A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

Start Date20 Mar 2025

Sponsor / Collaborator

City of Hope National Medical Center

[+1]

100 Clinical Results associated with PDGFRα x c-Kit x CSF-1R x PDGFRβ

100 Translational Medicine associated with PDGFRα x c-Kit x CSF-1R x PDGFRβ

0 Patents (Medical) associated with PDGFRα x c-Kit x CSF-1R x PDGFRβ

Literatures (Medical) associated with PDGFRα x c-Kit x CSF-1R x PDGFRβ

01 Oct 2022·Bioorganic & Medicinal Chemistry Letters

Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors

Article

Author: Smith, Bryan D ; Caldwell, Timothy M ; Hood, Molly M ; Patt, William C ; Flynn, Daniel L ; Kaufman, Michael D ; Bulfer, Stacie L ; Vogeti, Subha ; Lu, Wei-Ping ; Vogeti, Lakshminarayana ; Wise, Scott C ; Le Bourdonnec, Bertrand ; Samarakoon, Thiwanka ; Mi Ahn, Yu ; Yates, Karen M

Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-β, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.

01 Nov 2021·Molecular Cancer TherapeuticsQ2 · MEDICINE

Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages

Q2 · MEDICINE

Article

Author: Sharma, Maitreyi ; Kaufman, Michael D. ; Leary, Cynthia B. ; Davis, Lara E. ; Caldwell, Timothy M. ; Lu, Wei-Ping ; Ruiz-Soto, Rodrigo ; Vogeti, Subha ; Smith, Bryan D. ; Flynn, Daniel L. ; Vogeti, Lakshminarayana ; Wilky, Breelyn A. ; Ahn, Yu Mi ; Wise, Scott C. ; Tan, Gege

AbstractMacrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.

02 Oct 2020·Expert Review of Clinical PharmacologyQ2 · MEDICINE

Overview of the clinical use of erdafitinib as a treatment option for the metastatic urothelial carcinoma: where do we stand

Q2 · MEDICINE

Review

Author: Galli, Ilaria Camilla ; Roviello, Giandomenico ; Bortoletti, Carlotta ; D’Angelo, Alberto ; Bagby, Stefan

INTRODUCTIONErdafitinib is the first orally administered pan-fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the Food and Drug Administration (FDA).AREAS COVEREDSpecifically binding to FGFR family (FGFR-1 to FGFR-4), erdafitinib leads to reduced cell signaling and cellular apoptosis. Coupled with the ability to bind to vascular endothelial growth factor 2 (VEGFR-2), KIT, Fms-related tyrosine kinase 4 (FLT4), platelet-derived growth factor receptor α and β (PDGFR-α and PDGFR-β), RET and colony-stimulating factor 1 receptor (CSF-1 R), erdafitinib has further reported antitumor features causing cell killing.EXPERT OPINIONIn this review, we provide a comprehensive overview of erdafitinib chemical structure, pharmacologic properties, and current knowledge of clinical efficacy in the treatment of locally advanced or metastatic urothelial carcinoma. This treatment, recently approved in the U.S., is available for adult patients harboring FGFR2/FGFR3 genetic alterations who progressed within 12 months of an adjuvant or neoadjuvant chemotherapy regimen including platinum or progressed during or after prior a chemotherapy regimen including platinum.

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