These are pretty dramatic results, especially in a condition where Phase I is highly predictive of final outcome:
Oral and Poster Abstracts
Oral Session: Chronic Myeloid Leukemia - Therapy: Managing Resistance and Residual Disease
Monday, December 7, 2009: 4:30 PM
Conference Auditorium AB (Ernest N. Morial Convention Center)
Jorge Cortes, MD1*, Moshe Talpaz, MD2, Michael Deininger, MD, PhD3, Neil Shah, MD, PhD4, Ian W Flinn, MD5, Michael J. Mauro, MD3, Thomas O'Hare, PhD6*, Natalie Spinos7*, Simin Hu, PhD7*, Lori Berk7*, Narayana Narasimhan, PhD7*, Victor M. Rivera, PhD7, Tim Clackson, PhD7*, Frank Haluska, MD, PhD7* and Hagop M. Kantarjian, MD1
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Comprehensive Cancer Ctr., University of Michigan, Ann Arbor, MI
3Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR
4University of California, San Francisco, San Francisco, CA
5Sarah Cannon Research Institute, TN
6Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR
7ARIAD Pharmaceuticals, Inc., Cambridge, MA
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 CML or baseline cytopenia. Pharmacokinetic data demonstrate that the half life of the drug is 19-45 hours. The relationship of Cmax to dose is linear over the dosing range. The Cmax on day 1 at the 30 mg dose is approximately 55 nM. After one 28-day cycle, the AUC is 2.5- to 3-fold higher than single dose AUC. PD data demonstrate inhibition of CrkL phosphorylation at doses of 8 mg and higher. Overall best hematologic response was complete hematologic response (CHR) in 16 of 18 CP pts (88%), 5 of whom had CHR on entry, major hematologic response (MHR) in 2 of 4 AP pts, and no response in 4 BP and 1 ALL pts. Cytogenetic responses were 4 complete cytogenetic responses (CCyR) and 2 PCyR. Of the 12 patients with T315I mutations, 9 remain on study without progression. Best hematologic response in the T315I subset was CHR in 5 of 6 CP pts (83%), 2 of whom had CHR on entry, MHR in 2 of 2 AP pts, resolution of extramedullary symptoms in 1 BP pt, and no response in 2 BP and 1 ALL pts. Nine of 12 T315I pts are evaluable for CyR: 2 (1 CP, 1 AP) achieved CCyR after 2 and 5 months (at 4 mg and 15 mg), and 1 CP achieved PCyR after 3 months at 15 mg. Of 3 pts with dasatinib resistant F317L, 1 discontinued for an unrelated AE (CNS ischemia), and 2 remain on study in CP at 8 and 15 mg. One pt with nilotinib resistant F359C remains on study with CHR, CCyR, and major molecular response after 4 months at 15 mg. Conclusions: No DLTs have been observed at doses up to 30 mg AP24534. PK and PD demonstrate that blood levels at 30 mg exceed those needed for in vitro inhibition of resistant mutant BCR-ABL isoforms, including T315I. Preliminary analysis reveals evidence of clinical antitumor activity in patients with resistance to approved second-line TKIs dasatinib and nilotinib, including pts with the T315I mutation of BCR-ABL.
Disclosures: Cortes: ARIAD: Research Funding. Deininger: Novartis : Consultancy; BMS : Consultancy; Celgene: Consultancy; ARIAD : Consultancy; Genzyme: Research Funding. Shah: Novartis : Consultancy; Bristol-Myers Squibb: Consultancy. Spinos: ARIAD: Employment. Hu: ARIAD: Employment. Berk: ARIAD: Employment, Equity Ownership. Narasimhan: ARIAD: Employment, Equity Ownership. Rivera: ARIAD: Employment, Equity Ownership. Clackson: ARIAD: Employment, Equity Ownership. Haluska: ARIAD: Employment, Equity Ownership |
