Arog Pharmaceuticals (United States)

BackgroundPlatelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).MethodsWe used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays.ResultsFifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0–48h and CMAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls.ConclusionsChildren tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.

7027 Background: Development of D835 is a common mechanism of resistance to most FLT3 inhibitors. Crenolanib, a type I FLT3 tyrosine kinase inhibitor, has in vitro activity against FLT3 ITD and FLT3 D835. Crenolanib trials in relapsed/refractory FLT3 mutant AML (FLT3 ITD, FLT3 D835, FLT3 ITD/D835) are ongoing (NCT01522469, NCT01657682). Methods: Clinical data on the first 19 patients (7M, 12F) with a median age of 47 years (21-81) are currently available. 6 patients were refractory and 7 had relapsed within 6 months of induction therapy. 4 had undergone prior allogeneic transplants. 11/19 had progressed after exposure to ≥1 prior FLT3 TKI (8 Sorafenib, 7 AC220, 2 PLX3397, 1 PKC412,). 3 had received 2 or more prior FLT3 TKIs. Initially, crenolanib was given at a fixed dose of 100 mg PO TID but the dose was subsequently individualized to 200 mg/m2/d given in 3 divided doses. Results: Crenolanib had a Tmax of 1.5-2 hours and a T1/2 of 8-9 hours. Median day 15 trough levels (from 11 patients) ranged from 136 -785 nM (median 473nM). Commonly observed side effects included nausea and vomiting and transaminase elevations (primarily grade 1, 2). No patient had to go off study due to toxicity. One patient each required crenolanib dose reduction to 80mg TID due to grade 3 nausea or transaminitis, respectively. No QT prolongations on EKG were observed in any patient. 18 patients are currently evaluable for response. 1 patient achieved a rapid molecular and clinical CR with full count recovery. 2 patients achieved a CR with incomplete count recovery (CRi). An additional 4 patients had a partial response. 4 patients were bridged to transplant. Conclusions: Crenolanib is a FLT3 TKI that is showing preliminary clinical activity in a heavily pretreated population with both FLT3 D835 and compound FLT3 ITD/D835 mutant AML. Importantly, crenolanib is also the first agent to demonstrate clinical activity in patients refractory to other FLT3 TKIs via the major clinical resistance mechanism. Trials of crenolanib in newly diagnosed as well as first relapsed AML patients, are being initiated. Clinical trial information: NCT 01522469, NCT01657682. Patient No. N=18 CR/CRi 3 (17%) Partial Response 4 (22%) Blast Response 2 (11%) Overall Response 9 (50%) Patients bridged to transplant 4 (22%)

Abstract Background: 8-10% of gastrointestinal stromal tumors (GIST) have activating mutations of the platelet-derived growth factor receptor alpha (PDGFRA) kinase. The most common PDGFRA mutation is the D842V substitution that is encoded by exon 18. This gain-of-function mutation results in auto-phosphorylation and constitutive activation of PDGFRA kinase activity. Type II receptor tyrosine kinase (RTK) inhibitors, such as imatinib and sunitinib, which only bind to the inactive conformation of the RTK, have little or no in vitro activity against this mutation. Clinically, these drugs are not effective for the treatment of GIST patients with D842V mutation. In addition, the D842V mutation can develop as a secondary imatinib resistant mutation during treatment of GISTs with primary imatinib-sensitive PDGFRA mutations (e.g. primary exon 12 mutations), or treatment of patients with hypereosinophillic syndrome with translocations involving PDGFRA. CP-868,596 is an orally bioavailable, highly potent and selective PDGFR TKI. CP-868,596 is a benzimidazole compound that has IC50s of 0.9 nM and 1.8 nM for PDGFRA and PDGFRB, respectively. Phase I trials of CP-868,596 have shown good oral bioavailability, a favorable toxicity profile, and achievable serum concentrations as high as 2000 nM. Methods: Mutant PDGFRA isoforms were expressed by transient transfection of Chinese Hamster ovary cells. The transfected cells were treated with various concentrations of CP-868,596 before preparation of protein lystates. PDGFRA protein was assayed for activation status (phosphorylation) by immunoprecipitation using an anti-PDGFRA antibody, followed by sequential immunoblotting for phospho PDGFRA (using antiphosphotyrosine antibody) or total PDGFRA (anti-PDGFRA monoclonal antibody). IC50 was measured by densitometry of the phospho PDGFRA bands and normalization using total PDGFRA expression (to correct for variations in loading of PDGFRA protein in the various lanes). Results: CP-868,596 inhibited the phosphorylation of wild type PDGFRA at an IC50 of 10 nM and PDGFRA D842V with an IC50 between 10 to 30 nM. Imatinib was ineffective in blocking PDGFRA D842V phosphorylation in these experiments (IC50 > 1000 nM). Profiling of CP-868,596 against other GIST-relevant primary and secondary PDGFRA mutations is ongoing and will be reported. Discussion: GISTs due to D842V activating mutations of PDGFRA gene are clinically resistant to imatinib, sunitinib, and other commercially available tyrosine kinase inhibitors. CP-868,596 blocks phosphorylation of the PDGFRA D842V mutant at clinically achievable concentrations, providing a potentially new therapeutic modality for GIST patients. A clinical trial in GIST patients with primary or secondary PDGFRA D842V mutations is being initiated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3586. doi:10.1158/1538-7445.AM2011-3586

Abstract Diazonamide A is a natural product originally isolated from a marine organism. It potently induces G2/M cell cycle arrest. Its molecular mode of action is not fully understood but its potential as a cancer therapeutic is high. To streamline our diazonamide synthesis and to define a minimal pharmacophore, we prepared a series of truncated structures. Its simplified structure and shortened synthesis allowed for extensive structure activity relationship analyses. Several modifications markedly improved activity. Among them, JP2295 and JP2362 were studied in details. Both compounds were highly efficacious in a wide spectrum of tumors from different origin both in vitro and in vivo. They were >20 fold more potent than AB5, a closely related analog of the natural product, in a MIA Paca-2 pancreatic cancer xenograft model. At dose 10-fold higher than the efficacious dose, JP2295 or JP2362 did not cause any apparent toxicity. Three out of 7 mice were completely free of tumor even 6 months after the initial treatment. In the same model, taxanes, i.e. paclitaxel and docetaxel, and vinca alkaloids, i.e. vinorelbine, vinblastine, and vincristine, were either less efficacious or causing severe body-weight loss, even animal death. Similar effects were observed in other xenograft models. Safety studies were further carried out in NIH Swiss mice and Sprague Dawley rats with similar results. In summary, JP2295 and JP2362 demonstrated over 20-fold bigger therapeutic window than taxanes and vinca alkaloids in rodents. Such a large therapeutic window is unique for a small molecule anti-mitotic and suggests further development is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5423. doi:10.1158/1538-7445.AM2011-5423

Phosphoinositide 3‐kinase p110δ (PI3Kδ) plays a pivotal role in the recruitment and activation of inflammatory cells. The role of PI3Kδ in a mouse model of cockroach antigen (CRA)‐induced acute allergic airway inflammation was investigated using IC87114, a selective PI3Kδ inhibitor. BALB/c mice exposed to CRA developed airway eosinophilia associated with increased expression of IL‐2, IL‐17, IFNγ, IL‐4 and IL‐5 in lung tissue as well as of pro‐inflammatory chemokines eotaxin‐1 and MCP‐1 in bronchoalveolar lavage fluid (BALF) and lung tissue. Further, these mice developed airway hyperresponsiveness (AHR) to inhaled methacholine. Oral administration of IC87114 significantly attenuated CRA‐induced influx of inflammatory cells in the BALF (eosinophils and macrophages) and lung tissue and suppressed CRA‐induced AHR. Moreover, levels of IL‐2, IL‐17, IFNγ, IL‐4, and IL‐5 in lung tissue and of eotaxin‐1 and MCP‐1 in BALF as well as lung tissue were substantially reduced. Treatment of human eosinophils with IC87114 significantly inhibited eosinophil rolling on human umbilical vein endothelial cells as well as VCAM‐1 in vitro. Overall, these findings implicate that inhibition of the PI3Kδ may have therapeutic potential for the treatment of allergic airway inflammation. Supported by National Institutes of Health grants HL0793041 and AI35796.