US-12616683-B2 - Combination therapy for the treatment of gastrointestinal stromal tumors

Abstract

The present disclosure relates to the use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, or a pharmaceutically acceptable salt thereof, in combination with a MAPKAP kinase inhibitor for the treatment of cancers, including c-KIT-mediated cancers, such as GIST.

Inventors

• Daniel L. Flynn
• Bryan D. Smith
• Anu Gupta

Assignees

• DECIPHERA PHARMACEUTICALS, LLC

Dates

Publication Date

20260505

Application Date

20240410

Claims (1)

1. 1 . A method of treating a solid tumor in an imatinib resistant patient, comprising: administering to the patient an effective amount of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, or a pharmaceutically acceptable salt thereof; and administering to the patient an effective amount of a MAPKAP kinase inhibitor selected from the group consisting of trametinib, binimetinib, cobimetinib, and ulixertinib, wherein the solid tumor is gastrointestinal stromal tumor (GIST).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is divisional of U.S. application Ser. No. 16/943,821 filed Jul. 30, 2020, which is a continuation of International Application Number PCT/US2019/016148 filed Jan. 31, 2019, which claims priority to U.S. Ser. No. 62/624,448 filed Jan. 31, 2018, the contents of which are incorporated herein by reference in their entirety. BACKGROUND c-KIT (also known as KIT, CD117, and stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that acts as a type-III receptor. The c-KIT proto-oncogene, located on chromosome 4q11-21, encodes the c-KIT receptor, whose ligand is the stem cell factor (SCF, steel factor, kit ligand, mast cell growth factor). The receptor has tyrosine-protein kinase activity, and binding of the ligand SCF leads to the autophosphorylation of c-KIT and its association with substrates such as phosphatidylinositol 3-kinase (PI3K). Tyrosine phosphorylation by protein tyrosine kinases is of particular importance in cellular signaling and can mediate signals for major cellular processes, such as proliferation, survival, differentiation, apoptosis, attachment, invasiveness and migration. The role of c-KIT expression and activity has been studied in hematologic and solid tumors, such as acute leukemias and gastrointestinal stromal tumors (GISTs). Most GISTs have primary activating mutations in the genes encoding the closely related RTKs c-KIT (75-80% of GIST) or PDGFRα (8% of the non-c-KIT mutated GIST), and gain-of-function mutations of the c-KIT gene and the expression of constitutively phosphorylated c-KIT are found in many GIST. The majority of primary GIST-causing c-KIT mutations affect the juxtamembrane (JM) region of the protein encoded by exon 11 and consist of in-frame deletions or insertions, or missense mutations (i.e., V560D). c-KIT exon 11 mutations have been identified as primary mutations in approximately 65% of GISTs. Such JM domain mutations disrupt the autoinhibition mechanism of c-KIT kinase, leading to constitutive kinase activity and cell-transforming events causative of GIST. Other primary GIST-causing c-KIT mutations are located in exon 9 (AY501-502 duplication/insertion, 8%), exon 13 (mutation, 1%), and exon 17 (mutation, 1%). The clinical importance of c-KIT expression in malignant tumors was demonstrated in studies with Gleevec® (imatinib mesylate, STI571 (signal transduction inhibitor number 571), Novartis Pharma AG Basel, Switzerland), which specifically inhibits tyrosine kinase receptors. Moreover, a clinically relevant breakthrough has been the finding of anti-tumor effects of this compound in GIST, a group of tumors regarded as being generally resistant to conventional chemotherapy. However, while major responses were seen after first-line treatment of GIST with Gleevec®, an inhibitor of c-KIT, and a substantial number of patients with metastatic and/or inoperable GIST benefit from treatment with Gleevec®, complete tumor remissions are rare, and about 50% of patients experience disease recurrence within two years of treatment. It has also been reported that a combination of the c-KIT inhibitor imatinib and the MEK kinase inhibitor MEK162 resulted in an increased growth suppression in vitro and tumor regression in vivo in various GIST cancer cell lines compared to treatment with either single agent. GIST most often become Gleevec® resistant, and molecularly targeted small molecule therapies that target c-KIT secondary mutations remain elusive. GIST patients who relapse after treatment with Gleevec® or Sutent® have disease still driven by c-KIT mutations. These secondary mutations occur on the same alleles as the primary JM-region mutation, and thus represent even more aggressive activated forms of c-KIT than the original primary mutation. These secondary mutants of c-KIT identified in GIST lead to acquired drug resistance. Secondary mutations are found in the ATP binding pocket (exon 13, i.e. K642E, V654A; exon 14, i.e. T670I), and activation loop (exon 17, i.e. N822K, D816H, D816V, D820A; exon 18 A829P). These various secondary c-KIT mutations have been reported. Sunitinib malate (Sutent™, Pfizer) is an inhibitor of multiple RTKs, notably in this context, c-KIT and PDGFRα, and has been shown to be effective against certain imatinib-resistant c-KIT mutants, such as the ATP-binding pocket mutants V654A and T670I. Certain Gleevec®-resistant mutants are also resistant to sunitinib, such as D816H and D816V which are located in the activation loop of the c-KIT catalytic domain encoded by exon 17. Median survival after progression due to Gleevec®-resistance remains relatively short. It has been demonstrated that complex, multiple secondary c-KIT mutations can arise and vary within individual patients, such variation in mutational status of c-KIT being demonstrated by biopsy samples obtained from different progressing metastases within each patient. The complex c-KIT mutational heterogeneity within individual