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Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: A children's oncology group study
Author(s) -
Bagatell Rochelle,
Norris Robin,
Ingle Ashish M.,
Ahern Charlotte,
Voss Stephan,
Fox Elizabeth,
Little Anthony R.,
Weigel Brenda J.,
Adamson Peter C.,
Blaney Susan
Publication year - 2014
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.24874
Subject(s) - medicine , nausea , gastroenterology , neutropenia , temozolomide , irinotecan , temsirolimus , vomiting , regimen , refractory (planetary science) , cancer , chemotherapy , pi3k/akt/mtor pathway , apoptosis , biochemistry , chemistry , physics , colorectal cancer , astrobiology , discovery and development of mtor inhibitors
Background mTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Methods Escalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21‐day cycles. IRN (50 mg/m 2 /dose escalated to a maximum of 90 mg/m 2 /dose) and TMZ (100 mg/m 2 /dose escalated to a maximum of 150 mg/m 2 /dose) were administered orally (PO) on days 1–5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly. Results Seventy‐one eligible pts (median age 10.9 years, range 1.0–21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose‐limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35 mg/m 2 IV weekly, with IRN 90 mg/m 2 and TMZ 125 mg/m 2 PO on days 1–5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional ≥grade 3 regimen‐related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through ≥14 cycles of therapy. Conclusion The combination of TEM (35 mg/m 2 /dose IV weekly), IRN (90 mg/m 2 /dose days 1–5) and TMZ (125 mg/m 2 /dose days 1–5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing. Pediatr Blood Cancer 2014;61:833–839. © 2013 Wiley Periodicals, Inc.