Suman Malempati

Rhabdomyosarcoma: Review of the Children's Oncology Group (COG) soft‐tissue Sarcoma committee experience and rationale for current COG studies

The prognosis for children and adolescents with rhabdomyosarcoma (RMS) has improved with refinements in multi‐modal therapy. Since 1972, the Intergroup Rhabdomyosarcoma Study Group (now the Childrens Oncology Group Soft‐Tissue Sarcoma Committee) has conducted serial studies for RMS. This review describes the IRSG and COG experience with RMS, presents the current risk stratification definitions, and provides rationale for the current generation of COG RMS studies. Pediatr Blood Cancer 2012; 59: 5–10.

Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group

PURPOSE A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). PATIENTS AND METHODS Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels-6 and 9 mg/kg-were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. RESULTS Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. CONCLUSION Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.

Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study CCG-1952

PURPOSE The event-free survival (EFS) of children with standard-risk acute lymphoblastic leukemia (SR-ALL) is now more than 80%. However, prognosis after relapse continues to be poor. We examined postrelapse outcomes of children initially treated on the Childrens Cancer Group CCG-1952 study. PATIENTS AND METHODS We evaluated outcomes after bone marrow (BM) relapse and isolated extramedullary (EM) relapse for 347 patients with SR-ALL (WBC < 50,000/microL; age, 1 to 9 years). The prognostic significance of several factors for EFS after relapse (EFS2) was assessed by Cox regression analysis. Stem-cell transplant (SCT) was compared with chemotherapy as salvage treatment. RESULTS The mean +/- SE times to isolated central nervous system relapse, BM relapse, and isolated testicular relapse were 23 +/- 1 months (range, 1 to 88 months), 36 +/- 1 months (range, 2 to 79 months), and 40 +/- 2 months (range, 16 to 64 months), respectively. The estimated percent +/- SE 3-year EFS2 and overall survival rates after BM relapse were 37% +/- 4% and 46% +/- 4%, respectively, and rates after isolated EM relapse were 57% +/- 5% and 71% +/- 5%, respectively. By multivariate analysis, we found the duration of first remission to be the most significant predictor of EFS2 for either BM relapse or isolated EM relapse. Outcome was equivalent with SCT or chemotherapy after early or late relapse of SR-ALL at any site. CONCLUSION Duration of first remission remains the most significant predictor of outcome after either BM or isolated EM relapse of SR-ALL. Prognosis after early BM relapse remains poor and is not improved with SCT in this cohort.

Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children's Oncology Group.

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.

Prevalence of transient hyperglycemia during induction chemotherapy for pediatric acute lymphoblastic leukemia

Transient hyperglycemia (TH) is a recognized side effect of the corticosteroids and asparaginase given during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL). Information is needed about how TH has been impacted by changes in ALL therapy. This study examined the prevalence of TH in a cohort of pediatric ALL patients and the impact on TH of type of steroid or asparaginase used and of risk factors such as age, gender, and overweight.

Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma

Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance. Mol Cancer Ther; 10(4); 697–707. ©2011 AACR.

Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group

PURPOSE We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. PATIENTS AND METHODS Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. RESULTS Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. CONCLUSION Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: a Children's Oncology Group study.

Pemetrexed is a multi‐targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile.

Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group.

Rhabdomyosarcoma (RMS), the most common soft‐tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children.

Rhabdomyosarcoma in infants younger than 1 year

Rhabdomyosarcoma (RMS), the most common soft‐tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children.