Methods of treating epithelioid cell tumors comprising administering a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin
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Publication Number
US-10973806-B2
Publication Date
2021-04-13
Expiration Date
Abstract
The present invention provides methods and compositions for treating epithelioid cell tumors (such as a PEComa) by administering a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
Core Innovation
The invention relates to a method of treating a malignant perivascular epithelioid cell tumor (PEComa) in an individual by intravenously administering an effective amount of a composition comprising nanoparticles comprising sirolimus and an albumin. The disclosed approach is centered on intravenously administering the nanoparticle composition containing sirolimus and albumin as a treatment for malignant PEComa, including malignant PEComa subtypes and related epithelioid cell tumors described in the document.
The nanoparticle composition uses sirolimus in a specified effective amount and is administered on days 1 and 8 of a 21-day cycle. The nanoparticle composition is configured to deliver sirolimus via albumin-associated nanoparticles, where the sirolimus is within nanoparticles comprising albumin.
The disclosure also includes formulation constraints for the nanoparticles and the albumin–sirolimus association, including nanoparticle mean/average diameter limits and albumin–sirolimus weight ratio constraints, together with optionally stabilized colloidal formulations intended to reduce or avoid surfactants. In addition, the disclosure includes patient selection concepts involving mTOR-pathway gene mutations, phosphorylation status of mTOR-pathway proteins, and expression of proliferation/apoptosis markers, along with therapeutic response and survival/progression endpoints.
Claims Coverage
The claim coverage centers on an intravenously administered albumin-associated nanoparticle composition comprising sirolimus for treating malignant PEComa, with a specific sirolimus effective-dose range and dosing schedule. Dependent claims further refine the treated PEComa context and add formulation constraints, including nanoparticle size limits, albumin:sirolimus weight-ratio ranges, and albumin coating or association with sirolimus inside the nanoparticles.
Intravenous nanoparticle albumin-sirolimus treatment for malignant PEComa
A method of treating a malignant perivascular epithelioid cell tumor (PEComa) in an individual by intravenously administering an effective amount of a composition comprising nanoparticles comprising sirolimus and an albumin.
Specified sirolimus effective dose in the nanoparticle composition
The effective amount of sirolimus in the nanoparticle composition is about 56 mg/m2 to about 100 mg/m2.
Dosing on days 1 and 8 of a 21-day cycle
The nanoparticle composition is administered on days 1 and 8 of a 21-day cycle.
Nanoparticle average diameter maximum constraint
The nanoparticles have an average diameter of no greater than about 150 nm.
Albumin to sirolimus weight ratio constraint
The weight ratio of albumin to sirolimus is approximately 1:1 to approximately 9:1.
Albumin coating or association with sirolimus in nanoparticles
Sirolimus contained in the nanoparticles is coated with albumin.
Treated PEComa subtype selection
The malignant PEComa is selected from pulmonary clear cell “sugar” tumor or PEComa not otherwise specified (PEComa-NOS).
Overall, the claim coverage centers on intravenously administering albumin-associated nanoparticles comprising sirolimus to treat malignant PEComa, with a specific sirolimus dose range and a defined 21-day-cycle schedule, further refined by nanoparticle size, albumin:sirolimus weight ratio, albumin association or coating, and specified PEComa subtype selection.
Stated Advantages
Improved aqueous suspendability and stability of the mTOR inhibitor nanoparticle compositions.
Substantially avoids toxic organic solvents and/or surfactants, including being substantially free of surfactant such as Cremophor and Cremophor EL.
Provides stability performance characterized by avoiding visible precipitation and/or agglomeration over stated time windows.
Documented Applications
Treating a malignant perivascular epithelioid cell tumor (PEComa) in an individual by intravenously administering sirolimus-and-albumin nanoparticle composition on days 1 and 8 of a 21-day cycle.
An Example of a phase II study of Nab-sirolimus in advanced malignant PEComa.
Therapeutic response assessment and survival/progression endpoints in connection with the described Nab-sirolimus treatment in malignant PEComa.
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