A Phase 1, Multicenter, Open-Label, Dose Escalation Study of Tandutinib (Formerly MLN518) in Combination With Temozolomide and Bevacizumab Following Concurrent Radiation Therapy and Temozolomide in the Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme.

This is a safety study of tandutinib in combination with temozolomide and bevacizumab after people have received radiation therapy and temozolomide treatment. This study will determine the maximum safe dose of tandutinib when combined with temozolomide and bevacizumab and evaluate the safety of the combination treatment.

Start Date01 Jun 2009

Sponsor / Collaborator

Millennium Pharmaceuticals, Inc.

NCT00379080 / CompletedPhase 1/2IIT

A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma

This phase I/II trial is studying the side effects and best dose of tandutinib and to see how well it works in treating patients with recurrent or progressive glioblastoma.Tandutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Start Date01 Jan 2007

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with PDGFRα x c-Kit x FLT3 x PDGFRβ

100 Translational Medicine associated with PDGFRα x c-Kit x FLT3 x PDGFRβ

0 Patents (Medical) associated with PDGFRα x c-Kit x FLT3 x PDGFRβ

Literatures (Medical) associated with PDGFRα x c-Kit x FLT3 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.

01 Sep 2021·Modern PathologyQ1 · MEDICINE

Myeloid/lymphoid neoplasms with FLT3 rearrangement

Q1 · MEDICINE

Article

Author: Hsi, Eric D ; Medeiros, L Jeffrey ; Bose, Prithviraj ; Rogers, Heesun J ; Tang, Guilin ; Bagg, Adam ; Hasserjian, Robert P ; Bueso-Ramos, Carlos E ; Miranda, Roberto N ; Quesada, Andres E ; Wang, Wei ; Tam, Wayne ; Foucar, Kathryn ; Orazi, Attilio ; Arber, Daniel A ; Short, Nicholas J ; Nardi, Valentina ; Hurwitz, Stephanie N ; Wang, Sa A ; Wu, David

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.

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