Krailo, Mark

9019 Background: Pemetrexed is a new multi-targeted antifol that inhibits enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Methods: A phase 1 dose escalation and pharmacokinetic study (PK) was performed in children with refractory solid tumors to define the dose limiting toxicities (DLTs) and a recommended phase 2 dose. Pemetrexed was administered as a 10 min iv infusion every 21 days. All patients received folic acid (400 mcg/day po), vitamin B12 (500–1000 mcg every 3rd course IM) and dexamethasone (0.1 mg/kg/dose bid × 3 days each course) . Cohorts of 3 to 6 children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910 and 2,480 mg/m2. DLT was defined as any Gr. 3 or 4 non-hematological toxicity (except nausea/vomiting, alopecia, or AST/ALT elevation that returns to Gr. 1), Gr. 4 neutropenia or Gr. 4 thrombocytopenia ≥ 7 days. Results: 33 subjects (31 fully evaluable for toxicity), median age of 12 yrs (range, 1–21), with diagnoses including osteosarcoma (12), Ewing’s sarcoma (3), hepatoblastoma (2), renal cell carcinoma (2), brainstem glioma (3), glioma (3), and other (n=8) were enrolled. DLT occurred in 1/6 patients at 1,470 mg/m2 (Gr. 3 AST and ALT), and in 2/4 at 2,480 mg/m2 (Gr. 3 ANC and Gr. 3 rash in both). Other DLTs at 2,480 mg/m2 that occurred in 1 patient included Gr. 3 diarrhea and rectal hemorrhage, and Gr. 4 thrombocytopenia, lipase, GGT, hypophosphatemia, hypokalemia and hyponatremia. At 1,910 mg/m2, 0/6 patients had DLT. The median number of courses administered was 1 (range 1 to 17). No CRs or PRs have been observed. Results of PK and other correlative studies will be presented. Conclusions: The recommended phase 2 dose of pemetrexed for children and adolescents with recurrent solid tumors is 1,910 mg/m2 administered q21 days with dexamethasone, folic acid and B12 supplementation. A phase II COG study is planned. No significant financial relationships to disclose.

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.

9513 Background: CD22, a 135kd protein restricted to B-cells, is expressed in > 90% of childhood B-precursor acute lymphoblastic leukemia (ALL). We conducted a feasibility/phase 2 study of epratuzumab, a humanized monoclonal antibody against CD22, with reinduction chemotherapy in children with relapsed CD22+ ALL. Methods: The feasibility portion (n=12) of the study is reported here. Patients with first or later ALL marrow relapse at any time following diagnosis, ± extramedullary disease, with = 25% blasts expressing CD22 and a presenting white blood cell count (WBC) of = 50,000/μl, were eligible. Therapy consisted of a 14-day single agent phase (epratuzumab 360 mg/m2 /dose IV twice weekly × 4 doses), followed by 4 weekly doses of epratuzumab in combination with standard reinduction chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin). Remission induction rates and minimal residual disease (MRD) by flow cytometry were determined at the end of this 6-week period. PK studies were performed by ELISA based immunoassay (prior + 30 minutes after infusions). Results: 12 evaluable patients, median age 10 years (range 3 - 18), were accrued. 9 pts were in 1st (n=5 early; n=4 late), and 3 pts in 2nd or later marrow relapse. The mean (±SD) trough epratuzumab concentration increased from 69±23 to 232±74 μg/ml during the initial 14 days. Surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration in all but one patient, indicating effective targeting of leukemic cells by epratuzumab. The most frequent toxicities were grade 1–2 infusion reactions (n=9). Two dose limiting toxicities occurred: one patient had a Grade 4 seizure of unclear etiology and one patient had asymptomatic Grade 3 ALT elevation. 9 patients achieved a complete remission following chemoimmunotherapy, of whom 7 were MRD-negative. Conclusions: Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and well tolerated in children with relapsed ALL, producing favorable early responses in the majority of patients. The phase II portion of the study is ongoing. [Table: see text]

PURPOSE Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups’ historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort ( P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.

Abstract Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

AbstractBackgroundThe prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES.MethodsPatients had localized ES and were treated on two consecutive protocols using five‐drug chemotherapy (INT‐0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event‐free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log‐rank test, and modeled using Cox multivariate regression.ResultsPatients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS.ConclusionClinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.