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DuBois S.G.,University of California at San Francisco | Shusterman S.,Harvard University | Reid J.M.,Rochester College | Ingle A.M.,Childrens Oncology Group Operations Center | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m 2/day. This study was conducted to evaluate sunitinib given as a powder formulation. Methods: Sunitinib 15 mg/m 2 was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated. Results: 12 patients, median age 13 (range 4-21) years, were treated. The most common first-cycle toxicities were leucopenia (n = 6), fatigue (n = 5), neutropenia (n = 4), and hypertension (n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand-foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6-36) ng/ml was reached at a median of 4 (range 4-8) h after the first dose. The median exposure (AUC 0-48) was 585 (range 196-1,059) h ng/l. The median half-life was 23 (range 13-36) h. The median trough concentration measured before day 14 dosing was 32 (range 12-58) ng/ml. Conclusions: The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib. © 2011 Springer-Verlag.


DuBois S.G.,University of California at San Francisco | Shusterman S.,Harvard University | Ingle A.M.,Childrens Oncology Group Operations Center | Ahern C.H.,Baylor College of Medicine | And 8 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. Experimental Design: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m 2/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. Results: Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m 2/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. Conclusions: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m 2/d for 28 days followed by a 14-day break. ©2011 AACR.


Weigel B.,University of Minnesota | Malempati S.,Oregon Health And Science University | Reid J.M.,Mayo Medical School | Voss S.D.,Dana-Farber Cancer Institute | And 6 more authors.
Pediatric Blood and Cancer | Year: 2014

Purpose: This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. Patients and Methods: Patients with relapsed or refractory solid tumors were treated with 9mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. Results: One hundred sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway. © 2013 Wiley Periodicals, Inc.


Appel B.E.,Hackensack University Medical Center | Chen L.,Childrens Oncology Group Operations Center | Buxton A.,Childrens Oncology Group Operations Center | Wolden S.L.,Sloan Kettering Cancer Center | And 2 more authors.
Pediatric Blood and Cancer | Year: 2012

Background: Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). Procedure: Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). Results: The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. Conclusions: This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy. © 2012 Wiley Periodicals, Inc.


Souid A.-K.,New York University | Dubowy R.L.,New York University | Ingle A.M.,Childrens Oncology Group Operations Center | Conlan M.G.,Cytokinetics Inc. | And 3 more authors.
Pediatric Blood and Cancer | Year: 2010

Purpose: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. Subjects and Methods: Ispinesib was administered as 1-hr intravenous infusion weekly×3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12mg/m 2/dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. Results: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12mg/m 2 dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9mg/m 2 dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44)hr and the plasma drug clearance was 5 (1-14)L/hr/m 2. Conclusions: The maximum tolerated and recommended phase II dose for ispinesib administered weekly×3 every 28 days for children with solid tumors is 9mg/m 2/dose. Plans for a phase II trial in select pediatric solid tumors are in development. © 2010 Wiley-Liss, Inc.


Mosse Y.P.,Children's Hospital of Philadelphia | Lipsitz E.,Children's Hospital of Philadelphia | Fox E.,Children's Hospital of Philadelphia | Teachey D.T.,Children's Hospital of Philadelphia | And 6 more authors.
Clinical Cancer Research | Year: 2012

Purpose: MLN8237, a selective small-molecule inhibitor of Aurora kinase A, has activity in a broad range of preclinical pediatric cancer models. We conducted a phase I trial in children with refractory/recurrent solid tumors to define the maximum-tolerated dose, toxicities, and pharmacokinetic properties of MLN8237. Experimental Design: MLN8237 was administered orally either once daily or divided twice daily for seven days, every 21 days. Using a rolling-six design, four dose levels (45, 60, 80, and 100 mg/m2/day) were evaluated on the once-daily schedule, and two dose levels (60 and 80 mg/m 2/d) on the twice-daily schedule. Pharmacokinetic studies were conducted with the initial dose and trough drug concentrations also measured at the steady state. Results: Thirty-seven patients were enrolled. On the once-daily dosing schedule, myelosuppression was dose limiting in three of four patients at 100 mg/m2, and one of six patients had dose-limiting mood alteration at 80 mg/m2. At 45 mg/m2, one of six patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m2 on the twice-daily schedule, and one of five patients at 60 mg/m2 on the twice-daily schedule experienced a dose-limiting alkaline phosphatase. Five of 11 patients experienced hand-foot-skin syndrome with twice-daily dosing versus one of 21 after once-daily dosing. There was one partial response and six with prolonged stable disease among 33 evaluable subjects. Conclusion: The twice-daily dose regimen is well tolerated in adults; however, children experienced a greater frequency of myelosuppression and hand-foot-skin syndrome on this schedule. Children tolerated a higher dose and the recommended pediatric phase II dose is 80 mg/m2/d once daily for seven days. ©2012 AACR.


Mosse Y.P.,Children's Hospital of Philadelphia | Lim M.S.,University of Michigan | Voss S.D.,Dana-Farber Cancer Institute | Wilner K.,Pfizer | And 10 more authors.
The Lancet Oncology | Year: 2013

Background: Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. Methods: In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. Findings: 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1-21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). Interpretation: The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. Funding: Pfizer and National Cancer Institute grant to the Children's Oncology Group. © 2013 Elsevier Ltd.


Su J.M.,Texas Childrens Hospital | Li X.-N.,Texas Childrens Hospital | Thompson P.,Texas Childrens Hospital | Ou C.-N.,Baylor College of Medicine | And 5 more authors.
Clinical Cancer Research | Year: 2011

Purpose: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state. Patients and Methods: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique. Results: Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed. Conclusions: VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors. ©2010 AACR.


Macdonald T.J.,Emory University | Vezina G.,George Washington University | Stewart C.F.,St Jude Childrens Research Hospital | Turner D.,St Jude Childrens Research Hospital | And 5 more authors.
Neuro-Oncology | Year: 2013

BackgroundCilengitide, an v integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population.MethodsCilengitide (1800 mg/m2/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1-20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point.ResultsToxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11-114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28-325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively.ConclusionsWe conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded. © 2013 © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


PubMed | Childrens Oncology Group Operations Center, University of Minnesota, National Cancer Institute, Baylor College of Medicine and 4 more.
Type: Clinical Trial, Phase I | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2015

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

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