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

Abstract

Purpose To determine the maximum tolerated dose (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 CNS tumors were enrolled of who 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (1) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (2) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (3) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2 and (4) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included: hypercholesterolemia, fatigue, thrombocytopenia, and increased ALT. Target inhibition (decreased S6K1 and PAkt) in PBMNCs was noted at all dose levels. Marked interpatient variability in temsirolimus PK parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2946 ng•h/mL (range, 937–5536) with a median sirolimus AUC of 767 ng•h/mL (range, 245–3675). Conclusions The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively.

Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children's Oncology Group

“…Finally, this analysis was based on the data obtained in patients receiving a combination therapy of temsirolimus and cixutumumab. The CL observed in the previous Phase I study of combination therapy was comparable with that observed at the same dose in the study of temsirolimus monotherapy [10,28]. However, sample size may not have been large enough to conclude no effect of coadministration of cixutumumab on temsirolimus pharmacokinetics.…”

“…The population PK analysis was performed using PK data collected in a subset of patients who participated in a Children's Oncology Group phase I dose finding and safety trial of the anti‐ insulin‐like growth factor I receptor antibody cixutumumab (IMC‐A12), combined with temsirolimus in children with recurrent solid tumours (ADVL0813, http://clinicaltrials.gov Identifier: NCT00880282) . Demographic characteristics of participants are described in Table .…”

“…Allometrically scaled body weight was used to account for differences in body size as follows (Equation ): where BW i is body weight for individual i, BW standard is 70 kg, and power is the coefficient set at 0.75 for CL and 1 for V . The temsirolimus dose was examined as a covariate to account for the nonlinearity between dose and AUC, which was observed in the prior noncompartmental analysis (Equation ). where Dose i is the temsirolimus dose normalized by body weight.…”

“…The temsirolimus dose was examined as a covariate to account for the nonlinearity between dose and AUC, which was observed in the prior noncompartmental analysis [28] (Equation (3)).…”

Modulating autophagy as a therapeutic strategy for the treatment of paediatric high‐grade glioma

“…This binding is mediated by Lysosomal‐Associated Membrane Protein‐2A (LAMP‐2A) and the lysosomal heat shock protein 90 complex. Once bound, the target protein is unfolded and translocated into the lysosomal lumen where it is degraded . In this way, recognition motif presentation by target proteins and the highly orchestrated cycling of LAMP‐2A levels tightly regulate CMA .…”