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Purpose Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes after 131 I-metaiodobenzylguanidine ( 131 I-MIBG) therapy in patients with neuroblastoma. Methods and Materials We conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated with 131 I-MIBG as monotherapy or in combination with systemic putative radiation sensitizers. We collected serial peripheral blood samples after 131 I-MIBG infusions and quantified a panel of protein and messenger RNA markers. We plotted relative change from baseline to assess degree of modulation over time and then evaluated association of marker modulation with toxicity and response endpoints. Results The cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 after 131 I-MIBG. Greater fold increase of plasma FLT3 ligand was associated with subsequent grade 4 neutropenia ( P =.039). Modulation of peripheral blood BCLXL and DDB2 was associated with grade 3+ nonhematologic toxicity ( P =.043 and .048, respectively). No markers were associated with tumor response. Greater plasma FLT3 ligand, BCLXL , and BCL2 modulation was observed in patients receiving 131 I-MIBG in combination with radiation sensitizers. Among 9 patients who received 2 courses, the degree of modulation in serum amylase was significantly lower after the second course ( P =.012). Conclusions Peripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after 131 I-MIBG. The degree of modulation of a subset of these markers is associated with toxicity and receipt of concomitant radiation sensitizers.

// Kieuhoa T. Vo 1 , Erin E. Karski 1 , Nicole M. Nasholm 1 , Shelly Allen 1 , Fabienne Hollinger 1 , W. Clay Gustafson 1 , Janel R. Long-Boyle 2 , Stephen Shiboski 3 , Katherine K. Matthay 1 and Steven G. DuBois 1 1 Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 2 Department of Clinical Pharmacy, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 3 Department of Epidemiology and Biostatistics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA Correspondence to: Kieuhoa T. Vo, email: // Keywords : phase 1, mTOR, sirolimus, topotecan, cyclophosphamide Received : August 23, 2016 Accepted : October 13, 2016 Published : October 25, 2016 Abstract Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population. Materials and Methods: Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m 2 /dose) on days 1-21 and oral topotecan (0.8 mg/m 2 /dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated. Results: Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m 2 /dose; and topotecan 0.8 mg/m 2 /dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 ( p =0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline. Conclusions: The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.

Background Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. Procedure We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan–Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. Results A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age

Children with high-risk or relapsed hepatoblastoma continue to represent treatment challenges. Multiple case reports have documented the use of high-dose chemotherapy with stem cell rescue (HDC) for this population; however, the efficacy and appropriate use of HDC remains unclear.A literature search was performed to identify cases of hepatoblastoma that were treated with HDC. Additional patients were identified by a query through the Pediatric Blood and Marrow Transplant Consortium. All cases were categorized as undergoing HDC as part of their initial treatment or for relapsed disease. Overall survival (OS) and event-free survival (EFS) proportions were calculated for each group. Subgroup analyses were performed looking at the effects of remission status, initial stage, and relapse site.Forty-two patients were identified. Thirty-one patients received HDC as part of their initial treatment and 55% were long-term survivors with 48% event-free. Eleven received HDC for relapsed disease and 64% were long-term survivors, 36% without events.It is difficult to draw firm conclusions from a small number of nonrandomized patients who had different stages, treatments, and events before undergoing HDC. However, our calculated EFS and OS proportions are consistent with current data using multimodal therapy without HDC, suggesting that HDC (at least as currently delivered) for hepatoblastoma may not be beneficial.

388 Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.

BACKGROUND: Rhabdoid tumors (RTs) are aggressive, rare tumors usually diagnosed in early childhood. They portend poor prognosis, despite multi-modality treatment. Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anti-cancer T-cell activity. The iMATRIX-Atezolizumab study (phase I/II, open-label; NCT02541604) assessed safety, pharmacokinetics, and preliminary activity of atezolizumab in pediatric/young adult patients. METHODS: Patients aged

10524 Background: Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anticancer T-cell response. The iMATRIX-Atezolizumab study (phase I/II, multicenter, open-label; NCT02541604) assessed the safety, pharmacokinetics (PK) and preliminary activity of atezolizumab in pediatric/young adult patients with refractory/relapsed solid tumors. Methods: Patients aged < 30 years with refractory/relapsed non-central nervous system solid tumors received atezolizumab every 3 weeks until loss of clinical benefit ( < 18 years old, 15mg/kg [maximum dose 1200mg]; ≥18 years old, 1200mg). Safety/PK were assessed across tumor types and initial response was assessed by tumor-type cohorts after approximately 10 patients in each cohort had been treated. Results: As of July 19 2016, 74 patients (median age 14 years; range 2–29) were enrolled: osteosarcoma, n = 12; Ewing sarcoma, n = 11; neuroblastoma, n = 11; rhabdomyosarcoma (RMS), n = 10; non-RMS soft tissue sarcoma, n = 10; Wilms tumor, n = 6; Hodgkin lymphoma (HL), n = 5; non-HL, n = 1; other tumor types, n = 8. PK data (n = 48) were similar to that in adults (geometric mean Cmin, µg/mL [cycle 2, day 1, pre-dose]: 53.6 [2– < 6 years old]; 54.1 [6– < 12 years old]; 62.0 [12– < 18 years old]; 68.0 [adult]). Most tumors, except HL, had < 1% (score 0) tumor cell [TC]/tumor-infiltrating immune cell (IC) PD-L1 expression with overall TC/IC-positive expression rates (≥1%, score 1–3) of 7% and 10%, respectively. All available HL samples had ≥5% (score 2–3) TC/IC PD-L1 expression. 67/71 patients who received atezolizumab (median cycles 2; range 1–10) had ≥1 adverse event (AE; mainly immune-related grade 1–2); 17 patients (24%) had treatment-related grade 3–4 AEs. One AE (grade 3 transaminase increase) led to study drug discontinuation. Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%). 2/5 patients with HL had a partial response (PR); the only patient with atypical rhabdoid tumor (RT) had an unconfirmed PR. Conclusions: The PK and safety profile of atezolizumab in pediatric and young adult patients is similar to that in adults. Preliminary antitumor activity was seen in HL and RT; new cohorts are planned in RT and atypical teratoid RT. Clinical trial information: NCT02541604.

BackgroundThe peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥40 years at diagnosis. We describe the clinical characteristics and survival of this rare group.MethodsThis retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer.ResultsPatients ≥40 years of age were more likely to have extra-skeletal tumors (66.1% vs. 31.7%; p < 0.001), axial tumors (64.0% vs. 57.2%; p = 0.01), and metastatic disease at diagnosis (35.5% vs. 30.0%; p = 0.04) compared to younger patients. Five-year survival for those age ≥40 and age

10060 Background: Neuroblastoma (NB) is the most common solid extra-cranial tumor of childhood. 131I-mIBG is a targeted radiopharmaceutical for patients with advanced NB and is one of the most active agents in this treatment resistant population. To date, no clinically relevant biomarkers of response or toxicity have been reported in patients treated with 131I-mIBG. Methods: Patients with relapsed or refractory NB who received 131I-mIBG at UCSF were eligible to participate in this prospective correlative study. Blood samples were obtained at baseline and 72 hours after 131I-mIBG infusion. We quantified a panel of biomarkers shown to be effected in patients receiving other forms of radiation, including: serum amylase; plasma Flt-3 ligand; plasma monocyte colony stimulating factor (MCSF); and CDKN1A mRNA in mononuclear cells. Extent of modulation of each marker was evaluated using paired t-tests at hour 0 and 72. We assessed potential differential modulation between groups based on response (PR/CR vs SD/PD), toxicity (grade 3 non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia) or administration of combination therapy (131I-mIBG alone vs in combination with vincristine/irinotecan or vorinostat) using unpaired t-tests. Results: 26 patients (21 male; median age 7 years) participated and received a median 131I-mIBG dose of 18 mCi/kg. 16 patients received 131I-mIBG in combination. We observed robust modulation of amylase (median fold increase from baseline 3.1; p 131I-mIBG had more robust modulation of Flt-3 ligand (mean difference 296 pg/mL; p=0.02) compared to single agent 131I-mIBG. No correlations with clinical response or toxicity were found. Conclusions: Amylase, Flt-3 ligand, and CDKN1A mRNA all show robust modulation after 131I-mIBG treatment. Patients receiving 131I-mIBG in combination demonstrated the largest changes in plasma Flt-3 ligand. In this initial analysis, no associations were found between response or toxicity and the proposed biomarkers.