bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib study of abemaciclib in combination with pembrolizumab for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (MBC) (NCT02779751): Interim results.
Authors: Rugo Hope S. , Kabos Peter , Beck Joseph Thaddeus , Chisamore Michael Jon , Hossain Anwar , Chen Yanyun , Tolaney Sara M. 
Published: May 2020

1051 Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase (CDK)4 and 6 inhibitor, approved to treat HR+, HER2- MBC patients (pts) on a continuous twice daily dosing schedule as monotherapy or in combination with an aromatase inhibitor as initial endocrine based therapy or in combination with fulvestrant. Abemaciclib monotherapy increased tumor immunogenicity and synergized with anti-PD-1 to boost antitumor efficacy in murine models. Here we report safety and antitumor activity of abemaciclib plus pembrolizumab in HR+, HER2- MBC pts. Methods: This multicenter, nonrandomized, open-label, multi-cohort phase Ib study of abemaciclib plus pembrolizumab enrolled a cohort of endocrine resistant HR+, HER2- MBC pts who had received 1 or 2 prior chemotherapy regimens for MBC. No prior CDK4/6 inhibitor was allowed. Patients received 150mg abemaciclib orally every 12 hours plus pembrolizumab 200mg IV on day 1 every 21 days. Primary objective was to characterize safety of the abemaciclib plus pembrolizumab combination. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Of 28 pts enrolled, 15 (54%) received 1 line and 10 (36%) 2 lines of prior systemic chemotherapy in the locally advanced/metastatic setting. Safety of the combination was generally consistent with known side effects of abemaciclib and pembrolizumab and was generally manageable. Grade 3/4 adverse events in >2 pts included neutropenia (8 pts/29%), AST increase (5 pts/18%), diarrhea, and ALT increase (3 pts/11% each). Eight pts had confirmed partial response (29% ORR), and disease control rate (complete response [CR]+partial response [PR]+stable disease [SD]) was 82%. Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 46%. Median PFS and OS were 8.9 months (95% CI 3.9, 11.1) and 26.3 months (95% CI 20.0, 31.0), respectively. Conclusions: Combination of abemaciclib plus pembrolizumab demonstrated a generally tolerable safety profile with numerically higher rate of transaminase elevations than reported for the individual treatments. Compared to historical data for abemaciclib monotherapy in a similar pt population, a numerically higher but not obviously different ORR, PFS, and OS was observed. Clinical trial information: NCT02779751 .
Underdiagnosis and undertreament of modifiable cardiovascular risk factors: A Childhood Cancer Survivor Study (CCSS) report.
Authors: Chow Eric Jessen , Chen Yan , Armstrong Gregory T. , Baldwin Laura-Mae , Gibson Todd M. , Hudson Melissa M. , McDonald Aaron , Nathan Paul C. , Syrjala Karen L , Tonorezos Emily S. , Oeffinger Kevin C. , Yasui Yutaka 
Published: May 2020

10515 Background: Survivors of childhood cancer exposed to cardiotoxic therapies are at increased risk of heart disease. Hypertension, dyslipidemia, and diabetes are modifiable cardiovascular risk factors (CVRFs) that synergistically increase this risk. Therefore, we aimed to determine the prevalence of and predictors associated with CVRF underdiagnosis and undertreatment in this population. Methods: CCSS participants at increased risk of heart disease due to prior cancer therapy were enrolled in an ongoing randomized intervention trial (NCT03104543) to improve CVRF identification and treatment. Participants completed a baseline survey (CVRF status, lifestyle habits, attitudes towards healthcare), anthropometry, and blood draw. Blood pressure, low density lipoprotein, triglyceride, glucose and Hgb A1c were measured and classified as normal/abnormal per standard clinical criteria. Multivariable logistic regression estimated odds ratios (OR [95% confidence intervals]) associated with predictors and risk of CVRF underdiagnosis and undertreatment. Results: As of January 2020, 522 participants (43% male) were available for analysis (47% response), with a median age 38y (range 20-65) and 28y (18-49) from original cancer treatment (75% anthracycline, 47% chest radiation). With mean measured BMI 27.3±6.5 kg/m2, self-reported prevalence rates were hypertension 27%, dyslipidemia 33%, and diabetes 9%. While 90% of participants had a routine check-up ≤2y ago, 58% had a measured CVRF in the abnormal range. Specifically, among previously undiagnosed participants, we observed rates of abnormal blood pressure (26%), lipids (17%), and glucose tolerance (27%). Among those with pre-existing hypertension, dyslipidemia, and diabetes, 11%, 49%, and 54%, respectively, had measurements outside of the usual therapeutic target range. In multivariable analysis, BMI ≥25 kg/m2 (vs < 25) was associated with risk of underdiagnosis (OR 1.8 [1.2-2.8]). For undertreatment, significant adverse factors included older age ( > 35 vs ≤35y: OR 2.5 [1.2-5.1]), BMI ≥30 kg/m2 (vs < 25: OR 3.3 [1.7-6.4]), and greater perceived reliance on others for healthcare decisions (OR 1.7 [1.2-2.4]). Those with greater health-related self-efficacy were less likely to be undertreated (OR 0.5 [0.3-0.96]). Conclusions: CVRF underdiagnosis and undertreatment among childhood cancer survivors at increased risk of heart disease was common. Greater awareness among survivors and primary care providers and more aggressive control of CVRFs may mitigate this risk.
Evaluation of CD22 modulation as a mechanism of resistance to inotuzumab ozogamicin (InO): Results from central CD22 testing on the Children’s Oncology Group (COG) phase II trial of INO in children and young adults with CD22+ B-acute lymphoblastic leukemia (B-ALL).
Authors: Shah Nirali N. , O'Brien Maureen Megan , Yuan Constance , Ji Lingyun , Xu Xinxin , Rheingold Susan R. , Bhojwani Deepa , Yi Joanna , Harris Andrew , Brown Patrick A. , Borowitz Michael J. , Devidas Meenakshi , Raetz Elizabeth A. , Gore Lia , Loh Mignon L. 
Published: May 2020

10519 Background: The COG AALL1621 phase 2 trial evaluated the efficacy of InO in children and young adults with relapsed/refractory CD22+ B-cell ALL. We report results of central surface CD22 expression on ALL and impact on response. Methods: Optional central CD22 testing was performed on bone marrow and/or peripheral blood at the NCI flow cytometry (FC) laboratory pre/post cycle 1. Percentage of blasts with CD22+ expression (CD22%) was measured by multiparameter FC and the BD Biosciences QuantiBRITE system quantified the CD22 site density by measuring CD22 antibody bound per cell (ABC). Comparison of ABC and CD22% between subgroups was based on Wilcoxon rank sum test or signed rank test as appropriate. Post-treatment CD22 assessments could only be performed on those with residual ALL. Results: Amongst 48 patients, 28 (58.3%) achieved a complete response (CR) or CR with incomplete count recovery. The median CD22 ABC, pre and post-cycle 1, was 2688 (range, 290-10715, n = 33) and 1098 (184-6822, n = 15) respectively. Amongst 27 subjects with paired pre/post samples, median pre-treatment CD22 ABC was lower in those with residual ALL (n = 13) than in those without residual ALL (ABC 1005 (290-8848) vs ABC 4123 (762-10715), p = 0.003). Baseline CD22% ranged more widely in those with residual ALL, median 99% (40-100%) vs. 99% (92.9-100%, no residual ALL) p = 0.025; and significant decreases in CD22% were seen compared to baseline in those with residual ALL, with median post-treatment CD22% 82% (1.4%-100%), p = 0.007. Amongst 3 subjects with baseline partial CD22% (40%, 79% and 83% partial CD22+ populations), post-cycle 1 evaluations revealed emergence of predominantly CD22 negative populations (6.5%, 34% and 48% CD22+, respectively), precluding eradication of minimal residual disease. Amongst those with KMT2A rearrangement, 2 of 4 had partial CD22 expression and 4 of 4 had low ABC ( < 1500). Conclusions: Baseline CD22 expression, specifically low CD22 ABC and partial CD22% were significantly associated with response to treatment, emerging as potential biomarkers for poor InO response. This is particularly relevant to patients with KMT2Arearrangement who may be predisposed to CD22 partial positivity and low ABC. Evolution of CD22 negative/dim disease post-therapy suggests CD22 modulation is a mechanism of resistance to InO. Response to InO monotherapy may be limited in those with baseline CD22 negative/dim populations. Clinical trial information: NCT02981628.
Comparison of chemotherapy dose intensity for AYAs on COG AALL1131 versus CALGB 10403.
Authors: McNeer Jennifer Lynn , Ji Lingyun , Xu Xinxin , Burke Michael , Salzer Wanda , Devidas Meenakshi , Laumann Kristina M , Wood Charlotte , Advani Anjali S. , Larson Richard A. , Luger Selina M. , Stock Wendy , Loh Mignon L. , Hunger Stephen , Raetz Elizabeth A. 
Published: May 2020

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.
OSTPDL1: A phase II study of avelumab, a monoclonal antibody targeting programmed death-ligand 1 (PD-L1) in adolescent and young adult patients with recurrent or progressive osteosarcoma.
Authors: Bishop Michael William , Kaste Sue C. , Sykes April , Pan Haitao , Dela Cruz Filemon S. , Whittle Sarah , Mascarenhas Leo , Thomas Paul G , Youngblood Ben , Harman Jennifer L , Wang Lisa L. , Meyers Paul A. , Pappo Alberto S. 
Published: May 2020

10521 Background: Outcomes for recurrent osteosarcoma are poor and novel therapies are needed. Osteosarcoma has a high mutational burden with overexpression of PD-L1 in metastatic lesions, providing a rationale for testing immune checkpoint inhibitors in this population. We therefore evaluated the activity of the PD-L1 inhibitor avelumab in patients with recurrent or progressive osteosarcoma. Methods: We conducted a single-arm, open-label phase 2 trial at 4 collaborating institutions. Eligible subjects were ages 12 to ≤50 years with recurrent or progressive osteosarcoma and radiographic evidence of measurable disease. Subjects received avelumab 10 mg/kg intravenously every 2 weeks of 28-day cycles until disease progression or unacceptable toxicity. Primary endpoints were objective response rate (CR + PR according to RECIST v.1.1), and progression-free survival (PFS) at 16 weeks. Kaplan-Meier methods were used to estimate PFS. Secondary endpoints included toxicity. Correlative objectives included measurement of subsets of peripheral blood mononuclear cells and serum markers of immune activation, and measures of cell proliferation, co-inhibitory receptor expression on CD8 T cells, T cell repertoire, and epigenetic programming of T cells. Results: Between February 2017 and October 2019, 18 eligible subjects [67% male, median age 16.8 years (12.8-22.9)] were enrolled. Subjects had received median 3 prior systemic therapies (range 1-5). Sites of disease included lung/pleura (94%), bone (56%), and soft tissue (28%). Subjects received a median of 2 cycles (range 1-4) of avelumab. Median PFS was 8 weeks (95% CI 6.7-9.1). No objective responses occurred (17 with progressive disease), and the 16-week PFS was 0%. The most common adverse events (AEs) were alanine aminotransferase (ALT) elevation (17%), aspartate aminotransferase (AST) elevation, dyspnea, hyponatremia, and pain (each 11%). Treatment-related serious AEs (≥Grade 3) included dyspnea (n = 2), ALT/ALT elevation, hyponatremia, pericardial effusion and anemia (n = 1). Immune-related AEs included pneumonitis, Hashimoto thyroiditis, and pericardial effusion (all n = 1). One patient discontinued therapy after 1 dose due to grade 4 ischemic stroke, unrelated to avelumab. One death occurred on study due to rapid disease progression. Conclusions: Avelumab did not demonstrate activity in recurrent osteosarcoma. Correlative biology studies are ongoing to elucidate mechanisms of resistance to this therapy. Clinical trial information: NCT03006848.
Phase I trial of pazopanib in combination with irinotecan and temozolomide (PAZIT) for children and young adults with advanced sarcoma.
Authors: Vo Kieuhoa T. , Michlitsch Jennifer G. , Shah Avanthi T. , Reid Joel M. , Burhow Sarah A. , Graham Eloise M. , Hollinger Fabienne , Zapala Matthew A. , Long-Boyle Janel , Kim Mi-Ok , Matthay Katherine K. , DuBois Steven G. 
Published: May 2020

10526 Background: Pro-angiogenic factors may represent therapeutic targets in sarcoma. Preclinical studies have demonstrated a potential additive or synergistic interaction between anti-angiogenic agents and chemotherapy. The purpose of this study was to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetic (PK) and pharmacodynamics (PD) effects of PAZIT in patients with advanced sarcoma. Methods: Patients 6-30 years of age with relapsed/refractory sarcomas were eligible. In the initial dose escalation plan (A), patients received pazopanib PO (225-450 mg/m2/dose) on Days 1-21 of 21-day cycles. Pazopanib was combined with fixed doses of irinotecan (IV 50 or PO 90 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Due to DLTs, an amendment was made to the dose escalation plan (B) and patients received fixed doses of pazopanib PO (225 mg/m2/dose) on Days 1-21 of 21-day cycles and reduced irinotecan doses (IV 25-37.5 or PO 45-67.5 mg/m2/dose) and temozolomide PO 100 mg/m2/dose on Days 1-5. Oral cephalosporin diarrhea prophylaxis was required. Dose escalation followed a 3+3 design. Correlative studies included PK (pazopanib, irinotecan) and PD (angiogenic factors, ctDNA) effects. Results: Sixteen patients were treated (median age 16 years, range 7-21). The dose levels in the table were evaluated. First cycle DLTs occurred at all dose levels (Table) and included diarrhea, pancreatitis, colitis, neutropenia, hypertension, deep vein thrombosis, and ALT increase. Due to excessive toxicity, an MTD could not be established. One patient with osteosarcoma had a partial response. Four patients had prolonged stable disease > 4 cycles, including 2 patients with Ewing sarcoma (5 and 6 cycles), rhabdomyosarcoma (9 cycles), and desmoplastic small round cell tumor (6 cycles). Mean±SD plasma exposures to pazopanib, irinotecan, and SN-38 in patients treated on dose level 1B (n = 4) on Day 4 were 601±83, 1.4±0.2 and 0.1±0.04 ug/mL*hr, respectively. Analyses of correlative studies are ongoing. Conclusions: Combination PAZIT therapy is not tolerable as evaluated at these doses/schedules. This study provides important toxicity data to inform future clinical trials using combination anti-angiogenic strategies in sarcoma. Clinical trial information: NCT03139331. [Table: see text]
Tag-n-trak study: Preliminary analysis of an unselected biobank tumors with NTRK fusion transcript, the French SFCE society contribution.
Authors: Lemelle Lauriane , Guillemot Delphine , Brisse Hervé , Gauthier Arnaud , Carton Matthieu , Hermann Anne-Laure , Corradini Nadege , Rome Angélique , Boutroux Hélène , Jourdain Anne , Marie Cardine Aude , Jannier Sarah , Castex Marie Pierre , Defachelles Anne Sophie , Aerts Isabelle , Karanian Marie , Doz Francois P. , Delattre Olivier , Pierron Gaëlle , Orbach Daniel 
Published: May 2020

10540 Background: NTRK ( Neurotrophic receptor tyrosine kinase) fusion transcript was initially described in infantile fibrosarcoma (IFS) and is now known to be present in many other rare types of tumor with a lower incidence. The main objective of the study is to describe the presentation and outcome of unselected tumors with NTRK fusion transcript (NTRK-FTT) to better consider the role of TRK inhibitors (TRKi) in such entities. Methods: We selected patients (pts) from the Institut Curie biobank (adults and children) with NTRK-FTT and which were assessed by RT-qPCR then RNA sequencing in a prospective or retrospective process, between 2001 and 2019. Results: We identified 62 NTRK-FTT among 2119 screened tumors (2.2 cases/year with RT-qPCR and 6.9 cases/year with RNA seq after 2016), NTRK3 (44 cases) (including 41 NTRK3-ETV6), NTRK2 (9) or NTRK1 (9). Most of pts had under 2 years (y) (74%) and only 7 pts were adults. We report preliminary analysis of clinical observation for the first 27 pts. Median age was 0.4 y [0-60.2]. Pathologic diagnosis was IFS (12 cases), various CNS tumors (4), atypical teratoid rhabdoid tumor (1), myofibroblastic inflammatory tumor (2), benign tumors (3), cellular congenital mesoblastic nephroma (2), lipofibromatosis like neural tumor, myxoïd liposarcoma, unclassifiable sarcoma (1 each). Two pts had metastatic tumors. Among all, 22 had surgery (1 mutilating), 15 chemotherapy, 4 radiotherapy, and 5 received TRKi, as second line treatment (2 pts) or ≥ third line (3 pts). After a median follow-up of 50 months [range, 1-155], 20/27 pts remained in complete remission, 3 had stable residue, and 4 had progressive disease (associated to 1 disease-related and 1 toxic deaths). Five-year OS is 88% [95%CI, 73.5-100] and 5y-EFS 59.5% [95%CI, 41.7-84.9]. Conclusions: This descriptive study showed that NTRK-FTT is rare (2.9%), encompasses a variety of different histotypes (n = 14). Systematic RNA sequencing allowed to depict 3.5 times more NTRK-FTT than targeted RT-qPCR. Overall outcome is favorable despite frequent tumor events. According to tumor type and the uncertainties regarding the long-term side effects of TRKi, the benefit/risk ratio must be carefully evaluated before using these drugs in first line.
Naxitamab, a new generation anti-GD2 monoclonal antibody (mAb) for treatment of relapsed/refractory high-risk neuroblastoma (HR-NB).
Authors: Mora Jaume , Chan Godfrey Chi-Fung , Morgenstern Daniel A. , Nysom Karsten , Bear Melissa K , Dalby Lene Worsaae , Lisby Steen , Kushner Brian H. 
Published: May 2020

10543 Background: NB is a rare cancer but represents the most common extracranial solid tumor of childhood. Most HR-NB patients present with or develop metastatic disease typically in bone or bone marrow (BM). Despite advances in frontline multimodal therapy ~50% of patients relapse. Refractory or relapsed disease represents an unmet medical need. GD2 is an adhesion molecule abundantly expressed in NB. Naxitamab is a humanized anti-GD2 mAb with high receptor affinity. Methods: We evaluated naxitamab in HR-NB patients with disease in bone and/or BM, who were refractory to initial treatment(s) or who had insufficient response to therapy for progressive/relapsed disease. Patients were treated in an outpatient setting with naxitamab as a planned 30-minute i.v. infusion and s.c. granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients received 3 infusions of naxitamab 3 mg/kg/dose during the first week of a treatment cycle repeated initially every 4 weeks. Patients were evaluated for safety (CTCAE V4.0) and efficacy (INRC, Park et al. 2017). Results: We report on 24 patients recruited from April 2018 with a data cut off in June 2019. At diagnosis, 21 patients were stage 4, 1 was stage 3, 2 were unknown. At study entry, 11 patients had metastases in bone, 1 in BM and 12 in both bone and BM. Overall objective response was 75% (18/24), with complete response (CR) in 67% (16/24) and partial response in 8% (2/24). Of the 13 patients with BM involvement at enrollment, 12 achieved CR in BM during trial therapy. 6 treatment-related SAEs were reported in 5 patients (anaphylactic reaction, pyrexia, and respiratory depression). Conclusions: Naxitamab is an anti-GD2 mAb under development for HR-NB. In addition to a high CR rate of 67% and an overall objective response rate of 75% in a high-risk patient population, naxitamab offers an unique option for treatment of patients in the outpatient setting. These data and convenience to patients are strongly supportive of further drug development. Clinical trial information: NCT03363373.