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Clin Cancer Res. 2015 Apr 1;21(7):1558-65. doi: 10.1158/1078-0432.CCR-14-0595. Epub 2014 Dec 2.

A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report.

Author information

1
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. maryam.fouladi@cchmc.org.
2
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
3
Mayo Clinic College of Medicine, Rochester, Minnesota.
4
Children's Oncology Group Operations Center, Arcadia, California.
5
University of Cincinnati, Cincinnati, Ohio.
6
Nationwide Children's Hospital, Columbus, Ohio.
7
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
8
University of Minnesota, Minneapolis, Minnesota.
9
Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas.

Abstract

PURPOSE:

To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.

EXPERIMENTAL DESIGN:

Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle.

RESULTS:

Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m(2), the median temsirolimus AUC was 2,946 ng • h/mL (range, 937-5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245-3,675).

CONCLUSIONS:

The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m(2), respectively.

PMID:
25467181
PMCID:
PMC4454739
DOI:
10.1158/1078-0432.CCR-14-0595
[Indexed for MEDLINE]
Free PMC Article

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