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{{Chembox {{Chembox
| Verifiedfields = changed
⚫ | verifiedrevid = 434316721
| Watchedfields = changed
⚫ | verifiedrevid = 443232265
| ImageFile = Crenolanib.svg | ImageFile = Crenolanib.svg
| ImageSize = 200px | ImageSize = 200px
| IUPACName = 1-(2-{5--1''H''-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine | IUPACName = 1-(2-<nowiki/>{5--1''H''-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine
| OtherNames = CP-868,596; ARO 002 | OtherNames = CP-868,596; AR-868,596-26
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| IUPHAR_ligand = 7882
⚫ | CASNo = 670220-88-9
| CASNo_Ref = {{cascite|correct|??}}
⚫ | PubChem = 10366136
⚫ | CASNo = 670220-88-9
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⚫ | PubChem = 10366136
| ChEBI = 145365
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 2105728
| ChEMBL1_Ref = {{ebicite|changed|EBI}}
| ChEMBL1 = 2146086
| KEGG = D10102
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| ChemSpiderID = 8541584 | ChemSpiderID = 8541584
| SMILES = O(c5cc4ncn(c1nc3c(cc1)cccc3N2CCC(N)CC2)c4cc5)CC6(COC6)C | SMILES = O(c5cc4ncn(c1nc3c(cc1)cccc3N2CCC(N)CC2)c4cc5)CC6(COC6)C
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'''Crenolanib''' besylate (CP-868,596-26 or AR-868,596-26, 4-piperidinamine, 1--1H-benzimidazol-1-yl]- 8-quinolinyl]-, {{chem name|monobenzenesulfonate}}) is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including ] (AML),<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01657682?term=aml%2C+crenolanib&rank=1 |title=A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref><ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01522469?term=aml%2C+crenolanib&rank=2 |title=Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref> ] (GIST),<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01243346?term=gist%2C+crenolanib&rank=1 |title=Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref> and ].<ref>{{cite web|url=http://www.clinicaltrials.gov/ct2/show/NCT01393912?term=glioma%2C+crenolanib&rank=1 |title=PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma - Full Text View |publisher=ClinicalTrials.gov |access-date=2014-04-08}}</ref>
'''Crenolanib''' is an ] being developed by AROG Pharmaceuticals, LLC for the treatment of certain types of ]. Crenolanib is a ] that acts by specifically inhibiting the receptor tyrosine kinases ] and ].
Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of ] and mutant isoforms of class III receptor tyrosine kinases (RTK) ] (FMS-like Tyrosine Kinase 3), ] α (Platelet-Derived Growth Factor Receptor), and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to ] active kinases with the ‘DFG in’ conformation ].<ref>{{cite web |url=http://www.gistsupport.org/media/GISTS_2012/POSTER--AROG--AACR%202012_type%20I%20vs%20type%20II%20poster.pdf |title=CRENOLANIB, A NOVEL TYPE I, MUTANT -SPECIFIC INHIBITOR OF CLASS III RECEPTOR TYROSINE KINASES, PREFERENTIALLY BINDS TO PHOSPHORYLATED KINASES |author1=A. Ramachandran |author2=H. Marshall |author3=V. Jain |publisher=gistsupport.org |access-date=2014-04-08}}</ref>


== Contents == == Background ==
Type III ], including ], ] and ], have been directly implicated in the ] of ], ], and ].<ref>{{cite journal |doi=10.1016/j.cell.2010.06.011 |title=Cell Signaling by Receptor Tyrosine Kinases |year=2010 |last1=Lemmon |first1=Mark A. |last2=Schlessinger |first2=Joseph |journal=Cell |volume=141 |issue=7 |pages=1117–34 |pmid=20602996 |pmc=2914105}}</ref>
Crenolanib is an orally bioavailable, selective small molecule inhibitor of the ] ]) tyrosine kinase, inhibiting both ] and ] at picomolar concentrations.


] ] (RTK), including ], PDGFRα and PDGFRβ, have been directly implicated in the pathogenesis of ], ], and ].<ref>{{cite journal | doi= 10.1016/j.cell.2010.06.011 |pmid=20602996 | title= Cell Signaling by Receptor Tyrosine Kinases | year= 2010 | last1= Lemmon | first1= Mark A. | last2= Schlessinger | first2= Joseph | journal= Cell | volume= 141 | issue= 7 | pages= 1117–1134 | pmc= 2914105}}</ref> The PDGF/PDGFR pathway is the primary driver of ] in several ] including ] (GIST),<ref>{{cite journal | doi= 10.1200/JCO.2003.04.190 | pmid = 14645423 | title= Kinase Mutations and Imatinib Response in Patients with Metastatic Gastrointestinal Stromal Tumor | year= 2003 | last1= Heinrich | first1= M. C. | journal= Journal of Clinical Oncology | volume= 21 | issue= 23 | pages= 4342–4349 | last2= Corless | first2= CL | last3= Demetri | first3= GD | last4= Blanke | first4= CD | last5= Von Mehren | first5= M | last6= Joensuu | first6= H | last7= McGreevey | first7= LS | last8= Chen | first8= CJ | last9= Van Den Abbeele | first9= AD}}</ref> both adult<ref>{{cite journal | doi= 10.1016/j.ccr.2009.12.020 | pmid = 20129251 | title= Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1 | year= 2010 | last1= Verhaak | first1= Roel G.W. | last2= Hoadley | first2= Katherine A. | last3= Purdom | first3= Elizabeth | last4= Wang | first4= Victoria | last5= Qi | first5= Yuan | last6= Wilkerson | first6= Matthew D. | last7= Miller | first7= C. Ryan | last8= Ding | first8= Li | last9= Golub | first9= Todd | journal= Cancer Cell | volume= 17 | pages= 98–110 | issue= 1 | pmc= 2818769}}</ref> and pediatric ],<ref>{{cite journal | doi= 10.1200/JCO.2009.26.7252 |pmid = 20479398 | title= Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences with the Adult Disease | year= 2010 | last1= Paugh | first1= B. S. | last2= Qu | first2= C. | last3= Jones | first3= C. | last4= Liu | first4= Z. | last5= Adamowicz-Brice | first5= M. | last6= Zhang | first6= J. | last7= Bax | first7= D. A. | last8= Coyle | first8= B. | last9= Barrow | first9= J. | journal= Journal of Clinical Oncology | volume= 28 | issue= 18 | pages= 3061–3068 | pmc= 2903336}}</ref> as well as a subset of ] (NSCLC).<ref>{{cite journal | doi= 10.4161/cbt.8.21.9764 | pmid = 19755855 | title= Amplification of chromosomal segment 4q12 in non-small cell lung cancer | year= 2009 | last1= Ramos | first1= Alex H. | last2= Dutt | first2= Amit | last3= Mermel | first3= Craig | last4= Perner | first4= Sven | last5= Cho | first5= Jeonghee | last6= Lafargue | first6= Christopher J. | last7= Johnson | first7= Laura A. | last8= Stiedl | first8= Ann-Cathrin | last9= Tanaka | first9= Kumiko E. | journal= Cancer Biology & Therapy | volume= 8 | issue= 21 | pages= 2042–2050 | pmc= 2833355}}</ref> These malignancies often respond to treatment with non-selective inhibitors of ] like ] and ]. Crenolanib is a 100-500-fold more potent inhibitor of PDGFRα and PDGFRβ than other commercially available TKIs. It is currently being developed as an ] in cancers. Mutations of ] comprise one of the most frequently identified types of genetic alterations in acute myeloid leukemia.<ref name="ncbi.nlm.nih.gov">{{cite journal|title=Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications |date=2011-04-01 |pmc=3076284 |pmid=21453545 |doi=10.1186/1756-8722-4-13 |volume=4 |journal=J Hematol Oncol |pages=13 | last1 = Takahashi | first1 = S |doi-access=free }}</ref><ref>{{cite journal|title=Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia|journal=New England Journal of Medicine |volume=368 |issue=22 |year=2013 |pages=2059–2074 |issn=0028-4793 |doi=10.1056/NEJMoa1301689 |pmid=23634996 |pmc=3767041|author1=Cancer Genome Atlas Research Network |last2=Ley |first2=T. J. |last3=Miller |first3=C. |last4=Ding |first4=L. |last5=Raphael |first5=B. J. |last6=Mungall |first6=A. J. |last7=Robertson |first7=A. |last8=Hoadley |first8=K. |last9=Triche Jr |first9=T. J. |last10=Laird |first10=P. W. |last11=Baty |first11=J. D. |last12=Fulton |first12=L. L. |last13=Fulton |first13=R. |last14=Heath |first14=S. E. |last15=Kalicki-Veizer |first15=J. |last16=Kandoth |first16=C. |last17=Klco |first17=J. M. |last18=Koboldt |first18=D. C. |last19=Kanchi |first19=K. L. |last20=Kulkarni |first20=S. |last21=Lamprecht |first21=T. L. |last22=Larson |first22=D. E. |last23=Lin |first23=L. |last24=Lu |first24=C. |last25=McLellan |first25=M. D. |last26=McMichael |first26=J. F. |last27=Payton |first27=J. |last28=Schmidt |first28=H. |last29=Spencer |first29=D. H. |last30=Tomasson |first30=M. H. |display-authors=29 }}</ref> Approximately one-third of ] patients present with a mutation in this gene.<ref name="hindawi.com">{{cite journal|title=The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias |date=2013 |publisher=Hindawi.com |doi=10.1155/2013/275760 |doi-access=free |last1=Testa |first1=Ugo |last2=Pelosi |first2=Elvira |journal=Leukemia Research and Treatment |volume=2013 |pages=1–14 |pmid=23936658 |pmc=3725705 }}</ref> The majority of these mutations result in constitutive activation of downstream signaling pathways and aberrant cell growth.<ref name="ncbi.nlm.nih.gov"/> Mutations in FLT3 have also been reported in ] (ALL)<ref>{{cite journal|title= Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children|date=2014-01-24 |pmid=10233379 |doi=10.1111/j.1365-2141.1999.01284.x |volume=105 |issue=1 |journal=Br. J. Haematol. |pages=155–62 | last1 = Xu | first1 = F | last2 = Taki | first2 = T | last3 = Yang | first3 = HW | last4 = Hanada | first4 = R | last5 = Hongo | first5 = T | last6 = Ohnishi | first6 = H | last7 = Kobayashi | first7 = M | last8 = Bessho | first8 = F | last9 = Yanagisawa | first9 = M | last10 = Hayashi | first10 = Y|s2cid=40898615 | doi-access = free }}</ref> and ] (MDS).<ref>{{cite journal|title= Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines|date=2014-01-24 |pmid=9324277 |volume=11 |issue=10 |journal=Leukemia |pages=1605–9 | last1 = Yokota | first1 = S | last2 = Kiyoi | first2 = H | last3 = Nakao | first3 = M | last4 = Iwai | first4 = T | last5 = Misawa | first5 = S | last6 = Okuda | first6 = T | last7 = Sonoda | first7 = Y | last8 = Abe | first8 = T | last9 = Kahsima | first9 = K | last10 = Matsuo | first10 = Y | last11 = Naoe | first11 = T|doi=10.1038/sj.leu.2400812 |s2cid=12003642 | doi-access = }}</ref>


Activating mutations in ] have been detected in 5-12% of ].<ref>{{cite journal |doi=10.1126/science.1079666 |title=PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors |year=2003 |last1=Heinrich |first1=M. C. |journal=Science |volume=299 |issue=5607 |pages=708–10 |pmid=12522257 |last2=Corless |first2=CL |last3=Duensing |first3=A |last4=McGreevey |first4=L |last5=Chen |first5=CJ |last6=Joseph |first6=N |last7=Singer |first7=S |last8=Griffith |first8=DJ |last9=Haley |first9=A |last10=Town |first10=A |last11=Demetri |first11=GD |last12=Fletcher |first12=CD |last13=Fletcher |first13=JA|s2cid=11725958 }}</ref> Fusion of ] has been found to be responsible for hematological malignances like ].<ref name="Ref6">{{cite book |doi=10.1016/S0065-230X(06)97011-0 |pmid=17419949 |title=PDGF Receptors as Targets in Tumor Treatment |series=Advances in Cancer Research |year=2007 |last1=Östman |first1=Arne |last2=Heldin |first2=Carl‐Henrik |isbn=9780120066971 |volume=97 |pages=247–274}}</ref> The amplification of ]q12, the site of the ] gene{{Citation needed|date=September 2014}}, has been identified in 13-29% of adult ]{{Citation needed|date=September 2014}} and in 29% to 36% of diffuse intrinsic ] gliomas (]){{Citation needed|date=September 2014}}, a subset of high-grade gliomas (HGG) in pediatric patients. Activation of ], a third member of the type III RTK family, has been implicated in the development of ] due to the fusion of ] with the TEL gene.<ref name="Ref6" /> Furthermore, ] translocation to the COL1A1 gene locus has been identified to be responsible for ] (DFSP).<ref name="Ref6" /> In cancer cells, ] promotes tumor development and migration via proto-oncogenic downstream mediators like ] and ]{{citation needed|date=September 2014}}. In ] ], ] activation leads to local tissue invasion, production and secretion of ], and elevated intratumoral interstitial pressure{{citation needed|date=September 2014}}. In stromal ], ] activation mediates vascular stability.<ref name="Ref6" /> Thus, either FLT3 or ]/] pathway is the primary driver of ] in the above malignancies and can be targeted by crenolanib therapy{{citation needed|date=September 2014}}.

== Mechanism ==

===]: wild-type and mutant===
Crenolanib inhibits both wild type ] and its constitutively active mutations. In vitro studies have shown that crenolanib has low ] for the ] enzyme with constitutively activating internal tandem duplication (ITD) mutations and ] domain (TKD) mutations, D835H and D835Y, as compared to wild type. Crenolanib tightly binds to ]-ITD, ]-D835H and ]-D835Y with ] of 0.74 nM, 0.4 nM, and 0.18 nM, respectively.<ref name="Ref7">{{cite journal |doi=10.1158/1538-7445.AM2012-3683 |title=Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases |year=2012 |last1=Muralidhara |first1=C. |last2=Ramachandran |first2=A. |last3=Jain |first3=V. K. |journal=Cancer Research |volume=72 |issue=8 Supplement |page=3683}}</ref> Crenolanib inhibits the phosphorylation of the ]-ITD receptor in transfected TF-1 cells and the ]-D835Y TKD mutation in transfected Ba/F3 cells at nanomolar ] concentrations of 1.3 nM and 8.8 nM, respectively.<ref name="Ref8">{{cite journal |doi=10.1158/1538-7445.am2012-3660 |title=Abstract 3660: Crenolanib: A next generation FLT3 inhibitor |year=2012 |last1=Galanis |first1=A. |last2=Rajkhowa |first2=T. |last3=Muralidhara |first3=C. |last4=Ramachandran |first4=A. |last5=Levis |first5=M. |journal=Cancer Research |volume=72 |issue=8 Supplement |page=3660}}</ref> ] experiments performed in the ] ]-ITD positive cell line show that crenolanib inhibits downstream signaling of ] at a concentration of 10 nM.<ref name="Ref8" /> ] measurements of crenolanib ] evaluated in the ]-ITD expressing cell lines ] and ], showed that crenolanib is toxic at ] concentrations of 7 nM and 8 nM, respectively.<ref name="Ref8" />

===PDGFRα: wild-type and mutant===
Crenolanib has been shown to inhibit ] with an ] of 0.4&nbsp;ng/mL in porcine aortic epithelial cell lines. In ] cells expressing ], crenolanib inhibited the phosphorylation of wild type ] at an ] of 10 nM.<ref name="Ref9">{{cite journal |doi=10.1158/1078-0432.CCR-12-0625 |title=Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors |year=2012 |last1=Heinrich |first1=M. C. |last2=Griffith |first2=D. |last3=McKinley |first3=A. |last4=Patterson |first4=J. |last5=Presnell |first5=A. |last6=Ramachandran |first6=A. |last7=Debiec-Rychter |first7=M. |journal=Clinical Cancer Research |volume=18 |issue=16 |pages=4375–84 |pmid=22745105|doi-access=free }}</ref> Additionally, crenolanib completely blocked ] phosphorylation and downstream ] signaling at a concentration between 0.1 and 1 uM in Ink4a/Arf-/- mouse ] transfected to stably co-express both human ] and ] AA.<ref>{{cite journal |doi=10.1158/1538-7445.am2011-1111 |title=Abstract 1111: Preclinical evaluation of CP868,596, a novel PDGFR Inhibitor for treatment of glioblastoma |year=2011 |last1=Yang |first1=X.-L. |last2=Mashimo |first2=T. |last3=Su |first3=Y. |last4=Vemireddy |first4=V. |last5=Guntipalli |first5=P. |last6=Ramachandran |first6=A. |last7=Chaudhary |first7=P. |last8=Mickey |first8=B. |last9=Hatanpaa |first9=K. |last10=Maher |first10=E. |last11=Bachoo |first11=R. M. |journal=Cancer Research |volume=71 |issue=8 Supplement |page=1111}}</ref> The ] cell line H1703, which is reported to have amplification of both ] (4q12) and PDGFC (4q32) genes on chromosome 4, and also overexpress ], was sensitive to crenolanib with an ] of ~80 nM.<ref>{{cite journal |doi=10.1158/1538-7445.am2011-3601 |title=Abstract 3601: CP-868,596, a highly potent and selective PDGFR TKI inhibits growth of PDGFR -driven lung cancer cells |year=2011 |last1=Peyton |first1=M. |last2=Chaudhary |first2=P. |last3=Ramachandran |first3=A. |last4=Minna |first4=J. |journal=Cancer Research |volume=71 |issue=8 Supplement |page=3601}}</ref> In ] cells expressing an activating exon 18 (D842V) ] mutation, crenolanib was effective at an ] of 6nM and IC90 of 25nM. In addition, crenolanib also inhibited phosphorylation of the double mutants ] (V561D + D842V and T674I + D842V).<ref name="Ref9" />

===PDGFRβ: wild-type===
Crenolanib has been shown to inhibit ] with an ] of 0.8&nbsp;ng/mL in porcine aortic epithelial cell lines. Crenolanib inhibits the ability of recombinant ] to phosphorylate a synthetic tyrosine substrate (]-tyrosine), with an ] of 0.4&nbsp;ng/mL. Evaluation of the antitumor activity of crenolanib in a genetically engineered BSG DIPG mouse model showed that it is highly selective for ] with an ] of 10 nM when measured by BrdU assay and 1.25 uM by ].

===C-Kit: wild-type and mutant===
Crenolanib has been shown to have ] and Kd values of 67 nM and 78 nM, respectively, for wild type ] in in vitro assays{{citation needed|reason=This claim doesn't have a citation. Reference 14 does NOT have actual Kd... it just says "still being determined"|date=September 2014}}. Similar assays show that crenolanib inhibits ] activating mutations D816H and D816V with ] concentrations of 5.4 and 2.5 nM, respectively.<ref name="Ref7" />{{citation needed|reason=This claim doesn't have a citation. Reference 14 does NOT have actual Kd... it just says "still being determined"|date=September 2014}} Human ] ] growth assays showed that crenolanib has modest effects on ] and ] driven colony formation at the ] concentration of 20 nM.<ref name="Ref8" />


== Clinical == == Clinical ==
Phase I single-agent<ref>{{cite journal | doi = 10.1200/JCO.2009.21.8487 | title = Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers | year = 2009 | last1 = Lewis | first1 = N. L. | last2 = Lewis | first2 = L. D. | last3 = Eder | first3 = J. P. | last4 = Reddy | first4 = N. J. | last5 = Guo | first5 = F. | last6 = Pierce | first6 = K. J. | last7 = Olszanski | first7 = A. J. | last8 = Cohen | first8 = R. B. | journal = Journal of Clinical Oncology | volume = 27 | issue = 31 | pages = 5262–5269 | pmid = 19738123 | pmc = 2773478}}</ref> and Phase Ib combination<ref>{{cite journal | doi = 10.1038/sj.bjc.6605941 | title = Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor | year = 2010 | last1 = Michael | first1 = M | last2 = Vlahovic | first2 = G | last3 = Khamly | first3 = K | last4 = Pierce | first4 = K J | last5 = Guo | first5 = F | last6 = Olszanski | first6 = A J | journal = British Journal of Cancer | volume = 103 | issue = 10 | pages = 1554–1561 | pmid = 20959830 | pmc = 2990584}}</ref> studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of CP-868,596 administered alone or in combination with docetaxel with or without axitinib have been completed. Results suggest that CP-868,596 is well tolerated as a single agent, and can also be safely combined with docetaxel and axitinib due to their non-overlapping toxicity profiles. Phase I single-agent<ref>{{cite journal |doi=10.1200/jco.2009.21.8487 |title=Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers |year=2009 |last1=Lewis |first1=N. L. |last2=Lewis |first2=L. D. |last3=Eder |first3=J. P. |last4=Reddy |first4=N. J. |last5=Guo |first5=F. |last6=Pierce |first6=K. J. |last7=Olszanski |first7=A. J. |last8=Cohen |first8=R. B. |journal=Journal of Clinical Oncology |volume=27 |issue=31 |pages=5262–9 |pmid=19738123 |pmc=2773478}}</ref> and Phase Ib combination<ref>{{cite journal |doi=10.1038/sj.bjc.6605941 |title=Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor |year=2010 |last1=Michael |first1=M |last2=Vlahovic |first2=G |last3=Khamly |first3=K |last4=Pierce |first4=K J |last5=Guo |first5=F |last6=Olszanski |first6=A J |journal=British Journal of Cancer |volume=103 |issue=10 |pages=1554–61 |pmid=20959830 |pmc=2990584}}</ref> studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of Crenolanib administered alone or in combination with ] with or without ] have been completed. Results suggest that Crenolanib is well tolerated as a single agent, and can also be safely combined with ] and ] due to their non-overlapping toxicity profiles.


== Proposed clinical trials == == Clinical trials ==
⚫ *{{ClinicalTrialsGov|NCT01229644|A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas}}
AROG Pharmaceuticals is planning three clinical trials for crenolanib:
*{{ClinicalTrialsGov|NCT01243346|Phase II Study of Crenolanib (CP-868,596), for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions in the PDGFRA Gene}}
⚫ *A Phase II Study of crenolanib in patients with adult gliomas<ref>NCT01229644: A Study of CP-868,596, a Selective and Potent Inhibitor of Platelet-Derived Growth Factor Receptors (PDGFR), for the Treatment of Adult Gliomas</ref>
*{{ClinicalTrialsGov|NCT01393912|PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma}}
*A Phase II Study of crenolanib in patients with advanced gastrointestinal stromal tumors (GIST) with the D842V mutation in the PDGFRA gene<ref>NCT01243346: Evaluation of CP-868,596 in Patients With Advanced Gastrointestinal Stromal Tumour (GIST) With the D842V Mutation in the PDGFRA Gene</ref>
*{{ClinicalTrialsGov|NCT01522469|Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations}}
*A Phase I/II clinical trial evaluating crenolanib as a single agent in children with recurrent, progressive or refractory high-grade glioma, as well as in combination with radiation for the treatment of children with newly diagnosed high grade glioma (HGG), including diffuse intrinsic pontine glioma.
*{{ClinicalTrialsGov|NCT01657682|A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations}}


== References == == References ==
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*, National Cancer Institute Thesaurus. *, National Cancer Institute Thesaurus.
*, AROG Pharmaceuticals LLC. *, AROG Pharmaceuticals LLC.

{{Growth factor receptor modulators}}


] ]