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.

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.