This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O’Farrell, A.-M. Articles by Cherrington, J. M. Search for Related Content PubMed PubMed Citation Articles by O’Farrell, A.-M. Articles by Cherrington, J. M.

An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients

¹ SUGEN Inc., South San Francisco, California;
² University of Alabama at Birmingham, Birmingham, Alabama;
³ University Hospital Hamburg-Eppendorf, Hamburg, Germany;
⁴ Universitatsklinkum Muenster, Muenster, Germany;
⁵ UCLA Stem Cell Service, Los Angeles, California;
⁶ Community Cancer Care Inc., Indianapolis, Indiana;
⁷ Oregon Health and Science Cancer Institute and Portland VA Medical Center, Portland, Oregon; and
⁸ Pharmacia Corp., Bedminster, New Jersey

ABSTRACT

Purpose: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor /ß, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML.

Experimental Design: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels.

Results: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3–wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition.

Conclusions: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics.

This article has been cited by other articles:

				J. M.G. Larkin, E. L.S. Kipps, C. J. Powell, and C. Swanton Review: Systemic therapy for advanced renal cell carcinoma Therapeutic Advances in Medical Oncology, July 1, 2009; 1(1): 15 - 27. [Abstract] [PDF]

				K. Burkitt, S. Y. Chun, D. T. Dang, and L. H. Dang Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment Mol. Cancer Ther., May 1, 2009; 8(5): 1148 - 1156. [Abstract] [Full Text] [PDF]

				P. Schoffski, R. Bukowski, P. Flodgren, and A. Ravaud Tyrosine kinase inhibition in renal cell carcinoma and gastrointestinal stromal tumours: case reports Ann. Onc., May 1, 2009; 20(suppl_1): i25 - i30. [Abstract] [Full Text] [PDF]

				N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro Cancer Res., April 1, 2009; 69(7): 3032 - 3041. [Abstract] [Full Text] [PDF]

				E. Weisberg, J. Roesel, G. Bold, P. Furet, J. Jiang, J. Cools, R. D. Wright, E. Nelson, R. Barrett, A. Ray, et al. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells Blood, December 15, 2008; 112(13): 5161 - 5170. [Abstract] [Full Text] [PDF]

				M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Blood, May 1, 2008; 111(9): 4788 - 4796. [Abstract] [Full Text] [PDF]

				T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]

				G. J.L. Kaspers and C. M. Zwaan Pediatric acute myeloid leukemia: towards high-quality cure of all patients Haematologica, November 1, 2007; 92(11): 1519 - 1532. [Abstract] [Full Text] [PDF]

				L. B. Saltz, L. S. Rosen, J. L. Marshall, R. J. Belt, H. I. Hurwitz, S. G. Eckhardt, E. K. Bergsland, D. G. Haller, A. C. Lockhart, C. M. Rocha Lima, et al. Phase II Trial of Sunitinib in Patients With Metastatic Colorectal Cancer After Failure of Standard Therapy J. Clin. Oncol., October 20, 2007; 25(30): 4793 - 4799. [Abstract] [Full Text] [PDF]

				H. Schepers, D. van Gosliga, A. T. J. Wierenga, B. J. L. Eggen, J. J. Schuringa, and E. Vellenga STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells Blood, October 15, 2007; 110(8): 2880 - 2888. [Abstract] [Full Text] [PDF]

				D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, P. G. Casali, P. Beck-Peccoz, and L. Fugazzola A Novel Tyrosine-Kinase Selective Inhibitor, Sunitinib, Induces Transient Hypothyroidism by Blocking Iodine Uptake J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3531 - 3534. [Abstract] [Full Text] [PDF]

				T.-l. Gu, T. Mercher, J. W. Tyner, V. L. Goss, D. K. Walters, M. G. Cornejo, C. Reeves, L. Popova, K. Lee, M. C. Heinrich, et al. A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia Blood, July 1, 2007; 110(1): 323 - 333. [Abstract] [Full Text] [PDF]

				D. B. Shankar, J. Li, P. Tapang, J. Owen McCall, L. J. Pease, Y. Dai, R.-Q. Wei, D. H. Albert, J. J. Bouska, D. J. Osterling, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia Blood, April 15, 2007; 109(8): 3400 - 3408. [Abstract] [Full Text] [PDF]

				L. Q.M. Chow and S. G. Eckhardt Sunitinib: From Rational Design to Clinical Efficacy J. Clin. Oncol., March 1, 2007; 25(7): 884 - 896. [Abstract] [Full Text] [PDF]

				K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, January 15, 2007; 109(2): 431 - 448. [Abstract] [Full Text] [PDF]

				E. Kulimova, E. Oelmann, G. Bisping, J. Kienast, R. M. Mesters, J. Schwable, F. Hilberg, G. J. Roth, G. Munzert, M. Stefanic, et al. Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors Mol. Cancer Ther., December 1, 2006; 5(12): 3105 - 3112. [Abstract] [Full Text] [PDF]

				P. Schoffski, H. Dumez, P. Clement, A. Hoeben, H. Prenen, P. Wolter, S. Joniau, T. Roskams, and H. Van Poppel Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review Ann. Onc., August 1, 2006; 17(8): 1185 - 1196. [Abstract] [Full Text] [PDF]

				R. J. Motzer, B. I. Rini, R. M. Bukowski, B. D. Curti, D. J. George, G. R. Hudes, B. G. Redman, K. A. Margolin, J. R. Merchan, G. Wilding, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA, June 7, 2006; 295(21): 2516 - 2524. [Abstract] [Full Text] [PDF]

				B. W. Parcells, A. K. Ikeda, T. Simms-Waldrip, T. B. Moore, and K. M. Sakamoto FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia Stem Cells, May 1, 2006; 24(5): 1174 - 1184. [Abstract] [Full Text] [PDF]

				H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF]

				S. Faivre, C. Delbaldo, K. Vera, C. Robert, S. Lozahic, N. Lassau, C. Bello, S. Deprimo, N. Brega, G. Massimini, et al. Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer J. Clin. Oncol., January 1, 2006; 24(1): 25 - 35. [Abstract] [Full Text] [PDF]

				R. J. Motzer, M. D. Michaelson, B. G. Redman, G. R. Hudes, G. Wilding, R. A. Figlin, M. S. Ginsberg, S. T. Kim, C. M. Baum, S. E. DePrimo, et al. Activity of SU11248, a Multitargeted Inhibitor of Vascular Endothelial Growth Factor Receptor and Platelet-Derived Growth Factor Receptor, in Patients With Metastatic Renal Cell Carcinoma J. Clin. Oncol., January 1, 2006; 24(1): 16 - 24. [Abstract] [Full Text] [PDF]

				R. E. Gale, R. Hills, A. R. Pizzey, P. D. Kottaridis, D. Swirsky, A. F. Gilkes, E. Nugent, K. I. Mills, K. Wheatley, E. Solomon, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia Blood, December 1, 2005; 106(12): 3768 - 3776. [Abstract] [Full Text] [PDF]

				H. S. Rugo, R. S. Herbst, G. Liu, J. W. Park, M. S. Kies, H. M. Steinfeldt, Y. K. Pithavala, S. D. Reich, J. L. Freddo, and G. Wilding Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results J. Clin. Oncol., August 20, 2005; 23(24): 5474 - 5483. [Abstract] [Full Text] [PDF]

				D. E. Lopes de Menezes, J. Peng, E. N. Garrett, S. G. Louie, S. H. Lee, M. Wiesmann, Y. Tang, L. Shephard, C. Goldbeck, Y. Oei, et al. CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia Clin. Cancer Res., July 15, 2005; 11(14): 5281 - 5291. [Abstract] [Full Text] [PDF]

				P. E. Huber, M. Bischof, J. Jenne, S. Heiland, P. Peschke, R. Saffrich, H.-J. Grone, J. Debus, K. E. Lipson, and A. Abdollahi Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy Cancer Res., May 1, 2005; 65(9): 3643 - 3655. [Abstract] [Full Text] [PDF]

				J. M. Cherrington Taking Biological Targeted Agents into Clinical Trial Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 23 - 29. [Full Text] [PDF]

				W. Fiedler, H. Serve, H. Dohner, M. Schwittay, O. G. Ottmann, A.-M. O'Farrell, C. L. Bello, R. Allred, W. C. Manning, J. M. Cherrington, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease Blood, February 1, 2005; 105(3): 986 - 993. [Abstract] [Full Text] [PDF]

				W. L. Carroll On target for advances in the treatment of childhood acute lymphoblastic leukemia Blood, January 15, 2005; 105(2): 438 - 439. [Full Text] [PDF]

				P. Brown, M. Levis, S. Shurtleff, D. Campana, J. Downing, and D. Small FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression Blood, January 15, 2005; 105(2): 812 - 820. [Abstract] [Full Text] [PDF]

				J. Cools, N. Mentens, P. Furet, D. Fabbro, J. J. Clark, J. D. Griffin, P. Marynen, and D. G. Gilliland Prediction of Resistance to Small Molecule FLT3 Inhibitors: Implications for Molecularly Targeted Therapy of Acute Leukemia Cancer Res., September 15, 2004; 64(18): 6385 - 6389. [Abstract] [Full Text] [PDF]

				J. Jiang, J. G. Paez, J. C. Lee, R. Bo, R. M. Stone, D. J. DeAngelo, I. Galinsky, B. M. Wolpin, A. Jonasova, P. Herman, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML Blood, September 15, 2004; 104(6): 1855 - 1858. [Abstract] [Full Text] [PDF]