bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.
Authors: Laetsch Theodore Willis , DuBois Steven G. , Nagasubramanian Ramamoorthy , Turpin Brian , Mascarenhas Leo , Federman Noah , Reynolds Mark , Smith Steven , Cruickshank Scott , Cox Michael Craig , Pappo Alberto S. , Hawkins Douglas S. 
Published: September 2018

10510 Background: Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Data from the adult phase I trial demonstrate prolonged responses in patients (pts) with TRK fusions and a favorable tolerability profile. Methods: This multicenter, rolling 6 phase I study enrolled pts with refractory solid or CNS tumors aged ≥ 1 month – 21 years. Pts were dosed orally BID on a continuous 28-day schedule either by capsule or solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended Phase II dose (RP2D) of 100 mg BID. The primary objective was to define the MTD / RP2D; secondary objectives included PK and efficacy using RECIST v1.1. Results: As of December 31, 2016, 17 pts (12 with TRK fusions, 5 without TRK fusions) with a median age of 5.2 years (0.4 – 18.3) were enrolled to 3 dose levels. Pts were enrolled with fusions of all 3 NTRK genes: NTRK1 (n=6), NTRK2 (n=1), and NTRK3 (n=5) in heterogeneous tumor diagnoses: infantile fibrosarcoma (IFS) (n=6), other sarcoma (n=4), and papillary thyroid cancer (n=2). Most common AEs regardless of attribution were vomiting, diarrhea, and fatigue. While 8 (47%) pts experienced grade 3-4 AEs, none were attributed to larotrectinib. No DLTs were observed and an MTD was not established. Both formulations delivered dose-dependent PK comparable to the adult RP2D at dose level 3. 12 pts (10 with TRK fusions, 2 without TRK fusions) remain on treatment with median follow-up of 2.8 months (0.7 – 8.4). Among TRK fusion pts, the vast majority have achieved confirmed RECIST responses regardless of tumor diagnoses. No responses were seen in pts without TRK fusions (n=4). 5 pts discontinued therapy, including 2 with TRK fusions: 1 pt with IFS had sufficient response to allow tumor resection, and 1 pt with IFS progressed with a documented acquired resistance mutation. Conclusions: Larotrectinib has demonstrated a favorable tolerability profile and histology-independent efficacy in pediatric pts harboring TRK fusions. Updated safety and efficacy data will be presented, including the RP2D, response rate, duration of response, and use of larotrectinib in the pre-surgical setting. Clinical trial information: NCT02637687.
Phase 1/2 KEYNOTE-051 study of pembrolizumab (pembro) in pediatric patients (pts) with advanced melanoma or a PD-L1+ advanced, relapsed, or refractory solid tumor or lymphoma.
Authors: Geoerger Birgit , Kang Hyoung Jin , Yalon-Oren Michal , Marshall Lynley V. , Vezina Catherine , Pappo Alberto S. , Laetsch Theodore Willis , Petrilli Antonio Sergio , Handgretinger Rupert , Toporski Jacek , Glade-Bender Julia , Nicholls Wayne , Fox Elizabeth , DuBois Steven G. , Macy Margaret , Cohn Susan Lerner , Pathiraja Kumudu , Diede Scott J. , Ebbinghaus Scot , Pinto Navin R. 
Published: September 2018

10525 Background: In phase 1 of the KEYNOTE-051 study (NCT02332668), the 2 mg/kg Q3W approved adult dose of pembro was also determined to be the pediatric recommended phase 2 dose. In phase 2, presented herein, we further evaluated this dose in pediatric pts with advanced cancer. Methods: Children aged 6 mo to < 18 y with advanced melanoma or a PD-L1+ advanced, relapsed or refractory solid tumor or lymphoma, measurable disease per RECIST v1.1, and performance score ≥50 using Lansky Play or Karnofsky scales received pembro 2 mg/kg Q3W for 35 cycles or until confirmed disease progression per immune-related RECIST by investigator review, intolerable toxicity, or pt/investigator decision to discontinue. Tumor imaging was performed every 8 wk for the first 6 mo, then every 12 wk thereafter. AEs were graded by NCI CTCAE v4.0. Key efficacy endpoints were ORR, disease control rate (DCR), and PFS per RECIST v1.1 by investigator and OS. Results: Of 369 pts prescreened, 364 were evaluable for PD-L1 expression; of these, 121 (33.2%) were PD-L1+. 66 pts were enrolled; median follow-up was 2.5 mo (range, 0.2-18). As of the data cutoff (Nov 7, 2016), 23 (34.8%) pts were still on treatment. Median age was 13 y (range, 1-17), 77.3% had metastatic disease, and 34.8% had ≥3 prior lines of therapy for recurrent/metastatic disease. Primary diagnoses were non-CNS solid tumors (n = 45), CNS tumors (n = 16), and lymphoma (n = 5). 5 (7.6%) pts had grade 3-4 treatment-related AEs (TRAEs), most commonly neutropenia (n = 2). No treatment-related deaths occurred; 1 pt discontinued for a TRAE (grade 3 AST increased). 1 pt each with Hodgkin lymphoma, adrenocortical carcinoma, mesothelioma, and glioblastoma had partial response for an ORR of 6.1% (95% CI, 1.7-14.8); 7 (10.6%) pts had stable disease for a DCR of 16.7% (95% CI, 8.6-27.9). Median PFS and OS were 1.8 mo and 9.2 mo, respectively; 12-mo PFS was 10.2% and OS was 40.5%. Potential effects of pembro on the developing immune system (eg, T and B cells, vaccinated antibodies) will also be presented. Conclusions: Pembro showed low toxicity and warrants further study to determine activity in select pediatric tumors. Enrollment in KEYNOTE-051 is ongoing. Clinical trial information: NCT02332668.
Risk stratification including FOXO1 fusion status (FOXO1) in patients with rhabdomyosarcoma (RMS) treated on six recent frontline trials: A report from the Children's Oncology Group (COG).
Authors: Hibbitts Emily , Hawkins Douglas S. , Arndt Carola A. S. , Chi Yueh-Yun 
Published: September 2018

10528 Background: Clinical risk factors associated with outcome in children with either localized or metastatic RMS were identified by Meza et al. (2006) and Oberlin et al. (2008). We re-examined risk stratification by adding FOXO1 to traditional clinical prognostic factors in children with localized or metastatic RMS in a large cohort from COG frontline clinical trials. Methods: Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1,853 eligible patients (two studies each for low, intermediate and high risk patients). Survival tree regression for event-free survival (EFS) and overall survival (OS) was conducted to determine prognostic impact of risk factors. Recursively, the factor most strongly associated with outcome was selected for branching and split using a goodness of fit measure. Factors included were age, FOXO1, group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Results: 5-year overall EFS and OS was 0.67 (SE, 0.01) and 0.77 (SE, 0.01), respectively. Survival trees for EFS and OS found localized versus metastatic at the first split and included FOXO1 as a significant risk factor. Conclusions: FOXO1 improves risk stratification of patients with localized RMS, although histology and pattern of metastases are more predictive for patients with metastatic RMS. Our findings support incorporation of FOXO1 in risk stratified clinical trials. [Table: see text]
Blinatumomab use in pediatric patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from an open-label, multicenter, expanded access study.
Authors: Locatelli Franco , Zugmaier Gerhard , Vora Ajay , Rossig Claudia , Peters Christina , Brethon Benoit , O'Brien Maureen Megan , Belton Laura , Handgretinger Rupert 
Published: September 2018

10530 Background:Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown antileukemia activity and tolerability in pts with r/r ALL. We further evaluated safety and efficacy of blin in the first 40 pediatric pts with r/r ALL enrolled in an expanded access study (NCT02187354). Methods: Eligible pts (28 d to < 18 yrs) had ≥ 5% blasts and r/r ALL (refractory, ≥ 2 relapses or relapse after transplant [HCT]). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (≥ 5 to < 25% blasts: 15 µg/m2/d; ≥ 25% blasts: 5 µg/m2/d on d1−7 in cycle 1, then 15 µg/m2/d). The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs); key efficacy endpoints were complete response (CR) and minimal residual disease (MRD, by PCR or flow cytometry) in the first 2 cycles, relapse-free survival, overall survival and HCT rate. Results: Of the first40 treated pts (median age, 9 [range, 1−17] yrs), 24 (60%) had ≥ 2 relapses, 20 (50%) relapsed after HCT and 5 (13%) were primary refractory; 18 (45%) had ≥ 50% blasts and 21 (53%) had prior HCT. Safety and key efficacy outcomes are shown in the table, including 63% CR in the first 2 cycles. There were 8 relapses and 20 deaths after treatment. Regardless of causality, the most frequent TEAEs were pyrexia (78%), cytokine release syndrome (CRS; 23%) vomiting (23%) and anemia (20%); all 9 CRS events were grade (gr) 1 or 2 and 1 tumor lysis syndrome was gr 3. 10 (25%) pts interrupted treatment and 2 (5%) discontinued due to TRAEs; 13 (33%) pts had gr ≥ 3 TRAEs, including 2 of 3 neurologic events (depressed level of consciousness and headache; both gr 3); 2 fatal AEs were considered unrelated to blin. Conclusions:Here single-agent blin showed antileukemia activity in pediatric pts with high-risk r/r ALL including t(17;19) and AEs consistent with those previously reported for r/r ALL. Clinical trial information: NCT02187354. [Table: see text]
Early response rates and Curie scores at end of induction: An update from a phase II study of an anti-GD2 monoclonal antibody (mAb) with chemotherapy (CT) in newly diagnosed patients (pts) with high-risk (HR) neuroblastoma (NB).
Authors: Furman Wayne Lee , Shulkin Barry L. , Federico Sara Michele , McCarville Mary B , Davidoff Andrew M. , Krasin Matthew J. , Wu Jianrong , Brennan Rachel Christine , Bishop Michael William , Helmig Sara E. , Navid Fariba , Santana Victor M. , Anthony Gwendolyn , Hank Jacquelyn A , Gillies Stephen D , Sondel Paul M. , Leung Wing H. , Pappo Alberto S. 
Published: September 2018

10534 Background: We are conducting a Phase II trial of the anti-GD2 mAb hu14.18K322A given concomitantly with CT in newly diagnosed pts with HR NB. Our primary objective is to compare the response rate (RR; defined as ≥ PR) after two courses of CT with cyclophosphamide (CTX)/topotecan (TPT) and hu14.18K322A with GM-CSF and IL-2 to the RR reported by Park et al. (JCO 29:4351, 2011), using identical CT with GCSF only, in a two-stage group sequential design. Semiquantitative MIBG scoring (Curie; CS) has been shown to be a prognostic indicator of outcome in pts with HR NB (Yanik et al, J Nucl Med, 2013), particularly, those with CS > 2 at end of induction (EoI) CT have inferior outcomes. Here we update the RR and report the CS at EoI CT. Methods: Pts received induction CT (6 cycles) as described by Park et al, with the addition of hu14.18K332A (on d 2-5; 40mg/m2/d x 4d), daily sc GM-CSF and sc IL-2 (1 x 106 IU/m2/dose) qod x 6. 123I-MIBG scans and scoring (CS) were obtained on all pts at diagnosis, after second course of CT and at EoI. Results: 42 evaluable pts completed the first two courses of CT (24 male, median age 2.9 yrs (range 6 m -15.2 yrs), 36 INSS 4, 19 MYCNamplified); 40/42 evaluable pts had measurable reductions in primary tumor volume after two courses of CT (median 79%, average 69%, range +5 – 100%). Responses (≥ PR) after two courses were seen in 32/42 (76.2%; 95% CI 61.3 – 87.9%); No mAb dose-reductions were made but 20/43 (47%) pts had infusion times extended. The development of human anti-human antibody reactivity (HAHA) to hu14.18K322A in the first 22 pts is minimal. Of the 36 INSS 4 pts, 1 withdrew prior to EoI and 2 are too early. The median CS at diagnosis for the 33 stage 4 pts who have completed induction CT was 18 (range 1 – 28). At EoI the median CS was 0 (range 0 -23); 29/33 INSS 4 pts had EoI CS ≤ 2. Conclusions: The addition of hu14.18K322A to two courses of CTX/TPT significantly improves the RR compared to two courses of CTX/TPT alone (32/42 vs 12/30 as reported by Park et al,; P = 0.000004). The improved median CS of the stage 4 patients from 18 at diagnosis to 0 at EoI suggest the improvement in early RR may translate into improved EFS as well. Clinical trial information: NCT01857934.
ADVL1522: A phase 2 study of IMGN901 (lorvotuzumab mertansine; IND# 126953, NSC# 783609) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma: A Children's Oncology Group study.
Authors: Geller James I. , Pressey Joseph Gerald , Smith Malcolm A. , Kudgus Rachel A. , Schoon Renee , McGovern Renee M. , Cajaiba Mariana , Reid Joel M. , Hall David , Barkauskas Donald A. , Dome Jeffrey , Fox Elizabeth , Weigel Brenda 
Published: September 2018

10537 Background: Lorvotuzumab mertansine (IMGN901; LM) is an antibody-drug conjugate, linking anti-mitotic agent (DM1) to an anti-CD56 antibody. Preclinical data show effects in Wilms tumor (WT), rhabdomyosarcoma (RMS), and neuroblastoma (NBL). Synovial sarcoma (SS), MPNST and pleuropulmonary blastoma (PPB) also express CD56. A phase 2 trial assessing the efficacy and tolerability of LM administered at the adult recommended phase 2 dose (RP2D) was conducted in children with relapsed tumors. Methods: LM (110 mg/m2/dose) was administered IV on days (d) 1 and 8 of 21 d cycles, with dexamethasone pre-medication. The tolerability of LM was assessed in 6 patients prior to trial activation group-wide. Dose limiting toxicity (DLT) was assessed using CTCAE. Response was assessed by RECIST. Pharmacokinetics (PK) were obtained during cycle 1. Peripheral blood CD56-positive cells were measured d1 and d8 pre-dose. Tumor CD56 expression by immunohistochemistry in archival tissue was scored (0-3+). Results: Sixty-two patients were enrolled. The median (range) age was 14.3 y (2.8–29.9); 35 were male. Diagnoses included WT (17), RMS (17), NBL (12), SS (10), MPNST (5) and PPB (1). One patient was ineligible due to lack of measurable disease. Of 61 eligible patients, 47 were evaluable for toxicity, 50 for response, 50 for tumor CD56 expression; and 18 consented to optional PK. Five patients experienced 9 DLTs: hyperglycemia (1), colonic fistula (1) with perforation (1), nausea (1) with vomiting (1), increased ALT (2 in cycle 1; 1 in cycle 2 with increased AST (1)). Non-dose limiting toxicities (Grade ≥3) attributed to LM included lymphopenia, anemia, vomiting, dehydration, hypokalemia, hyperuricemia, hypophosphatemia. Mean DM1 Cmax, t1/2 and AUC0-∞values were 922 ng/ml, 33 h and 27400 ng/ml*h, respectively. Tumor CD56 expression was 0 (8%), 1+(4%), 2+(12%), 3+(76%). LM and CD56 antibody PK, and response, will be reported. Conclusions: LM (110 mg/m2) is tolerated in children at the adult RP2D. Clinical trial information: NCT 02452554.
Role of radiotherapy to primary/metastatic sites in pediatric patients with metastatic rhabdomyosarcoma in the BERNIE study.
Authors: Cameron Alison , Chisholm Julia , Elze Markus C. , Casanova Michela , Geoerger Birgit , Gaze Mark , Oberlin Odile , Bachir Jeanette , Fürst-Recktenwald Sabine , Merks Johannes H.M. 
Published: September 2018

10541 Background: Local control is a key part of treatment of local/locoregional rhabdomyosarcoma (RMS) and often involves radiotherapy (RT) with/without surgery. The role of RT in metastatic RMS is uncertain, with little published evidence to guide clinicians. We analyzed data from the BERNIE trial to assess the benefit of RT for patients (pts) with metastatic RMS. Methods: In the BERNIE study (NCT00643565) pts aged ≥6 months to <18yrs with metastatic RMS and non-RMS soft tissue sarcoma were randomized to receive chemotherapy (CT) with/without bevacizumab (BEV), surgery, and/or RT (at cycle 6–9) then maintenance CT. RT was recommended for all sites of metastases if feasible (investigator discretion allowed, resulting in variability in actual RT given). Pts were categorized into those receiving: RT all sites, partial RT, no RT. Event-free survival (EFS) and overall survival (OS) were calculated using Cox proportional hazards models and a landmark approach: only pts who were event free at day 221 (i.e. end of cycle 9 + 1 month) were included (EFS, n=85; OS, n=97). Variables adjusted were: treatment (as randomized), disease type (alveolar/embryonal/other), risk group, age >10yrs, metastatic lesion count (1, 2–3, 4+). The analysis was non-randomized, exploratory and post hoc. Results: Of 102 pts with RMS, 22 received no RT, 49 partial RT, and 31 RT to all sites. Baseline characteristics were mostly balanced, and comparable proportions of pts received BEV. Better OS was observed in the RT group (Table) (comparable with unadjusted results). A non-significant EFS improvement was observed for the RT groups. Conclusions: Partial RT and RT to all sites of disease in metastatic RMS was associated with significant OS benefits, albeit in small pt numbers. This should be confirmed in a prospective randomized trial. Clinical trial information: NCT00643565. [Table: see text]
Phase I study of talazoparib and irinotecan in children and young adults with recurrent/refractory solid tumors.
Authors: Federico Sara Michele , Stewart Elizabeth , Coleman Jamie L. , Bishop Michael William , Santana Victor M. , Lam Catherine , Hawkins Dana , Wu Jianrong , Mao Shenghua , Goshorn David Ross , Pappo Alberto S. , Dyer Michael A. 
Published: September 2018

10542 Background: Poly (ADP-ribose) Polymerase inhibitors (PARPi) target tumors with deficiencies in DNA repair mechanisms. Talazoparib (TAL), a potent PARP inhibitor, demonstrated significant efficacy in a Ewing sarcoma model when combined with DNA-damaging irinotecan (IRN). We performed a phase I trial to determine the maximum tolerated doses (MTDs) of TAL and IRN in pediatric patients with solid tumors. Methods: Cohorts of 3-6 eligible patients (pts) with recurrent/refractory solid tumors received escalating doses of oral (PO) TAL and intravenous (IV) IRN in a 3+3 design (Table 1). Each course was 21 days. Serum for TAL and IRN pharmacokinetics (PK) were obtained. Toxicities were assessed using CTCAE v.4 and responses were evaluated by RECIST v.1.1. Results: Twenty-four pts (9 male; median age, 11 years; 18 recurrent) received a median of 2 courses (range, 1-18). Fifteen pts had prior exposure to IRN. Table 1 summarizes the dose-limiting toxicities (DLTs) in course 1. The most common grade 3 or higher non-hematologic and hematologic toxicities in 82 evaluable courses were febrile neutropenia (5), elevated gamma-glutamyltransferase (GGT, 4), neutropenia (22) and lymphopenia (17). Two of 22 evaluable patients had a response (CR Ewing sarcoma, 18 courses; PR synovial sarcoma, 10 courses) and 9 had disease stabilization, median 4 courses (range, 4-10). Results of PK tests will be presented. Conclusions: The recommended phase II doses are TAL 600mcg/m2 (max 1000mcg/dose) days 1-6 and IRN 40mg/m2/day days 2-6. This regimen is feasible with evidence of anti-tumor activity and warrants further investigation. Clinical trial information: NCT02392793. [Table: see text]
Noninvasive molecular profiling of high-risk relapsed neuroblastoma by plasma cell-free DNA analysis.
Authors: Kothari Prachi , Yang Julie , Berger Michael F. , Shukla Neerav Narendra , Modak Shakeel , Tsui Dana 
Published: September 2018

10552 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. 5-year survival rates for high-risk NB are < 50% despite intense multimodality treatment. Recent studies revealed that as opposed to diagnostic samples, relapsed NB tumors have a significantly higher mutational burden as a result of clonal evolution. This poses a challenge for the development of personalized therapies and warrants molecular profiling at relapse. However, tumor samples are not always accessible at relapse. Our study evaluates the feasibility of using cell-free DNA (cfDNA) to noninvasively characterize tumor profiles at relapse to identify targetable genetic variants. Methods: Tumor specimens, plasma and matched control samples from 10 patients with high-risk stage 4 NB were collected during multimodality treatment. Samples were analyzed using the MSK-IMPACT platform, a targeted deep sequencing assay to interrogate the exons and selected introns of 410 actionable genes. Tumor samples were collected from surgeries performed either at diagnosis, disease progression, or relapse. Plasma samples were collected at a time of disease progression, at an average 395 days (range of 47-1597 days) from tumor collection. Matched control samples were used to filter germline variants. Results: We detected somatic mutations and copy number alterations in tumor tissues and cfDNA of 10/10 and 6/10 patients, respectively. These included recurrent NB drivers such as MYCN amplification and ATRX mutations. In 4 patients, cfDNA also revealed somatic variants that were not detected in the original tumor specimens, including potentially targetable mutations in NRAS, MLL2, CIC and IDH2 that were recently reported to be enriched in the relapse setting, as well as ARID1B mutation that is associated with poor prognosis. Conclusions: This study suggests that it is feasible to noninvasively profile the dynamic genetic heterogeneity of NB by plasma cfDNA analysis. Such analysis can potentially supplement tumor profiling especially in the relapse setting to guide treatment plans. Our findings call for incorporation of cfDNA analysis in clinical trials to further evaluate its utility for clinical management of NB patients.
Solid organ transplant after treatment for childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Dietz Andrew Charles , Seidel Kristy , Leisenring Wendy M. , Mulrooney Daniel A. , Tersak Jean M. , Glick Richard D. , Burnweit Cathy A , Green Daniel M. , Diller Lisa , Oeffinger Kevin C. , Smith Susan A , Howell Rebecca M. , Stovall Marilyn , Robison Leslie L. , Armstrong Gregory T. , Termuhlen Amanda M. 
Published: September 2018

10559 Background: Childhood cancer therapy is associated with late onset, organ-specific impairment. However, the prevalence of and outcomes after solid organ transplant (SOT) in childhood cancer survivors (CCS) are unknown. Methods: Data on U.S-based participants in the Childhood Cancer Survivor Study were linked with the Organ Procurement and Transplantation Network. Cumulative incidence of transplant (CIT) 35 years after cancer diagnosis, multivariable Cox regression models for hazard ratios (HR), Kaplan-Meier (KM) survival and corresponding 95% confidence intervals (CI) were estimated. Results: Among 13,318 survivors, median follow-up age 39 years (interquartile range, IQR 33-46), and median time since cancer diagnosis 31 years (IQR 28-36 years), 100 CCS had SOT after study entry with characteristics and outcomes provided (table). Conclusions: Organ-specific radiation and chemotherapy exposure increase the risk for SOT after childhood cancer. Five-year survival rates after renal and cardiac SOT are favorable. [Table: see text]