Other Phase I/II Agents for ALL
Leukemia Insights - Spring 2012
4’-Thio-araC is structurally related to cytarabine and, like other drugs in this class (cytarabine and gemcitabine), requires conversion to the active triphosphate by intracellular kinases. But 4’-thio-araC was found to be 10- to 20-fold more potent as an inhibitor of DNA synthesis than the 5’-triphosphate of cytarabine12. In vitro studies have also shown potential anti-angiogenic effect. 4’-Thio-araC was more efficacious than cytarabine in nine of nine xenograft tumor models . Phase I studies in solid tumors have established the maximum tolerated dose, and a study is ongoing for salvage therapy in adult ALL.
The JAK-STAT signaling pathway is constitutively activated in a spectrum of human malignancies including AML and ALL. A series of studies has defined somatic alterations in JAK1, JAK2, and JAK3 in patients with ALL, including in Down syndrome-associated ALL and in patients with high risk and/or relapsed ALL13. INCB018424 has been very effective in the treatment of symptomatic myelofibrosis. After two or more weeks of INCB018424 therapy, 44 percent to 79 percent of patients showed a reduction in individual symptom scores of at least 50 percent when all dose levels were combined and assessed together. Given the promising results in myelofibrosis, we are now conducting a Phase I/II prospective study to determine the safety and efficacy of INCB018424 in patients with refractory or relapsed acute lymphoblastic leukemia.