Inhibitors of the BCR-ABL tyrosine kinase in Philadelphia (Ph) positive ALL
Leukemia Insights - Spring 2010
Phase I study of AP24534
AP24534 is an orally available inhibitor of the enzymatic activity of the native BCR-ABL in addition to the T315I-mutated ABL and all other tested variants. It also inhibits FLT-3 and c-SRC. Interestingly, it was designed as a pan BCR-ABL inhibitor using a structure-based approach. Preliminary results of an ongoing phase I clinical trial shows highly encouraging anti-leukemia activity [Cortes J, Blood 2009 114:Abstract 643]. Clinical responses have been seen in patients resistant to the second generation TKIs dasatinib and nilotinib, including those harboring the T315I mutation. Myelosuppression (neutropenia and/or thrombocytopenia) was more common in patients with more advanced stages of disease or with baseline cytopenias. The dose escalation phase of the trial is ongoing.
Phase I study of PHA-739358 (danusertib)
PHA-739358 (danusertib hydrochloride) is a small ATP competitive molecule that specifically inhibits Aurora A, B and C kinases. It possesses high affinity binding capacity to both wild-type ABL and T315I-mutated ABL in vitro. PHA-739358 was initially administered intravenously over 3 hours daily for 7 consecutive days every other week. Preliminary results in 23 patients with TKI-resistant (65% had the T315I mutation) Philadelphia positive ALL or advanced stage chronic myelogenous leukemia (CML) are encouraging [Cortes J, Blood 2009 114: Abstract 864]. The schedule has been modified for a more extended exposure over 14 days of a 21-day cycle.
Phase I study of DCC-2036
DCC-2036 is a novel TKI that overcomes imatinib resistance by binding to a different domain on the BCR-ABL protein, thus avoiding interaction with the mutated regions most commonly associated with resistance, particularly the T315I mutation. DCC-2036 is given orally either daily or twice daily continuously. The dose escalation phase of the study is ongoing.
Phase II study of SKI-606 (bosutinib)
SKI-606 (bosutinib) is an inhibitor of ABL kinase and the Src-family kinases. Bosutinib has shown remarkable activity against imatinib-resistant ABL mutations (except for T315I), likely related to its ability to bind both inactive and intermediate conformations of the BCR-ABL kinase. Unlike imatinib or dasatinib, bosutinib exerts no significant inhibition of c-KIT or PDGFR kinases, which partially accounts for its relatively benign toxicity profile. In this study, bosutinib is given orally once daily continuously. To be eligible, patients must be resistant or intolerant to full dose imatinib (600 mg). Preliminary activity has been observed in Ph positive ALL and advanced phase CML, including cases exposed to other TKIs besides imatinib [Gambacorti-Passerini C, J Clin Oncol 2008 26:Abstract 7049]. Treatment is generally well-tolerated with manageable gastrointestinal side effects. Accrual to the phase II portion of the trial continues.
Phase II study of BAY 43-9006 (sorafenib)
Sorafenib is an orally active multi-kinase inhibitor with potent activity against FLT-3 and the Raf/ERK/MEK pathway. In vitro, leukemia cells expressing BCR/ABL with the imatinib-resistant E255K or T315I mutations appear to have increased sensitivity to sorafenib. Sorafenib activates proapoptotic Bax and caspase-3, and specifically reduces mitochondrial membrane potential in BCR/ABL-driven cells. In this study, sorafenib is given orally 400 mg twice daily for 14 days of a 21-day cycle. Accrual to the phase II portion of this study continues.
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