Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

Background A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. Procedure 4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design. Results Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine response-evaluable patients, six had stable disease (SD)(4 – 26 courses); four with marrow- or bone disease-only had complete responses (CR)(10 - 46 courses). 4-HPR plasma levels were several fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached. Conclusions 4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.

We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, Δ, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between Δ and progression-free survival (PFS). NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their Δ values were correlated (Spearman = 0.67, < 0.0001), although bone marrow was 7.9 ± 0.5 stronger than blood When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity ( < 0.0001 and = 0.007). Bone marrow and blood Δ values correlated with PFS ( < 0.001; = 0.001) even when bone marrow was morphologically negative ( = 0.001; = 0.014). Multivariate analysis showed that bone marrow and blood Δ values were associated with PFS independently of clinical disease and gene status ( < 0.001; = 0.055). This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. .

Purpose:131 I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical with activity in patients with relapsed or refractory neuroblastoma. Irinotecan is a known radiosensitizer with activity in neuroblastoma. This phase I study aimed to determine the recommended phase 2 dose of MIBG together with fixed doses of vincristine and irinotecan. Experimental Design: Patients 1 to 30 years old with relapsed or refractory neuroblastoma and MIBGavid tumors were eligible. All patients had autologous hematopoietic stem cells (PBSC) available and met standard phase I organ function requirements. Irinotecan (20 mg/m 2 /dose IV) was given on days 0 to 4 and 7 to 11, with vincristine (1.5 mg/m 2 IV) on days 0 and 7. MIBG was given on day 1 following a 3 þ 3 phase I dose escalation design starting at 8 mCi/kg MIBG. PBSCs were administered at dose level 8 mCi/kg for prolonged myelosuppression and for all patients at 12 mCi/kg or more. Results: Twenty-four patients evaluable for dose escalation (median age, 6.7 years; range, 1.9-26.8 years) received 1 (n ¼ 17), 2 (n ¼ 5), or 3 (n ¼ 2) cycles of therapy. Myelosuppression and diarrhea were the most common toxicities. Two of 6 patients at the 18 mCi/kg dose level had dose-limiting toxicity (DLT), including one with protocol-defined DLT with prolonged mild aspartate aminotransferase elevation. Eighteen mCi/kg was the recommended phase 2 dose. Six additional patients were treated at 18 mCi/kg, with one additional DLT. Responses (2 complete and 4 partial responses) occurred in 6 of 24 (25%) evaluable patients.Conclusions: MIBG is tolerable and active at 18 mCi/kg with standard doses of vincristine and irinotecan.

Chemotherapy followed by reduced dose whole ventricular and local boost irradiation appears to be effective in patients with localized pure CNS germinoma with evidence of preservation of neurocognitive function.

Patients with LCH involving only the bones have a significantly better outcome than those with other organ involvement. Patients with multiple organ involvement who are less than 1 year of age are at high risk of death and should be approached more aggressively upfront.

BackgroundMany parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors' knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor‐prognosis childhood cancer.MethodsThe authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high‐risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child's likelihood of cure; their primary goal of care; the child's symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions.ResultsOnly 26% of parents recognized that the chance of cure was <25%. When asked to choose a single most important goal of care, approximately 72% chose cure, 10% chose longer life, and 18% chose quality of life. Parents were more likely to prioritize quality of life when they recognized the child's poor prognosis (P = .002). Approximately 41% of parents expressed regret about the most recent treatment decision. Parents were more likely to experience regret if the child had received higher intensity medical care (odds ratio [OR], 3.14; 95% CI, 1.31‐7.51), experienced suffering with limited benefit from the most recent treatment (OR, 4.78; 95% CI, 1.16‐19.72), or experienced suffering from symptoms (OR, 2.91; 95% CI, 1.18‐7.16).ConclusionsParents of children with poor‐prognosis cancer frequently make decisions based on unrealistic expectations. New strategies for effective prognosis communication are needed.

(131)I-Metaiodobenzylguanidine ((131)I-MIBG) has been used as a single agent or in combination with chemotherapy for the treatment of high-risk neuroblastoma. The activity and toxicity of (131)I-MIBG when combined with carboplatin, etoposide, and melphalan (CEM) and autologous stem cell transplantation (SCT) are now investigated in a phase II multicenter study. Fifty patients with MIBG-avid disease were enrolled into 2 cohorts, stratified by response to induction therapy. The primary study endpoint was response of patients with refractory (n = 27) or progressive disease (n = 15). A second cohort of patients (n = 8) with a partial response (PR) to induction therapy was included to obtain preliminary response data. (131)I-MIBG was administered on day -21 to all patients, with CEM given days -7 to -4, and SCT given on day 0. (131)I-MIBG dosing was determined by pre-therapy glomerular filtration rate (GFR), with 8 mCi/kg given if GFR was 60 to 99 mL/minute/1.73 m(2) (n = 13) and 12 mCi/kg if GFR ≥ 100 mL/minute/1.73 m(2) (n = 37). External beam radiotherapy was delivered to the primary and metastatic sites, beginning approximately 6 weeks after SCT. Responses (complete response + PR) were seen in 4 of 41 (10%) evaluable patients with primary refractory or progressive disease. At 3 years after SCT, the event-free survival (EFS) was 20% ± 7%, with overall survival (OS) 62% ± 8% for this cohort of patients. Responses were noted in 3 of 8 (38%) of patients with a PR to induction, with 3-year EFS 38% ± 17% and OS 75% ± 15%. No statistically significant difference was found comparing EFS or OS based upon pre-therapy GFR or disease cohort. Six of 50 patients had nonhematologic dose-limiting toxicity (DLT); 1 of 13 in the low GFR and 5 of 37 in the normal GFR cohorts. Hepatic sinusoidal obstructive syndrome (SOS) was seen in 6 patients (12%), with 5 events defined as dose-limiting SOS. The median times to neutrophil and platelet engraftment were 10 and 15 days, respectively. Patients received a median 163 cGy (61 to 846 cGy) with (131)I-MIBG administration, with 2 of 3 patients receiving >500 cGy experiencing DLT. The addition of (131)I-MIBG to a myeloablative CEM regimen is tolerable and active therapy for patients with high-risk neuroblastoma.