A Phase 1 Trial of Oral AP24534 in Patients with Refractory Chronic Myeloid Leukemia and Other Hematologic Malignancies: First Results of Safety and Clinical Activity against T315I and Resistant Mutations

• Published in: Blood 2009-11, Vol.114 (22), p.643-643
• Main Authors: Cortes, Jorge, Talpaz, Moshe, Deininger, Michael, Shah, Neil, Flinn, Ian W, Mauro, Michael J., O'Hare, Thomas, Spinos, Natalie, Hu, Simin, Berk, Lori, Narasimhan, Narayana, Rivera, Victor M., Clackson, Tim, Haluska, Frank, Kantarjian, Hagop M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.643.643

Abstract 643 AP24534 is an orally available multiple tyrosine kinase inhibitor (TKI) designed using a structure-based approach as a pan-BCR-ABL inhibitor. AP24534 potently inhibits the enzymatic activity of BCR-ABL-T315I, the native enzyme and all other tested variants. It also inhibits survival of cell lines expressing these BCR-ABL variants with IC50s of < 40 nM, and inhibits Flt3 and c-Src. We report here preliminary results from our ongoing phase 1 clinical trial. The objectives of this study are to assess the safety of AP24534, establish a maximum tolerated dose and schedule for further investigation, and provide preliminary assessments of clinical activity. The trial employs an open-label dose escalation design. Patients (pts) with hematologic malignancies refractory to treatment, ECOG status ≤ 2, adequate hepatic and renal function, and normal cardiac function are eligible and receive a single daily oral dose of AP24534. Thirty-two pts (16 males) have been enrolled, median age 63 years (range 31-79). Diagnoses include 27 CML (19 chronic [CP], 4 accelerated [AP], 4 blast phase [BP]), 1 Ph+ ALL, 2 myelofibrosis, 1 myeloma, 1 MDS. BCR-ABL mutation status in 28 Ph+ pts included 5 pts with no mutation, 12 T315I (8 at entry, 4 by history), 3 F317L, (2 at entry, 1 by history), 2 M351T, and 1 each L273M/F359V, G250E, E279K, F359C, L387F and E453K. Prior therapies in CML pts included imatinib (100% of pts), dasatinib (94%), nilotinib (53%), interferon (47%), chemotherapy (41%), and investigational (65%); 83% were resistant to 3 or more TKIs. Pts have been treated at the following dose levels: 2 mg (3 pts), 4 mg (6 pts), 8 mg (7 pts), 15 mg (8 pts), 30 mg (7 pts), and 60 mg (1 pt). 21 pts remain on study. Of 23 pts in the 4 highest (8-60 mg) dosing cohorts, 19 remain on study. Median time on study drug is currently 3.4 months (range 5 days to 10 months). At the time of this report, preliminary safety and efficacy data are available for 31 patients. No DLTs have been observed. The most common drug-related adverse events (AE) were nausea (15%), fatigue and dry eye (12% each), anorexia, arthralgia, dizziness, dry mouth, headache, hot flush, myalgia, vomiting (8% each), and QTc prolongation (1 pt in 2 mg, 1 pt in 4 mg cohort). Grade 3 or 4 thrombocytopenia occurred in 36% pts (18% entered with thrombocytopenia), and grade 3 or 4 neutropenia in 41% (18% entered with neutropenia). Both types of hematologic toxicity were more frequent in pts with advanced stages of