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A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).

ABSTRACT: A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors.Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180?mg/m(2) /day with dose escalations to 230 and 300?mg/m(2) /day). Bortezomib (1.3?mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1.Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300?mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n?=?1) and Grade 3 nausea and anorexia (n?=?1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-?B activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients.The recommended Phase 2 dose and schedule is vorinostat (230?mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3?mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

SUBMITTER: Muscal JA

PROVIDER: S-EPMC3511610 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).

Muscal Jodi A JA Thompson Patrick A PA Horton Terzah M TM Ingle Ashish M AM Ahern Charlotte H CH McGovern Renee M RM Reid Joel M JM Ames Matthew M MM Espinoza-Delgado Igor I Weigel Brenda J BJ Blaney Susan M SM

Pediatric blood & cancer 20120809 3

<h4>Background</h4>A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors.<h4>Procedure</h4>Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlativ ...[more]

PMID: 22887890

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Project description:BackgroundAxitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors.MethodsAxitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2 /dose and 3.2 mg/m2 /dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed.ResultsA total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≤6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified.ConclusionsIn children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2 /dose, which provides PK exposures similar to those of adults.

Dataset Information

A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).

Publications

A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).

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