10526 Background: Checkpoint inhibitors have produced impressive responses in cancer. We report results of a Phase 1 study of nivolumab (nivo) alone and in combination with ipilumumab (ipi) in children with relapsed/refractory solid tumors and activity of nivo in patients with osteosarcoma (OS) and Ewing sarcoma (EWS) treated with the RP2D. Methods: Children with relapsed/refractory solid tumors (excluding CNS tumors or metastases) were eligible for Phase I Cohorts A and C. Using a rolling 6 design, Cohort A tested nivo at the adult RP2D, 3mg/kg Q14d (cycle = 28d). Cohort C tested nivo + ipi at 2 dose levels (DLs): DL1 nivo 1mg/kg + ipi 1mg/kg and DL2 nivo 3mg/kg + ipi 1mg/kg Q21d x 4 then nivo alone Q14d. At the RP2Ds, 6 additional patients were enrolled in each cohort for pharmacokinetics (PK). Phase II expansion cohorts enrolled patients with measurable OS (Cohort B2, n = 10) or EWS (Cohort B4, n = 10) respectively to assess activity of the RP2D of single agent nivo. Results: Twelve evaluable patients enrolled in Cohort A, none had DLTs. The pediatric RP2D of nivo alone was identified as 3 mg/kg Q14d. Five evaluable patients enrolled in Cohort C:DL1 without DLT, then 12 patients enrolled in Cohort C:DL2 with one DLT within the 21d reporting period (Gr 2 creatinine increase), defining the RP2D of nivo 3mg/kg + ipi 1mg/kg at the schedule above. In 39 patients treated in cohorts A, B2, B4 and C, pleural effusions occurred in 7 with variable attributions to drug, leading to a protocol amendment mandating supportive care and corticosteroids for pleural effusions on study. Common toxicities included anemia, elevated liver enzymes, rash, fatigue, and nausea, generally Grade 1. In Cohort A, nivo C max , t 1/2 and Cl p values were 63.2±15.7 mg/mL, 10.7±1.8 d and 0.196±0.075 ml/h/kg, respectively. In the Phase II expansion cohorts, no objective responses were observed in OS or EWS. Conclusions: Nivo alone or with ipi at the doses tested is safe in pediatric patients with relapsed/refractory solid tumors. The pediatric RP2D of nivo is 3mg/kg alone or in combination with ipi 1mg/kg. Single agent nivo did not have antitumor activity in OS or EWS. Enrollment to other expansion cohorts with nivo or nivo/ipi is ongoing. Clinical trial information: NCT02304458.
Mad family proteins are transcriptional repressors that antagonize the activity of the c-Myc proto-oncogene product. Mad3 is expressed specifically during the S-phase of the cell cycle in both proliferating and differentiating cells, suggesting that its biological function is probably linked to processes that occur during this period. To determine the mechanisms that regulate the cell-cycle-specific transcription of Mad3, we used reporter gene assays in stably transfected fibroblasts. We show that the activation of Mad3 at the G1—S boundary is mediated by a single E2F (E2 promoter binding factor)-binding site within the 5′-flanking region of the gene. Mutation of this element eliminated transcriptional activation at S-phase, suggesting that the positively acting E2F proteins play a role in Mad3 regulation. Using electrophoretic mobility-shift assays and chromatin immunoprecipitation, we show that E2F1 binds to the Mad3 5′-flanking region both in vitro and in vivo. We thus identify Mad3 as a novel transcriptional target of E2F1.
To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy.Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, < or =500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor-related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4.Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults.A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE.
8527 Background: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine site on β-tubulin and inhibits microtubule polymerization. In adults, the maximum tolerated dose (MTD) is 250 mg daily x 7 days (d) or 200 mg daily x 21d. Dose limiting toxicities (DLTs) were ileus and peripheral neuropathy. Methods: Forty children ages 4 to 18 (median 13 yrs) with refractory solid tumors were enrolled, including 16 with NBL. For each cycle, patients received ABT-751 orally once daily for 7 consecutive days followed by a 14-day break or for 21 consecutive days followed by a 7-day break. Dose levels were 100 (n=4), 130 (n=6), 165 (n=6), 200 (n=7), and 250 (n=2) mg/m2/d on the 7d schedule and 75 (n=3), 100 (n=4), 130 (n=5), and 165 (n=3) mg/m2/d on the 21d schedule. PK sampling was performed on Day 1 of Cycle 1, and plasma concentrations were assayed using HPLC with tandem mass spectrometric detection method. Results: The MTD is 200 mg/m2/d (adult equivalent 375 mg) on the 7d schedule. DLTs included Grade (Gr) 2 motor neuropathy (n=1) at 130, Gr 3 constipation (n=1) at 165, and asymptomatic decrease left ventricular shortening fraction (n=2), neuropathic pain (n=1), fatigue (n=2), and neutropenia (n=1) at 250 mg/m2/d. On the 21d schedule, DLTs included Gr 4 neuropathy (n=1), vomiting and dehydration (n=1), Gr 3 fatigue (n=3), pain (n=1), and Gr 3 transaminase elevation (n=1) at 165 mg/m2/d. Accrual on the 21d schedule continues at 130 mg/m2/d (adult equivalent 260 mg). ABT-751 is rapidly absorbed (Tmax= 2.5 ± 1.2 h) and eliminated (t1/2 = 6.0 ± 2.5 h) (mean ± SD, N = 33). AUC and Cmax increase in proportion to the dose. Patients with NBL experienced prolonged disease stabilization. The median duration for evaluable patients with NBL (n=13) was 5 cycles (range 1–40); 7 patients continue on treatment and 3 are too early to evaluate. Three have had resolution of 123I-meta-iodobenzylguanidine (MIBG) positive lesions. Conclusions: ABT-751 is well tolerated in children at doses exceeding the adult MTD on the 7d and 21d schedules. Absorption after oral administration is rapid and exposure is dose proportional. Disease stabilization and improvement in MIBG scans suggests ABT-751 activity in neuroblastoma. A Phase 2 trial is in development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories
Abstract ID 129646Poster Board 407Introduction: Recurrent pediatric solid and CNS tumors pose significant challenges in pediatric oncology, resulting in considerable morbidity and mortality due to a lack of effective treatments. Dysregulation of the PI3K-Akt-mTOR pathway complex can lead to tumorigenesis and may be implicated in CNS tumors. nab-Sirolimus, also recognized as ABI-009, is a nanoparticle albumin-bound injectable form of sirolimus, a potent mTOR inhibitor. The pharmacokinetic behavior of nab-sirolimus is currently not completely elucidated in the pediatric population. Consistent with the nab-sirolimus US prescribing information and mTOR inhibitor class effects, toxicities commonly observed in the phase 1 trial of nab-sirolimus in adults (NCT00635284) included thrombocytopenia, mucositis, fatigue, rash, diarrhea, and hypertriglyceridemia. The aims of the present study were to characterize the population pharmacokinetics of nab-sirolimus in pediatric patients with relapsed/refractory solid tumors, including CNS tumors and to identify factors significantly affecting pharmacokinetic parameters. Methods:nab-Sirolimus was administered intravenously as a weekly dose on days 1 and 8 of a 21-day cycle at doses of 15, 20, and 35 mg/m2. Patients were assessed on days 1,2,4 and 8 of cycle 1 of single agent nab-sirolimus. Blood samples were collected at the following time points: at Day 1 (pre-dose, and 1, 2, 4, 8 hrs. after beginning the infusion), Day 2 (24 hrs. after beginning the Day 1 infusion), Day 4 (72 hrs. after beginning the Day 1 infusion), and Day 8 (pre-infusion) . A total of 29 pediatric patients (258 concentrations) were included in a population pharmacokinetic analysis. Non-linear mixed effect models were developed using the whole blood concentrations attained from the phase 1 clinical trial by implementing the Phoenix NLME program. Covariates that may be related to pharmacokinetics were screened using stepwise methods. The final model was validated by goodness-of-fit plots, visual predictive check, and non-parametric bootstrap. Results: A three-compartment model was selected as the best structural base model to adequately characterize nab-sirolimus pharmacokinetics. Body surface area (BSA) was the most influential factor on clearance of the central compartment, while BSA, age, sex and dose level affected the overall volume of distribution. The population estimates of clearance, and volume of distribution of the central compartment in the final model were 3.0 L/h, and 14.7 L respectively. Conclusion: The first robust population pharmacokinetic model of nab-sirolimus was successfully developed following the intravenous infusion of nab-sirolimus in pediatric patients with relapsed/refractory solid tumors, including CNS tumors. Notably, BSA emerged as a significant covariate influencing the pharmacokinetics of nab-sirolimus. This model serves as a valuable reference for guiding dose regimens in future pediatric studies involving nab-sirolimus. Keywords:nab- Sirolimus; Population Pharmacokinetics; Pediatric Oncology. This work has been supported by Mayo Clinic Cancer Center Grant Number P30 CA015083 from the National Cancer Institute (NCI), the National Institute of General Medical Sciences (NIGMS) grant T32GM 08685, AADi, The Pediatric Early Phase-Clinical Trials Network (PEP-CTN) UM1CA228823 and Cookies for Kids' Cancer.
Abstract Background: Inhibition of the WEE1 kinase by AZD1775 potentiates replicative stress induced by oncogenes or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. A pediatric phase I dose escalation study of AZD1775 in combination with irinotecan was completed within the COG DVL consortium. Methods: Patients age 1-21 years with relapsed/refractory solid or CNS tumors were eligible. Both agents were administered orally once daily on days 1-5 of a 21-day cycle with a step-wise inter-patient dose escalation of both agents. AZD1775 dose levels (DL) were 50 mg/m2 (DL1), 65 mg/m2 (DL 2 and 3), 85 mg/m2 (DL4) and 110 mg/m2 (DL5). Irinotecan, 70 mg/m2 day (DL 1-2), or 90 mg/m2/day (DL3-5), was administered with cefixime for diarrheal prophylaxis. Toxicity was graded according to CTCAE v4.0. Results: Thirty-one eligible patients, median age 14 years (range 5-20) were enrolled; 29 (93%) received prior chemotherapy (median 3 regimens) and 25 (81%) received prior radiation therapy. Sixteen patients had a primary CNS malignancy: malignant glioma (9), ependymoma (4), medulloblastoma (2) and CNS Ewings sarcoma (1). Fifteen patients had extracranial solid tumors: soft tissue sarcoma (6), neuroblastoma (2), carcinoma (4), osteosarcoma (2) and Wilms’ Tumor (1). The most common toxicities were hematologic and gastrointestinal (nausea, vomiting, diarrhea). Two patients experienced dose limiting toxicity, grade 3 diarrhea and dehydration at DL5 (AZD1775 110 mg/m2 and irinotecan 90 mg/m2). Conclusion: This is the first pediatric clinical trial of AZD1775 in combination with chemotherapy. The maximum tolerated dose in children and adolescents with solid tumors was AZD1775 85 mg/m2/day in combination with irinotecan 90 mg/m2/day for five days every 21 days. Accrual is ongoing for a pediatric PK expansion, PD analysis and Phase 2 expansion in patients with neuroblastoma or medulloblastoma / CNS PNET. Clinical trial information: NCT02095132 Citation Format: Kristina A. Cole, Joel M. Reid, Xiaowei Liu, Charles G. Minard, John M. Maris, Elizabeth Fox, Brenda J. Weigel. Pediatric phase I trial of the WEE1 inhibitor AZD1775 and irinotecan in patients with refractory solid and CNS malignancies; A Children’s Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT144. doi:10.1158/1538-7445.AM2017-CT144
10504 Background: NF-1 loss-of-function alterations are associated with development of plexiform neurofibromas (PNs). NF-1–associated PNs can arise early in life in different locations, with variable and significant morbidity. Many patients (pts) progress following surgery, and currently there are no approved systemic therapies. The MEK inhibitor trametinib is being evaluated in pediatric pts across a spectrum of tumor types in a dose-escalation cohort of a phase I/IIa study (NCT02124772) to determine a recommended dose; disease-expansion cohorts include pts with NF-1 PN. Here we present an interim analysis of safety and clinical benefit of trametinib in pediatric pts with NF-1–associated PN. Methods: Pts aged 1 mo to < 18 y with medically significant, unresectable NF-1–associated PN were treated with trametinib 0.025 to 0.040 mg/kg/d. The primary objective was safety, and secondary objectives included tumor response assessed by independent review (IR) using published MRI volumetric criteria. Results: Twenty-six pts received trametinib (0.025 mg/kg/d, n = 21; 0.032 mg/kg/d, n = 1; 0.040 mg/kg/d, n = 4). Presented here are results from the disease-expansion cohort (n = 10). Median duration of exposure was 408 d (range, 360-429 d), and 8 pts (80%) had treatment ongoing at the data cutoff (September 2017). Median age was 5.5 y (range, 1-16 y), and prior therapies included surgery (n = 5), biologics (n = 1), and targeted therapy (n = 1). Treatment-related AEs (TRAEs) were reported in 9 of 10 pts (90%), and 1 pt discontinued due to a TRAE. The most frequent TRAEs were paronychia (50%) and rash (40%). No deaths occurred on treatment. Analysis of the full NF-1 PN cohort (n = 26) is ongoing; across this cohort, 12 of 26 pts (46%) had a PR (≥ 20% volume reduction) by IR, and 10 of the 12 responses (83%) were ongoing. Conclusions: Trametinib demonstrated a manageable safety profile in pediatric pts with NF-1–associated PN. Using volumetric criteria for response determination, the objective responses observed with trametinib support continued investigation in this pt population. Clinical trial information: NCT02124772.
Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN.
