>>[469] A Phase I Study of INNO-406 in Patients with Advanced Philadelphia (Ph+) Chromosome-Positive Leukemias Who Are Resistant or Intolerant to Imatinib and Second Generation Tyrosine Kinase Inhibitors. Session Type: Oral Session
Hagop M. Kantarjian, Jorge Cortes, Philipp le Coutre, Arnon Nagler, Javier Pinilla, Andreas Hochhaus, Dan Jones, Adam R. Craig, Eileen Carroll, Oliver G. Ottmann Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Campus Virchow, Charite Universitatsmedizin Berlin, Berlin, Germany; Chaim Sheba Medical Center, Tel Hashomer, Israel; H. Lee Moffitt Cancer Center Research Institute, Tampa, FL, USA; Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Mannheim, Germany; Department of Hematopathology, UT MD Anderson Cancer Center, Houston, TX, USA; Innovive Pharmaceuticals, Inc., New York, NY, USA; Department of Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany
Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl expressing cell lines. Numerous Bcr-Abl mutant proteins are sensitive to INNO-406 in vitro, including the F317L mutant. Unlike other second generation tyrosine kinase inhibitors (TKIs), INNO-406 demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Methods: In this phase I dose finding study, patients (pts) with imatinib-resistant or -intolerant Philadelphia (Ph+) chromosome-positive leukemias were eligible for treatment with INNO-406 orally at doses ranging from 30 mg once daily (qd) through 480 mg twice daily (bid). Results: INNO-406 was administered to 41 pts (23M, 18F); median age 61 yrs (range, 20-76). Median duration of CML was 6 yrs (range, 0.1-23); median time on imatinib was 0.8 yrs (range, 0.1-6.5). Pts had CML in chronic phase (CP, n=21), accelerated phase (AP, n=7), or blast phase (BP, n=6), or Ph+ ALL (n=7). Previous treatment included nilotinib (n=9), dasatinib (n=13), and dasatinib/nilotinib (n=10). Pts have been treated with INNO-406 for a median of 42 days (range, 7-240+). Common mutations on study entry included Y253H (n=4), F311L (n=3), F317L (n=2), and T315I (n=2). Currently, 14 pts remain on study; 22 pts discontinued due to disease progression, 4 pts discontinued to pursue other treatment options, and 1 pt discontinued due to toxicity. Hematologic and cytogenetic responses have been reported. 2 of 7 CP pts who had failed only imatinib demonstrated a complete cytogenetic response, including 1 major molecular response. An additional pt had a minor cytogenetic response after 4 weeks of therapy before going off study to pursue an alternate treatment option. Among pts in CP who had failed more than one TKI, a complete cytogenetic response was reported in 1 pt who was intolerant to both imatinib (lung/skin toxicity) and dasatinib (pleural effusion). All 7 AP pts on study had failed multiple TKIs. In this population, 2 pts experienced complete hematologic responses. Additionally, in 1 pt, a reversion of the Y253H mutation was demonstrated, and 1 pt has experienced a disappearance of the F317L mutation. Related adverse events include reversible grade 2/3 elevation in the activity of transaminases. A DLT was reported in 1 pt in the 480 mg bid cohort (intrahepatic cholestasis and renal failure secondary to tumor lysis syndrome). Conclusions: INNO-406 is well tolerated in pts with clinical activity demonstrated across a range of dosing. Responses occur even in the setting of a heavily pretreated population thus making INNO-406 a viable option for CML therapy. The recommended phase II dose is anticipated to be 240 mg bid. Pivotal phase II studies are planned for late 2007.
Abstract #469 appears in Blood, Volume 110, issue 11, November 16, 2007<<
Comments? Doesn't look as though much changed. Expectations a little higher? Stock sure has been weak.
Cheers, Tuck |
