Phase I Study of Combination Chemotherapy Plus Ixazomib in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma (ALL)

Abstract

Introduction: The outcome of adult patients with relapsed/refractory ALL remains dismal. In pediatric patients with relapsed/refractory ALL, the combination of vincristine, doxorubicin, pegaspargase, dexamethasone (VXLD) and bortezomib yielded significant response rates. Based on those results, this study was designed to test the safety of VXLD combined with the oral proteosome inhibitor Ixazomib in adult patients with relapsed/refractory ALL.Study design: This was a phase I study combining vincristine 1.3 mg/m2 (maximum dose 2 mg) D1, 8, 15, and 22, doxorubicin 60 mg/m2 D1, PEGaspargase 2500 units/m2 (capped at 3750 mg) D2, D15, dexamethasone 10 mg/m2 D1-14, with escalating doses of ixazomib. Ixazomib dose was started at 2.3 mg D1, 8, and 15 aiming to increase the dose to 4 mg.Results: Five patients were enrolled on the study between 10/1/13 and 2/26/16, prior to study termination. The median age was 49 years and 3 were female. Median number of prior regimens was 2 (range 2-3). At dose level one, 3 patients were enrolled. Of those patients, one developed grade 5 liver toxicity. That patient achieved complete remission, but died secondary to hyperbilirubinemia and liver failure. One patient developed grade 4 hyperbilirubinemia, did not respond to therapy and died from disease progression. The third patient developed transient grade 3 hyperbilirubinemia, had no response to treatment and went on to receive other therapies. Hepatic toxicities were attributed to pegaspargase. Based on that, the protocol was amended to remove pegaspargase (VXD + Ixazomib). Two patients were enrolled on dose level one (2.3 mg). One patient developed grade 5 infection. Due to increased toxicity in this population, the study was terminated.Conclusion: In our experience, VXLD and VXD were poorly tolerated in adult patients with relapsed/refractory ALL. Ixazomib should be studied with other chemotherapy combinations in adults with relapsed/refractory ALL. [Display omitted] DisclosuresAtallah:Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Hamadani:Takeda: Research Funding. Parameswaran:Takeda: Consultancy.