Park, Julie R.

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

AbstractBackgroundVorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD.MethodsIsotretinoin (cis‐13‐retinoic acid) 80 mg/m2/dose was administered by mouth twice daily on days 1–14 in combination with escalating doses of daily vorinostat up to 430 mg/m2/dose (days 1–4; 8–11) in each 28‐day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed.ResultsTwenty‐nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1–15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose‐limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2/day, days 1–4; 8–11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen.ConclusionsIncreased dose vorinostat (430 mg/m2/day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.

Abstract Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

Abstract Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081–9. ©2012 AACR.

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.