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Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia
Author(s) -
Place Andrew E.,
Pikman Yana,
Stevenson Kristen E.,
Harris Marian H.,
Pauly Melinda,
Sulis MariaLuisa,
Hijiya Nobuko,
Gore Lia,
Cooper Todd M.,
Loh Mig L.,
Roti Giovanni,
Neuberg Donna S.,
Hunt Sarah K.,
OrloffParry Sarah,
Stegmaier Kimberly,
Sallan Stephen E.,
Silverman Lewis B.
Publication year - 2018
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.27062
Subject(s) - medicine , everolimus , adverse effect , vincristine , mucositis , gastroenterology , chemotherapy , leukopenia , cyclophosphamide
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 (≤10 −3 by polymerase chain reaction–based assay). The CR2 rate for patients with B‐cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. Conclusions Everolimus combined with four‐drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end‐reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four‐drug reinduction is 5 mg/m 2 /day. This promising combination should be further evaluated in a larger patient cohort.