bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib dose escalation study of combined inhibition of IDO1 (GDC-0919) and PD-L1 (atezolizumab) in patients (pts) with locally advanced or metastatic solid tumors.
Authors: Burris Howard A. , Gordon Michael S. , Hellmann Matthew David , LoRusso Patricia , Emens Leisha A. , Hodi F. Stephen , Lieu Christopher Hanyoung , Infante Jeffrey R. , Tsai Frank Yung-Chin , Eder Joseph Paul , Cleary James M. , Jelovac Danijela , Tsuhako Amy L. , Mueller Lars , Lin Ray , Morrissey Kari , Mahrus Sami , Morley Roland , Pirzkall Andrea , Davis Sarah Lindsey 
Published: September 2018

105 Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.
A high-risk genetic profile for premature menopause (PM) in childhood cancer survivors (CCS) exposed to gonadotoxic therapy: A report from the St. Jude Lifetime Cohort (SJLIFE) and Childhood Cancer Survivor Study (CCSS).
Authors: Brooke Russell J , Chemaitilly Wassim , Wilson Carmen Louise , Krasin Matthew J. , Li Zhenghong , Im Cindy , Morton Lindsay M. , Wu Gang , Wang Zhaoming , Chen Wenan , Howell Rebecca M. , Armstrong Gregory T. , Bhatia Smita , Chanock Stephen J. , Zhang Jinghui , Green Daniel M. , Sklar Charles A. , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka 
Published: September 2018

10502 Background: CCS are at increased risk of therapy-related PM but contribution of genetic factors is unknown. Methods: Using Affymetrix 6.0 SNP array, treatment exposures [cumulative alkylating agents (AA), ovarian radiotherapy (RT) dose] and clinically-assessed PM status (menopause < 40 years), a genome-wide association analysis was conducted using logistic regression in SJLIFE. A cluster of most statistically significant SNPs on chr4 was further examined, stratifying by ovarian RT and AA. Replication was performed using self-reported PM in CCSS. Results: PM was diagnosed in 30 of 805 SJLIFE female survivors. A loci of 13 SNPs in 4 linkage disequilibrium blocks (mean r2 = 0.51) in the upstream regulatory region of Neuropeptide Receptor 2 ( NPY2R) was identified with a minimum p-value of 3.3x10-7 (all <10-5). ENCODE gene expression, motifs, and chromatin remodeling data suggest these SNPs alter transcription factor binding sites, potentially disrupting neuroendocrine events necessary for ovulation. Among CCS exposed to ovarian RT, homozygous carriers of a risk profile (RP) defined by 4 of the 13 SNPs, found in over half of the survivors with clinically-diagnosed PM and 1 in 7 in the general population, significantly increased PM risk (odds ratio (OR) 25.8, p=5.4x10-5) (Table). This finding was replicated using self-reported PM status of 1644 survivors in CCSS (OR 4.2, p=4.6x10-4). Prediction of clinically-diagnosed PM (in the SJLIFE discovery cohort) improved by adding the RP to the model with age and treatment (area under ROC curve 0.84 vs. 0.93, p=0.011). Conclusions: The common RP is associated with PM risk in pediatric cancer survivors and may have potential for clinical application. [Table: see text]
Temporal trends in late-onset morbidity and mortality after medulloblastoma diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Salloum Ralph , Chen Yan , Yasui Yutaka , Packer Roger , Leisenring Wendy M. , Wells Elizabeth M. , King Allison A. , Howell Rebecca M. , Gibson Todd M. , Krull Kevin R. , Robison Leslie L. , Oeffinger Kevin C. , Fouladi Maryam , Armstrong Gregory T. 
Published: September 2018

10516 Background: Therapy for medulloblastoma and primitive neuroectodermal tumor has evolved from surgery and adjuvant radiotherapy to risk-adapted multimodal regimens. The impact of these changes in treatment on long-term outcomes remains unknown. Methods: Cumulative incidence of late mortality ( > 5 years from diagnosis), subsequent malignant neoplasms (SMN), chronic health conditions and psychosocial functioning were evaluated among 5-year survivors in CCSS diagnosed between 1970 and 1999. Survivors were stratified according to treatment decade (1970s, 1980s, 1990s) and treatment exposure (surgery + craniospinal irradiation [CSI] ≥30 Gy, no chemotherapy; surgery + CSI ≥30 Gy + chemotherapy [high-risk therapy], surgery + CSI ˂30 Gy + chemotherapy [standard-risk therapy]). Rate ratios (RRs), odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for long-term outcomes among treatment eras and exposure groups using multivariable piecewise-exponential models. Results: Among 1,380 eligible survivors (median [range] age 29 [6-20] years; 21.4 [5-44] years from diagnosis), the 15-year cumulative incidence of all-cause (21.9% 1970s vs. 12.8% 1990s; p = 0.003) and recurrence-related (16.2% vs 9.6%, p = 0.03) late mortality decreased with no reduction in mortality attributable to late effects of therapy including SMN. Among 959 participants, the incidence of SMN did not decrease by era or by treatment group. However, survivors treated in the 1990s had an increased cumulative incidence of severe, life-threatening and fatal health conditions (16.9% 1970s vs 25.4% 1990s; p = 0.03), and were more likely to develop multiple severe or life-threatening health conditions, RR = 2.98 (95% CI, 1.10-8.07). Survivors of standard-risk therapy were less likely to use special education services than high-risk therapy patients, OR = 0.51 (95% CI, 0.33-0.78). Conclusions: Historical changes in therapy have improved 5-year survival, reduced risk of late mortality due to disease recurrence, and reduced special education utilization, at the cost of increased risk for multiple, severe and life-threatening chronic health conditions.
Longitudinal analysis of quality of life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children’s Oncology Group (COG) AALL0932.
Authors: Zheng Daniel , Lu Xiaomin , Ross Wilhelmenia L. , Angiolillo Anne L. , Schore Reuven , Balsamo Lyn M. , Devidas Meenakshi , Whitley Moira K. , Kadan-Lottick Nina S. 
Published: September 2018

10522 Background: 5-year event-free survival for average-risk acute lymphoblastic leukemia (AR-ALL) in children is ~95%. However, therapy involves multi-agent chemotherapy, frequent hospital visits (duration of therapy is 26 months for girls and 38 months for boys) and painful procedures that can adversely affect quality of life (QOL). Methods: AR-ALL patients enrolled on COG AALL0932 were offered participation if ≥4 years old at diagnosis with an English-speaking parent. At ~2, 8, 17, 26, and 38 (boys only) months after diagnosis, parents completed the PedsQL4.0 and the Family Assessment Device instruments for QOL (assessing physical and emotional functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (i.e. 2 SD below population mean) were calculated at each timepoint. Patterns of impairment over time and potential predictors were examined. Results: 594 participants with AR-ALL (48% female, 68% white) were diagnosed at a median age of 5.6 (IQR: 4.6–7.1) years. At 2 months, a significant percentage of participants had impaired scores compared to population norms for physical (36.5 vs. 2.3; 95% CI 32.3-40.8) and emotional functioning (26.2 vs. 2.3; 95% CI 22.5-30.2). Although scores improved over time, elevations persisted at 26 months for physical (11.9 vs. 2.3; 95% CI 8.4-16.1) and emotional (9.8 vs. 2.3; 95% CI 2.0-6.7) functioning. In repeated measures analysis with multivariate modeling, emotional impairment at 2 months (OR 3.7; 95% CI 1.5-7.7) and abnormal family functioning (OR 1.5; 95% CI 1.1-2.1) significantly predicted emotional impairment. QOL outcomes were similar for girls at 26 months and boys at 38 months. Conclusions: Many children with AR-ALL experience severe impairment in both physical and emotional functioning that begins early in treatment and persists. Family functioning is a modifiable risk factor that may be targeted for early screening and intervention.
A phase I/II study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors (iMATRIX-Atezolizumab).
Authors: Geoerger Birgit , Karski Erin E. , Zwaan Michel , Casanova Michela , Marshall Lynley V. , DuBois Steven G. , Kowgier Matthew , Tagen Michael , Kwan Antonia , Das-Thakur Meghna , Trippett Tanya Maria 
Published: September 2018

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.
ADVL1412: Initial results of a phase I/II study of nivolumab and ipilimumab in pediatric patients with relapsed/refractory solid tumors—A COG study.
Authors: Davis Kara L. , Fox Elizabeth , Reid Joel M. , Liu Xiaowei , Minard Charles G. , Weigel Brenda , Mackall Crystal 
Published: September 2018

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 Cmax, t1/2 and Clpvalues 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.
Outcomes of children with hereditary medullary thyroid carcinoma (MTC) treated with vandetanib.
Authors: Kraft Ira Lignugaris , Akshintala Srivandana , Derse-Anthony Claudia , Steinberg Seth M. , Venzon David J. , Dombi Eva , Waguespack Steven G. , Kapustina Oxana Borisovna , Fox Elizabeth , Balis Frank M. , Shern John Frederick , Glod John , Widemann Brigitte C. 
Published: September 2018

10540 Background: Vandetanib is well tolerated and active in children with advanced or metastatic hereditary MTC (NCT00514046) [data cutoff 7/2011; Clin Cancer Res. 2013 Aug 1;19(15):4239-48]. We report outcomes as of 1/2017. Methods: We monitored toxicities, RECISTv1.0, carcinoembryonic antigen (CEA), and calcitonin (CT) response. Patients (pts) removed from the vandetanib trial were followed on a natural history study (NCT01660984). Results: Of 17 pts (8 male, age 13 years (9-17)*) enrolled, 1 was lost to follow-up. Of the 16 pts analyzed, 15 had a RET p.M918T germline mutation. The duration of vandetanib therapy was 5.6 years (0.1-9.2+) with treatment ongoing in 8 pts. Best response was partial response (PR) in 10, stable disease (SD) in 5, and progressive disease (PD) in 1 pt. Time to achieve PR (n = 10) was 0.6 years (0.4-2.4). Time to best response (n = 16) was 1.5 years (0.1-4.1). Duration of response was 5.1 years (1.3-8.6+) in pts with PR and 4.8 years (0.6-7.3+) in pts with SD. Seven of 8 pts with PD subsequently received sunitinib, sorafenib, and/or cabozantinib. Disease progression occurred as increase in target (n = 2), non-target/new lesions (n = 5), or CT/CEA (n = 1). Six pts died from disease 2.1 years (0.4-4.3) after stopping vandetanib. Progression free survival was 6.2 years (95% CI 3.0-na) and overall survival was 7.9 years (95% CI 5.9-na).Pts had no difference in enrollment age, baseline CT/CEA, or tumor size per response categories (n = 16). Rate of CEA/CT decrease during initial 4 months of treatment was not associated with PR/SD compared to PD (n = 16). While on vandetanib, 6 pts with PD had CEA or CT doubling time (DT) of < 2 years within 1 year prior to PD. All pts with ongoing PR/SD had CEA and CT DT > 2 years while on vandetanib. No pts came off treatment for toxicity. Dose reductions occurred in 8 pts for grade (gr) 2 weight loss (n = 2), palpitations (n = 1), arrhythmia (n = 1), elevated creatinine (n = 1), diarrhea (n = 2), and gr 3 constipation (n = 1). Conclusions: Many children with hereditary MTC sustained PR/SD on vandetanib. However, half ultimately developed PD and died from disease despite treatment with other targeted therapies. CEA/CT DT < 2 years within 1 year of progression on vandetanib may be associated with PD. *Median (range)
Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.
Authors: Gaspar Nathalie , Gallego Melcon Maria Soledad , Venkatramani Rajkumar , Bielack Stefan S. , Casanova Michela , Locatelli Franco , Thebaud Estelle , Rigaud Charlotte , Abbou Samuel , Gambart Marion , Morland Bruce , Aerts Isabelle , Kraljevic Silvija , Li Di , Maniar Hina , Hayato Seiichi , Dutcus Corina E , Campbell Hewson Quentin 
Published: September 2018

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had < 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.
Relationship between the cumulative burden (CB) of chronic health conditions (CHC) and health-related quality of life (HRQoL) among childhood cancer survivors (CCS): The St. Jude Lifetime (SJLIFE) cohort.
Authors: Bhakta Nickhill , Liu Qi , Ehrhardt Matthew J. , Ness Kirsten K. , Krull Kevin R. , Srivastava Deo Kumar , Ganz Patricia A. , Yasui Yutaka , Hudson Melissa M. , Robison Leslie L. , Huang I-Chan 
Published: September 2018

10560 Background: Adult CCS experience an excess burden of CHC. The association between disease burden (estimated using CB) and HRQoL has not been extensively assessed. Methods: 2878 CCS (mean [range] age 32.1 [18.3-66.2] years; time from diagnosis 25.0 [10.2-51.0] years) were enrolled in SJLIFE (eligibility: survived >10 years and >18 years of age) and clinically evaluated for 168 graded CHC using the St. Jude modified Common Terminology Criteria for Adverse Events. HRQoL was assessed using the Short Form 36 survey and categorized into Low (< -0.5 SDs), Average (-0.5 to 0.5 SDs), and High (> 0.5 SDs) subgroups from the Physical and Mental Component Summary (PCS, MCS) and Vitality Scale using cohort age- and sex-specific values. CB (average number of grade 3-4 [severe/life-threatening] CHC/survivor) for each CHC was calculated and summed for each HRQoL subgroup. Results: Survivors with low PCS had, on average, more CHC CB compared to those with High and Average PCS. Higher CHC CB was also associated with poorer Vitality and MCS, but the differences in effect size were smaller than PCS. When CB for each of the 3 HRQoL scores were compared by subgroups across 12 organ systems and subsequent neoplasms, CB at age 50 differed significantly (p<0.05) across PCS, MCS, and Vitality in 9, 3 and 7 of the 13 systems, respectively. Conclusions: Survivors with lower HRQoL scores have more CHC, but the patterns of this association vary in PCS, MCS and Vitality by CHC organ systems, suggesting adult CCS adjust better to certain types of CHC than others. Future research will focus on CHC with greatest impact on functioning. [Table: see text]