Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

Place, A. E.; Pikman, Y.; Stevenson, K. E.; Harris, M. H.; Pauly, M.; Sulis, M. L.; Hijiya, N.; Gore, L.; Cooper, T. M.; Loh, M. L.; Roti, G.; Neuberg, D. S.; Hunt, S. K.; Orloff-Parry, S.; Stegmaier, K.; Sallan, S. E.; Silverman, L. B.

Pediatr Blood Cancer. 2018 Apr 1; 65(7):e27062


BACKGROUND: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. PROCEDURE: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m(2) /day). Additional patients were enrolled at the 3- and 5 mg/m(2) /day DLs to further evaluate toxicity (dose expansion). RESULTS: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m(2) /day). The most common grade >/=3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (

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