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

Maryam Fouladi, John P. Perentesis, Lars M. Wagner, Alexander A. Vinks, Joel M. Reid, Charlotte Ahern, George Thomas, Carol A. Mercer, Darcy A. Krueger, Peter J Houghton, L. Austin Doyle, Helen Chen, Brenda Weigel, Susan M. Blaney

Research output: Contribution to journalArticle

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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/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. 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/m2, 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/m2, respectively.

Original languageEnglish (US)
Pages (from-to)1558-1565
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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Neoplasms
Pharmacokinetics
Area Under Curve
Blood Cells
temsirolimus
anti-IGF-1R antibody A12
Central Nervous System Neoplasms
Mucositis
Sirolimus
Hypercholesterolemia
Alanine Transaminase
Thrombocytopenia
Fatigue
Research Design
Pediatrics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Fouladi, Maryam; Perentesis, John P.; Wagner, Lars M.; Vinks, Alexander A.; Reid, Joel M.; Ahern, Charlotte; Thomas, George; Mercer, Carol A.; Krueger, Darcy A.; Houghton, Peter J; Doyle, L. Austin; Chen, Helen; Weigel, Brenda; Blaney, Susan M.

In: Clinical Cancer Research, Vol. 21, No. 7, 01.04.2015, p. 1558-1565.

Research output: Contribution to journalArticle

Fouladi, M, Perentesis, JP, Wagner, LM, Vinks, AA, Reid, JM, Ahern, C, Thomas, G, Mercer, CA, Krueger, DA, Houghton, PJ, Doyle, LA, Chen, H, Weigel, B & Blaney, SM 2015, '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', Clinical Cancer Research, vol. 21, no. 7, pp. 1558-1565. https://doi.org/10.1158/1078-0432.CCR-14-0595
Fouladi, Maryam ; Perentesis, John P. ; Wagner, Lars M. ; Vinks, Alexander A. ; Reid, Joel M. ; Ahern, Charlotte ; Thomas, George ; Mercer, Carol A. ; Krueger, Darcy A. ; Houghton, Peter J ; Doyle, L. Austin ; Chen, Helen ; Weigel, Brenda ; Blaney, Susan M. / 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. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 7. pp. 1558-1565.
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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/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. 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/m2, 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/m2, respectively.",
author = "Maryam Fouladi and Perentesis, {John P.} and Wagner, {Lars M.} and Vinks, {Alexander A.} and Reid, {Joel M.} and Charlotte Ahern and George Thomas and Mercer, {Carol A.} and Krueger, {Darcy A.} and Houghton, {Peter J} and Doyle, {L. Austin} and Helen Chen and Brenda Weigel and Blaney, {Susan M.}",
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T1 - A phase I study of cixutumumab (IMC-A12) in combination with temsirolimus (CCI-779) in children with recurrent solid tumors

T2 - A Children's Oncology Group phase I consortium report

AU - Fouladi, Maryam

AU - Perentesis, John P.

AU - Wagner, Lars M.

AU - Vinks, Alexander A.

AU - Reid, Joel M.

AU - Ahern, Charlotte

AU - Thomas, George

AU - Mercer, Carol A.

AU - Krueger, Darcy A.

AU - Houghton, Peter J

AU - Doyle, L. Austin

AU - Chen, Helen

AU - Weigel, Brenda

AU - Blaney, Susan M.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. 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/m2, 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/m2, respectively.

AB - 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/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. 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/m2, 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/m2, respectively.

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