asp3026 and Neoplasms

Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required.. This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts.. Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group).. ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.. This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Appetite; Asian People; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Myositis; Nausea; Neoplasms; Protein Kinase Inhibitors; Sarcoma, Ewing; Sulfones; Treatment Outcome; Triazines

ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026.. Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1.. The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38%), fatigue (35%), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50%; 95% confidence interval 25-75%) and seven patients (44%) achieved stable disease.. ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors.. ClinTrials.gov: NCT01284192.

Topics: Administration, Oral; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Area Under Curve; Crizotinib; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome; Triazines; Vomiting; Young Adult

Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.

Topics: 3T3 Cells; Amides; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Binding Sites; Cell Cycle Proteins; Cell Line, Tumor; Humans; Mice; Microtubule-Associated Proteins; Molecular Docking Simulation; Neoplasms; Protein Structure, Tertiary; Pyrazines; Recombinant Fusion Proteins; Serine Endopeptidases; Solubility; Structure-Activity Relationship; Transplantation, Heterologous