A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.