Nineteen patients were enrolled and received everolimus for a median of 6.6 (5.3–10.9) months. Eleven (57.9 %) remained on 10 mg/day throughout the study and eight (42.1 %) required treatment modifications due to adverse events; none permanently discontinued treatment. Adverse events were overall grade 1/2 and most frequently included aphthous stomatitis/mucosal inflammation, hypercholesterolaemia/hypertriglyceridaemia, urinary tract infection, hypertension, dermatitis acneiform, and insomnia. Four (21.1 %) patients experienced grade 3 adverse events, none was grade 4, and only one (5.3 %) was serious (pneumonia). AML volume was reduced ≥30 % in 11 (57.9 %) patients and ≥50 % in 9 (47.4 %); none progressed. Right and left kidney sizes decreased in 16 and 14 patients, respectively.

Conclusions: These findings support the benefit of everolimus for renal AML due to a manageable safety profile accompanied by reduced AML and kidney volumes.

Trial registration: EudraCT number 2012-005397-63; date of registration 22 Nov 2012.

No MeSH data available.


Overall flow chart and main study assessments. Abbreviations: CT computed tomography, MRI magnetic resonance imaging
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Fig1: Overall flow chart and main study assessments. Abbreviations: CT computed tomography, MRI magnetic resonance imaging

Mentions: This was an open-label, single-arm, phase IIIb, expanded access trial carried out at 12 Spanish hospitals. Screening and baseline assessments were conducted over the 21 days prior to the first dose of everolimus (Fig. 1). Eligible patients then started once-daily oral administration of everolimus at a dose of 10 mg/day after signing the informed consent. Everolimus was administered until AML progression, occurrence of unacceptable toxicity according to investigator’s criteria, patient death or withdrawal for any reason. Another criterion to stop the trial was everolimus commercialisation for TSC-related AML in Spain, or 1 year after first patient enrolment; the latter was what occurred first. Treatment modifications were determined clinically on the basis of safety findings (i.e. according to the grade of adverse events as per the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute version 4.03 [21]), including dose adjustments, temporary treatment interruptions or permanent treatment discontinuation. Initial doses of 10 mg/day could be lowered to 5 mg/day (dosing level −1) or even to 5 mg/every other day (dosing level −2).Fig. 1


Everolimus safety and efficacy for renal angiomyolipomas associated with tuberous sclerosis complex: a Spanish expanded access trial
Overall flow chart and main study assessments. Abbreviations: CT computed tomography, MRI magnetic resonance imaging
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037621&req=5

Fig1: Overall flow chart and main study assessments. Abbreviations: CT computed tomography, MRI magnetic resonance imaging
Mentions: This was an open-label, single-arm, phase IIIb, expanded access trial carried out at 12 Spanish hospitals. Screening and baseline assessments were conducted over the 21 days prior to the first dose of everolimus (Fig. 1). Eligible patients then started once-daily oral administration of everolimus at a dose of 10 mg/day after signing the informed consent. Everolimus was administered until AML progression, occurrence of unacceptable toxicity according to investigator’s criteria, patient death or withdrawal for any reason. Another criterion to stop the trial was everolimus commercialisation for TSC-related AML in Spain, or 1 year after first patient enrolment; the latter was what occurred first. Treatment modifications were determined clinically on the basis of safety findings (i.e. according to the grade of adverse events as per the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute version 4.03 [21]), including dose adjustments, temporary treatment interruptions or permanent treatment discontinuation. Initial doses of 10 mg/day could be lowered to 5 mg/day (dosing level −1) or even to 5 mg/every other day (dosing level −2).Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Renal angiomyolipomas (AML) are usual manifestations of tuberous sclerosis complex (TSC) that may cause aneurism-related haemorrhages and renal impairment. Everolimus has emerged as an alternative to surgery/embolization. We provide further insight into everolimus safety and efficacy for TSC-related AML.

Methods: This was a Spanish expanded access trial including patients aged ≥18 years with TSC-related AML. They received 10 mg everolimus once daily until AML progression, unacceptable toxicity, death/withdrawal, commercialisation for TSC-related AML, or 1 year after first patient enrolment. The primary outcome was dose-limiting safety according to grade 3/4 adverse events, serious adverse events, or adverse events leading to treatment modification. Secondary outcomes included overall safety and efficacy.

Results: Nineteen patients were enrolled and received everolimus for a median of 6.6 (5.3–10.9) months. Eleven (57.9 %) remained on 10 mg/day throughout the study and eight (42.1 %) required treatment modifications due to adverse events; none permanently discontinued treatment. Adverse events were overall grade 1/2 and most frequently included aphthous stomatitis/mucosal inflammation, hypercholesterolaemia/hypertriglyceridaemia, urinary tract infection, hypertension, dermatitis acneiform, and insomnia. Four (21.1 %) patients experienced grade 3 adverse events, none was grade 4, and only one (5.3 %) was serious (pneumonia). AML volume was reduced ≥30 % in 11 (57.9 %) patients and ≥50 % in 9 (47.4 %); none progressed. Right and left kidney sizes decreased in 16 and 14 patients, respectively.

Conclusions: These findings support the benefit of everolimus for renal AML due to a manageable safety profile accompanied by reduced AML and kidney volumes.

Trial registration: EudraCT number 2012-005397-63; date of registration 22 Nov 2012.

No MeSH data available.