TY - JOUR
T1 - Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation
AU - Fathi, Amir T.
AU - Blonquist, Traci M.
AU - Hernandez, Daniela
AU - Amrein, Philip C.
AU - Ballen, Karen K.
AU - McMasters, Malgorzata
AU - Avigan, David E.
AU - Joyce, Robin
AU - Logan, Emma K.
AU - Hobbs, Gabriela
AU - Brunner, Andrew M.
AU - Joseph, Christelle
AU - Perry, Ashley M.
AU - Burke, Meghan
AU - Behnan, Tanya
AU - Foster, Julia
AU - Bergeron, Meghan K.
AU - Moran, Jenna A.
AU - Ramos, Aura Y.
AU - Som, Tina T.
AU - Rae, Jessica
AU - Fishman, Kaitlyn M.
AU - McGregor, Kristin L.
AU - Connolly, Christine
AU - Neuberg, Donna S.
AU - Levis, Mark J.
N1 - Funding Information:
Amir T. Fathi has participated in advisory boards for Agios and Pfizer; has provided consulting for Seattle Genetics, Amgen, Medi-mmune, and Celgene; and has received grant support to conduct clinical trials from Takeda, Celgene, Exelixis, and Seattle Genetics. Traci M. Blonquist has received a salary partly supported by a grant from the pharmaceutical industry paid to the Dana-Farber Cancer Institute pediatric acute lymphoblastic leukemia consortium. Mal-gorzata McMasters reports that her spouse is employed by Merck & Co, Inc, and Vertex Pharmaceuticals. Gabriela Hobbs has received grant support to conduct clinical trials from Bayer, Kura, and Stem-line. Andrew M. Brunner reports clinical trial support from Cel-gene, Takeda, and Novartis. Mark J. Levis has provided consulting for Novartis, Daiichi, Astellas, Arog, and Agios and reports grants from Novartis and Astellas.
Publisher Copyright:
© 2017 American Cancer Society
PY - 2018/1/15
Y1 - 2018/1/15
N2 - BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)–mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD–altered tyrosine kinases. Cancer 2018;124:306-14.
AB - BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)–mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD–altered tyrosine kinases. Cancer 2018;124:306-14.
KW - FMS-like tyrosine kinase 3 (FLT3)
KW - acute myeloid leukemia
KW - resistance mutations
KW - targeted therapies
KW - tyrosine kinase inhibitors
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U2 - 10.1002/cncr.31038
DO - 10.1002/cncr.31038
M3 - Article
C2 - 28960265
AN - SCOPUS:85030641428
SN - 0008-543X
VL - 124
SP - 306
EP - 314
JO - Cancer
JF - Cancer
IS - 2
ER -