title: A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114).
abstract: The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m2weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m2weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m2weekly × 2 doses (DL-1). Sixteen patients were enrolled, 15 were evaluable for toxicity. Dose-limiting toxicity (DLT) occurred at all three dose levels and included hypertriglyceridaemia, mucositis, ulceration, hypertension with reversible posterior leucoencephalopathy, elevated gamma-glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re-induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in seven of fifteen patients. Three patients had minimal residual disease levels <0·01%. Inhibition of PI3K signalling was detected in patients treated at all dose levels of temsirolimus, but inhibition at an early time point did not appear to correlate with clinical responses at the end of re-induction therapy.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rheingold
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.affiliation: Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Whitlock
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.affiliation: Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.affiliation: Children's Oncology Group Operations Center, Monrovia, CA, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.|TX Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Minard
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.affiliation: Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.|TX Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods*; D007223:Infant; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000097:blood; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D058539:Phosphatidylinositol 3-Kinase; D020123:Sirolimus
keywords: acute lymphoblastic leukaemia; clinical trials; mTOR inhibitor; pharmacodynamics; relapse