Preliminary Clinical Activity in a Phase I Trial of the BCR-ABL/IGF- 1R/Aurora Kinase Inhibitor XL228 in Patients with Ph++ Leukemias with Either Failure to Multiple TKI Therapies or with T315I Mutation

Abstract XL228 is a protein kinase inhibitor with potent activity against wild-type and T315I isoforms of BCR-ABL (wild-type ABL kinase, IC50 = 5 nM; ABL T315I, 1.4 nM), Aurora A (3.1 nM), IGF-1R (1.6 nM), SRC (6.1 nM), and LYN (2 nM). A Phase 1 dose escalation clinical trial in patients (pts) with CML or Ph++-ALL who are resistant or intolerant to at least two prior standard therapies (including imatinib, dasatinib, and nilotinib) or have a known BCR-ABL T315I mutation is ongoing. XL228 is administered as a 1-hour IV infusion either once weekly or twice weekly. Twenty-seven pts have been enrolled into six cohorts with the once-weekly dosing schedule (dose range from 0.45 mg/kg to 10.8 mg/kg). All pts have failed prior imatinib therapy, and received nilotinib, dasatinib, and other therapies The majority of pts harbor mutations in BCR-ABL, with the most common mutations being T315I (n=10), F317L (n=7), and V299L (n=3). The maximum administered dose (MAD) of once-weekly IV dosing of XL228 is 10.8 mg/kg. Dose escalation of pts in the twice-weekly dosing schedule at an initial XL228 dose of 3.6 mg/kg on Days 1 and 4 of each week is ongoing. XL228 has been generally well-tolerated. Dose limiting toxicities observed with once-weekly dosing included Grade 3 syncope and hyperglycemia in two pts dosed at 10.8 mg/kg. Grade 2 adverse events reported to be possibly related to XL228 in the once-weekly dosing schedule were usually transient and manageable, and included hyperglycemia, fatigue, nausea, vomiting, and bradycardia. Pharmacokinetic analysis across five cohorts treated with once-weekly dosing of XL228 demonstrated an approximately dose-proportional exposure, with a mean terminal half life of 15 to 38 hours. In the 7.2 mg/kg cohort, the Cmax of approximately 13 μM exceeds the IC50 for modulation of phospho-CrkL levels determined in mouse K562 xenograft pharmacodynamic studies. Peak exposures of XL228 in the 7.2- and 10.8-mg/kg cohorts were associated with inhibition of peripheral blood leukocyte CrkL phosphorylation in several patients, including three harboring the T315I mutation. Transient increases in mean plasma glucose levels (up to three fold) and mean insulin levels (up to 40 fold) postinfusion are coupled, dose-related, and imply inhibition of the IGF1R and IR pathways by XL228. Preliminary evidence of clinical activity has been observed in pts treated at doses of 3.6 mg/kg and higher, including stable or decreasing white blood cell count and/or platelet count within 2 months (14 pts, 5 with T315I), and/or >1 log reduction in BCR-ABL levels by QPCR within 3 months (3 pts, 2 with T315I). Pts in the 7.2 mg/kg and higher cohorts have been followed a minimum of 1 month to a maximum of 4 months at the time of abstract submission. XL228 shows potential for treating drug-resistant CML and Ph+-ALL, including pts harboring the T315I gatekeeper mutation.

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