AXL kinase inhibitors and use of the same
Inventors
Siddiqui-Jain, Adam • Warner, Steven L. • Flynn, Paul • Bearss, David J. • Foulks, Jason Marc • TOMIMATSU, NOZOMI • FUJIMURA, KEN • Umehara, Hiroki • NONOYAMA, Akihito • Kiguchiya, Akihito
Assignees
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Publication Number
US-11400091-B2
Publication Date
2022-08-02
Expiration Date
Abstract
Tartrate salts of the compound of structure (I), crystalline forms thereof, and therapeutic applications thereof for treating solid tumors (e.g., advanced solid tumor) or hematopoietic cancers. Also provided herein are methods for synthesizing the tartrate salts and the crystalline forms thereof.
Core Innovation
The invention relates to cancer treatment using a crystalline form of a tartrate salt of the compound of structure (I). The crystalline tartrate salt is used to treat cancer in a subject in need thereof, and the cancer is defined as a listed solid tumor panel or a listed hematological cancer panel. The disclosure further characterizes the compound of structure (I) in relation to AXL inhibition, including representative metabolites and exposure information.
The document also describes tartrate salt crystalline forms, including tartrate stoichiometry and crystalline Form A, together with metabolite exposure and parent exposure using metabolite PK ratios. It links the tartrate salt form to pharmacokinetics, safety pharmacology, ADME/PK characterization, biomarker assessments, and treatment selection based on cytochrome P450 polymorphisms. Pharmaceutical compositions comprising the crystalline tartrate salt form and a pharmaceutically acceptable carrier or diluent are also described.
The disclosure includes treatment-cycle structures, oral daily dosing, and combination treatment concepts with other therapeutic agents, including immunotherapy and immune checkpoint inhibitors, targeted kinase inhibitors, chemotherapy, antimetabolites, and the BCL-2 inhibitor venetoclax. It also describes cardiovascular safety, weak hERG inhibition, receptor panel screening, and early clinical evaluation in advanced solid tumors.
Claims Coverage
The independent claim coverage centers on administering a therapeutically effective amount of a crystalline form of a tartrate salt of the compound of structure (I) for treating cancer, with the cancer limited to explicit solid tumor and hematological cancer panels. Dependent refinements add tartrate stoichiometry, crystalline Form A, treatment-cycle scheduling, oral daily dosing, and combination therapy options. The consolidated claim set contains six inventive features.
Crystalline tartrate salt treatment for cancer
A method of treating cancer by administering to a subject in need thereof a therapeutically effective amount of a crystalline form of a tartrate salt of the compound of structure (I).
Solid tumor panel limitation
The cancer is a solid tumor selected from non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), ovarian cancer, melanoma, breast carcinoma, neuroendocrine carcinoma, prostate adenocarcinoma, cholangiocarcinoma, uterine carcinoma, pancreatic cancer, lung adenocarcinoma, lung squamous cell carcinoma, urethral cancer, urothelial cancer, ductal cancer, endometrial cancer, or renal carcinoma.
Hematological cancer panel limitation
The cancer is a hematological cancer selected from multiple myeloma, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, chronic lymphogenous leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, or non-Hodgkin's lymphoma.
Tartrate salt crystalline form with specified molar ratio
The crystalline form is a tartrate salt crystalline form with a tartaric acid to compound of structure (I) molar ratio of about 2:1.
Crystalline Form A
The crystalline form includes crystalline Form A.
Combination therapy with enumerated additional therapeutic agents
One or more other therapeutic agents are selected from a listed group including immunotherapy agents and immune checkpoint inhibitors, targeted kinase inhibitors, cell-cycle/CDK inhibitors, specific antibody inhibitors, chemotherapy and platinum-based drugs, antimetabolites, and the BCL-2 inhibitor venetoclax.
The claims are directed to treatment of cancer with a crystalline tartrate salt of the compound of structure (I), limited to explicitly listed solid tumors or hematological cancers. The broader claim set further refines the crystalline form, tartrate stoichiometry, and combination therapy with specified therapeutic agents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer in a subject by administering a therapeutically effective amount of a crystalline form of a tartrate salt of the compound of structure (I), where cancer is limited to the listed solid-tumor panel or the listed hematological-cancer panel.
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