A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for Untreated BCR-ABL1-Positive ALL in Older Adults

IntroductionThe BCR-ABL1 gene fusion is the most common molecular aberration in adult ALL and confers an adverse prognosis. The incorporation of ABL1 tyrosine kinase inhibitors (TKIs) into ALL chemotherapy regimens has dramatically improved outcomes for BCR-ABL1+ ALL. Subsequently, reduced-intensity TKI-based regimens have been shown to be as effective and less toxic than intensive TKI-based regimens (Foa et al. Blood 2011; Chalandon et al. Blood 2015). Asciminib (ABL001) is a potent, specific allosteric inhibitor of ABL1 that binds to a site spatially distinct from the catalytic domain. Asciminib was developed for efficacy against BCR-ABL1 mutations conferring resistance to standard TKIs. Preclinical studies demonstrated that the combination of asciminib and TKI leads to sustained disease control in a cell line xenograft model of BCR-ABL1+ CML (Wylie et al. Nature 2017). We also observed that the addition of asciminib to TKI significantly prolongs survival in patient-derived xenograft models of BCR-AB1L+ ALL, even in the context of a pre-existing subclonal T315I mutation (unpublished). An ongoing phase I Novartis study (NCT02081378) has shown safety and efficacy of asciminib alone and in combination with TKIs in relapsed/refractory (R/R) BCR-ABL1+ ALL and CML. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and effective in older adults with BCR-ABL1+ ALL.