Methods of treating cancer with an mTOR inhibitor
Inventors
BITMAN, Bojena • GUSTAFSON, W. Clay • LORENZANA, Ed • MEYEROWITZ, Justin G. • YANG, Yu Chi • Singh, Mallika • Wang, Zhengping • WANG, Zhican
Assignees
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Publication Number
US-12121522-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present disclosure relates to methods for the treatment of diseases or disorders (e.g., cancer) with mTOR inhibitors. Specifically, the disclosure relates to methods of treating a subject having a cancer by administering a particular dosage of an mTOR inhibitor. In some embodiments this disclosure includes methods for delaying, preventing, or treating acquired resistance to RAS inhibitors using a dosage of an mTOR inhibitor. In some embodiments, this disclosure relates to methods of treating or preventing adverse events associated with administration of an mTOR inhibitor using tacrolimus.
Core Innovation
The invention relates to treatment methods for a subject having a cancer using an mTOR inhibitor compound, including RMC-5552 and RMC-6272, at a dosage of about 6 mg/week to about 25 mg/week. The compound includes stereoisomers, tautomers, oxepane isomers, pyran isomer and oxepane isomer forms, solvate forms including hydrate, and pharmaceutically acceptable salts.
In embodiments, the cancer is selected from breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, renal cancer, thyroid cancer, vulvar cancer, prostate cancer, or salivary gland cancer, or the cancer comprises a PIK3CA mutation, a PTEN mutation, a TSC1 mutation, a TSC2 mutation, or a combination thereof. The PTEN mutation is characterized as dominant negative in certain embodiments, and some descriptions include more than about 95% clonality of pathogenic variants.
The approach is described in connection with pathway biomarker modulation, including p4EBP1, pS6RP, and decreased 4EBP1, and measurable antitumor responses using ctDNA and RECIST. The document also describes treatment contexts involving delayed or prevented acquired resistance to a RAS inhibitor, including combination with a RAS inhibitor, and supportive use of tacrolimus solution, and in some embodiments dexamethasone mouthwash/ice, to treat or prevent mTOR-inhibitor-associated mucositis and stomatitis.
Claims Coverage
Three independent claim groupings are provided across the inputs. The inventive coverage centers on administering an mTOR inhibitor compound, including stereoisomers, tautomers, oxepane isomers, or pharmaceutically acceptable salts, at about 6 mg/week to about 25 mg/week, with cancer selection defined by either listed cancer types or mutation profiles involving PIK3CA, PTEN, TSC1, and TSC2.
Weekly dosage range for mTOR inhibitor compound in cancer treatment
A method of treating a subject having a cancer by administering a dosage of about 6 mg/week to about 25 mg/week of a compound, wherein the compound is or a stereoisomer, tautomer, or oxepane isomer thereof, or pharmaceutically acceptable salt of any of the foregoing.
Cancer type selection for weekly mTOR inhibitor administration
The method wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, renal cancer, thyroid cancer, vulvar cancer, prostate cancer, or salivary gland cancer.
Mutation-composition requirement for weekly mTOR inhibitor administration
The method wherein the cancer comprises a PIK3CA mutation, a PTEN mutation, a TSC1 mutation, a TSC2 mutation, or a combination thereof.
Dominant negative PTEN mutation characterization
The method wherein the PTEN mutation is a dominant negative mutation.
Clonality threshold of pathogenic variants for mutation-defined cancers
The method for treating or analyzing cancer characterized by more than about 95% clonality of pathogenic variants in PIK3CA, PTEN, TSC1, and TSC2, where the PTEN mutation is dominant negative.
Combination with a RAS inhibitor
RMC-5552 can be administered in combination with a RAS inhibitor, and the approach is described for delaying or preventing acquired resistance to a RAS inhibitor.
Claim coverage centers on administering the defined mTOR inhibitor compound in a weekly dosage range of about 6 mg/week to about 25 mg/week for cancer treatment. The independent claims are distinguished by cancer type selection or by specified mutation profiles in PIK3CA, PTEN, TSC1, and TSC2, with additional embodiments involving dominant negative PTEN, clonality thresholds, and combination with a RAS inhibitor.
Stated Advantages
Enables higher mTOR inhibitor dosing while reducing mucositis/stomatitis and other side effects.
RMC-6272 selectively inhibits mTORC1 over mTORC2.
Observed dose-exposure relationship above about 6 mg/week.
Tacrolimus solution, and in some embodiments dexamethasone mouthwash/ice, mitigates mucositis and stomatitis and enables higher dosing.
Delaying or preventing acquired resistance to RAS inhibitors.
Tumor regression and tumor apoptosis.
Surprising efficacy/tolerability is asserted for the described approach.
The approach is intended to address efficacy and tolerability.
The approach is associated with pathway biomarker modulation, including p4EBP1 and pS6RP, and antitumor responses.
Documented Applications
Treating a subject having cancer by administering an mTOR inhibitor compound at about 6 mg/week to about 25 mg/week.
Treating cancer selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, renal cancer, thyroid cancer, vulvar cancer, prostate cancer, and salivary gland cancer.
Treating cancer comprising a PIK3CA mutation, a PTEN mutation, a TSC1 mutation, a TSC2 mutation, or a combination thereof.
Delaying or preventing or treating acquired resistance to a RAS inhibitor.
Using the approach in combination with a RAS inhibitor.
Treating or preventing mTOR-inhibitor-associated mucositis, including stomatitis, using tacrolimus solution.
Demonstrating pharmacodynamics/efficacy related to RMC-5552 and associated tumor regression and tumor apoptosis.
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