bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported outcomes (PROs) from the phase III IMspire150 trial of atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in patients (pts) with BRAFV600+melanoma.
Authors: Lewis Karl D. , Robert Caroline , Ascierto Paolo Antonio , Stroyakovskiy Daniil , Gogas Helen , Protsenko Svetlana , Pereira Rodrigo Perez , Eigentler Thomas K. , Rutkowski Piotr , Demidov Lev V. , Manikhas Georgy Moiseevich , Tadesse-Bell Sara , Huang Kuan-Chieh , McNally V. , Mulla Sohail , McArthur Grant A. , Gutzmer Ralf 
Published: May 2020

10073 Background: In IMspire150, A+C+V significantly improved investigator-assessed progression-free survival vs placebo (Pbo)+C+V in previously untreated pts with unresectable stage IIIc/IV BRAFV600+melanoma. PRO data from this trial are now reported. Methods: 514pts were randomized 1:1 to 28-day cycles of A+C+V or Pbo+C+V. Pts received C+V in cycle 1; A or Pbo was added on days 1 and 15 from cycle 2 onward. Pts completed the EORTC QLQ-C30 questionnaire on day 1 of cycle 1 (baseline), days 1 and 15 of cycle 2 and cycle 3, day 1 from cycle 4 onward, within 28-d of treatment discontinuation, and ≤6 months post-treatment. Prespecified secondary PRO endpoints were time to confirmed deterioration (TTCD; defined as time from randomization to first ≥10-point decrease from baseline held for 2 consecutive assessments, or 1 assessment followed by death on treatment) in quality of life (QoL) and physical functioning (PF). Prespecified exploratory endpoints were TTCD in role functioning (RF); mean change from baseline and percentage of pts with a clinically meaningful change (≥10 points from baseline) in QoL, PF, and RF. Results: Questionnaire completion rates were > 80% for most of the treatment period. At baseline, mean QoL, PF, and RF scores were moderate to high (Table). At week 6 (cycle 2), following initiation of A, QoL, PF, and RF scores declined, but returned to near-baseline levels at week 10 (cycle 3) and were largely maintained until week 36 (cycle 10), when < 50% of pts contributed data. In this time, ≥56% pts in both arms did not experience a clinically meaningful deterioration in QoL, PF, and RF. TTCD on QoL (hazard ratio [HR] 1.23; 95% CI 0.90-1.67), PF (HR 1.27; 95% CI 0.93-1.74), and RF (HR 1.15; 95% CI 0.86-1.55) favored Pbo, but only one-third of pts overall experienced a confirmed deterioration. Conclusions: PRO data showed that A+C+V did not worsen QoL, PF, and RF in pts with advanced BRAFV600+melanoma, thus supporting its use as a treatment option. Clinical trial information: NCT02908672. [Table: see text]
Safety and clinical activity of gene-engineered T-cell therapy targeting HPV-16 E7 for epithelial cancers.
Authors: Norberg Scott , Nagarsheth Nisha , Sinkoe Andrew , Adhikary Sabina , Meyer Thomas , Lack Justin , Kanakry Jennifer Ann , Bagheri Mohammadhadi , Schweitzer Colleen , Astrow Stephanie H. , Bot Adrian , Stroncek David , Gkitsas Nikolaos , Highfill Steven , Hinrichs Christian S. 
Published: May 2020

101 Background: Genetically engineered T-cell therapy has shown remarkable clinical activity in hematologic malignancies. It is not known if this type of treatment can be applied effectively to epithelial cancers, which account for 80% to 90% of human malignancies. Methods: We conducted a phase I clinical trial with a 3 + 3 dose escalation in which patients with metastatic HPV-16+ epithelial cancers were treated with a one-time infusion of genetically engineered T cells expressing a T-cell receptor targeting an HLA-A*02:01-restricted epitope of HPV-16 E7 (E7 TCR-T cells). A lymphocyte-depleting conditioning regimen was administered before cell infusion, and high-dose systemic aldesleukin was administered after cell infusion. Results: Twelve patients, previously treated with a median of 4 (range, 3 to 7) anticancer agents, were treated. The cell dose was not limited by toxicity. Six patients demonstrated objective clinical responses, which included regression of bulky tumors and complete elimination of some tumors. Responses occurred in patients with vulvar, anal, head and neck, and cervical cancer. Four patients who previously received PD-1-based therapy responded. Response duration ranged from 3 to 9 months. Sustained, high-level engraftment of E7 TCR-T cells in peripheral blood was observed (median after approximately 6 weeks, 66% of total T cells, range 1% to 88%) and correlated with cell dose but not with clinical response. Infused T cell characteristics did not correlate strongly with response. Of the 4 resistant tumors that were studied, 3 demonstrated genetic defects in HLA-A*02:01 or B2M (necessary components of the target complex) and 1 demonstrated copy loss with decreased expression of antigen presentation and interferon response molecules (i.e. TAP1, TAP2, IFNGR1, IFNGR2). Of the 3 sensitive tumors studied, 0 showed genetic defects in these molecules. Conclusions: E7 TCR-T cells demonstrated safety and clinical activity in the treatment of highly refractory metastatic HPV-16+ cancers. Treatment resistance was linked to definitive genetic defects in the targeted peptide-HLA complex and to manifold defects in antigen processing and interferon response. Clinical trial information: NCT02858310.
Association of tumor mutational burden (TMB) and clinical outcomes with pembrolizumab (pembro) versus chemotherapy (chemo) in patients with metastatic triple-negative breast cancer (mTNBC) from KEYNOTE-119.
Authors: Winer Eric P. , Lipatov Oleg , Im Seock-Ah , Goncalves Anthony , Muñoz-Couselo Eva , Lee Keun Seok , Schmid Peter , Testa Laura , Witzel Isabell , Ohtani Shoichiro , Lunceford Jared , Karantza Vassiliki , Mejia Jaime Alberto , Cristescu Razvan , Aurora-Garg Deepti , Jelinic Petar , Huang Lingkang , Cortes Javier 
Published: May 2020

1013 Background: In the randomized, open-label, phase 3 KEYNOTE-119 study (NCT02555657) , OS was not significantly different with pembro monotherapy versus chemo in second- or third-line settings for mTNBC; however, the pembro treatment effect increased with increasing PD-L1 enrichment. We evaluated the association of TMB with efficacy of pembro monotherapy versus chemo in patients with previously treated mTNBC. Methods: Patients with centrally confirmed TNBC and 1 or 2 prior systemic treatments for metastatic disease were enrolled. Patients were randomly assigned 1:1 to pembro 200 mg Q3W or single-agent chemo per investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Association of TMB, as measured by FoundationOne CDx (Foundation Medicine), with response was an exploratory objective evaluated using receiver operator characteristic (ROC) analysis, logistic regression (ORR), and Cox regression (OS; PFS) within treatment arms; estimates of efficacy based on TMB cutpoint used a prespecified cutpoint of 10 mut/Mb. Results: TMB data were available for 253/601 (42.1%) treated patients (pembro, n = 132; chemo, n = 121); baseline characteristics were similar to that of the overall study population. One-sided P values for the association of TMB and clinical outcomes in pembro-treated patients were 0.154 for ORR, 0.014 for PFS, and 0.018 for OS; the area under the ROC curve ([AUROC] 95% CI) for predicting ORR was 0.58 (0.43-0.73). Two-sided P values for the association of TMB and clinical outcomes in chemo-treated patients were 0.114 for ORR, 0.478 for PFS, and 0.906 for OS; AUROC (95% CI) was 0.43 (0.27-0.59). Twenty-six patients had TMB ≥10 mut/Mb. Thus, the prevalence of TMB ≥10 mut/Mb was ~10%. Outcomes based on TMB cutpoint are reported in the Table. Conclusions: Data from this exploratory analysis from KEYNOTE-119 suggest a potential positive association between TMB and clinical benefit with pembro but not chemo in patients with mTNBC. Although precision is limited by sample size and the number of patients with TMB ≥10 mut/Mb, ORR and HRs for OS suggested a trend towards increased benefit with pembro versus chemo in patients with TMB ≥10 mut/Mb. Clinical trial information: NCT02555657 . [Table: see text]
A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.
Authors: Liu Yongheng , Lian Wei , Zhao Xi , Qi Wei , Xu Jian , Xiao Liang , Qing Yan , Xue Tongtong , Wang Jingyi 
Published: May 2020

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .
Randomized comparisons of bevacizumab (B) and irinotecan (I), added to temozolomide (T), in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB): First survival results of the ITCC-SIOPEN BEACON-Neuroblastoma phase II trial.
Authors: Wheatley Keith , Holt Grace , Owens Cormac , Laidler Jennifer , Valteau-Couanet Dominique , Gambart Marion , Castel Victoria , van Eijkelenburg Natasha , Castellano Aurora , Nysom Karsten , Gerber Nicolas U. , Laureys Genevieve , Ladenstein Ruth Lydia , Makin Guy , Vaidya Sucheta , Thebaud Estelle , Kearns Pamela , Pearson Andrew DJ , Moreno Lucas 
Published: May 2020

10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with: median age 5.8 years; 113 and 47 measurable and evaluable disease; 67 and 93 refractory and relapsed disease; 35 had MYCN amplification. Median follow-up was 15.4 months. PFS and OS are shown in the table. In the main comparisons (I v. no I, B v. no B), I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19). However, there was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT: p=0.06) and OS (HT: p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does. Twice as many patients had serious adverse events with BIT (57%) than with T (26%) or IT (27%), with BT at 40%. Conclusions: The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed. Clinical trial information: ISRCTN40708286. [Table: see text]
Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.
Authors: Geoerger Birgit , Bouffet Eric , Whitlock James A. , Moertel Christopher L. , Hargrave Darren R. , Aerts Isabelle , Cohen Kenneth J. , Kilburn Lindsay Baker , Wright Karen D. , Choi Jeea , Gasal Eduard , Russo Mark W. , Fox Elizabeth 
Published: May 2020

10506 Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.
Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.
Authors: Schore Reuven J. , Angiolillo Anne J. , Kairalla John A , Devidas Meenakshi , Rabin Karen R. , Zweidler-McKay Patrick A , Borowitz Michael J. , Wood Brent L. , Carroll Andrew J , Heerema Nyla A. , Relling Mary V. , Hitzler Johann , Lane Ashley R. , Maloney Kelly W. , Wang Cindy , Carroll William L. , Winick Naomi J. , Raetz Elizabeth A. , Loh Mignon L. , Hunger Stephen 
Published: May 2020

10509 Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC < 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) < 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD < 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.
Outcomes in children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): A Children’s Oncology Group (COG) report.
Authors: Rabin Karen R. , Chen Zhiguo , Devidas Meenakshi , Hitzler Johann , Larsen Eric , Burke Michael , Salzer Wanda L. , Schore Reuven J. , Carroll Andrew J , Heerema Nyla A. , Borowitz Michael J. , Wood Brent L. , Carroll William L. , Winick Naomi J. , Raetz Elizabeth A. , Hunger Stephen , Loh Mignon L. , Maloney Kelly W. , Angiolillo Anne L. 
Published: May 2020

10510 Background: Patients with DS and B-ALL experience increased rates of relapse and toxicities. Here, we report results from 4 COG trials (2003-2018). Methods: We analyzed clinical, and outcome data for DS (n = 743) and non-DS (n = 21,703) patients age 1-30 enrolled on standard-risk (SR) trials AALL0331 and AALL0932 and high-risk (HR) trials AALL0232 and AALL1131. Initially, DS-ALL patients on AALL0232/AALL0331 experienced excess mortality, prompting enhanced supportive care and omission of induction anthracycline except for slow responders on AALL1131. Other modifications included: non-random assignment to treatment strata without investigational agents; leucovorin rescue after intrathecal methotrexate (MTX); equal maintenance length for boys and girls; every 12-week maintenance vincristine/steroid pulses; and reduced anthracycline and intravenous MTX for HR patients. Results: Across all 4 trials, DS and non-DS patients did not differ significantly in age, sex, initial WBC, or CNS status. DS-ALL patients had significantly higher end of induction (EOI) minimal residual disease (MRD) vs non-DS patients on both AALL0932 and AALL1131, but the difference persisted at end of consolidation (EOC) only on AALL1131, with fewer EOI MRD+ DS patients achieving EOC MRD < 0.01% (76.1 vs 88.0%, p = 0.001). 5-year EFS and OS were significantly poorer for DS vs non-DS across all trials (EFS 79.6+2.1% vs 86.3+0.3%, p < 0.0001; OS 86.5+1.8% vs 93.1+0.2%, p < 0.0001), as well as on each individual trial. In Cox regression analysis for all DS patients, inferior EFS was associated with several known risk factors (age > 10, EOI MRD >0.01%) but not with cytogenetics or CRLF2 status Induction death was more frequent in DS patients (3.4% vs 0.8%, p < 0.0001) as was death in remission (4.8+0.8% vs 1.8+0.1%, p < 0.0001). For death in remission, the increased frequency occurred pre-maintenance and in patients taken off protocol therapy, but not during maintenance, in contrast to prior reports. Grade >3 mucositis, infections, and hyperglycemia were significantly more frequent in DS patients on all trials. Grade >3 seizures were significantly more frequent in DS patients on HR but not SR trials (4.1% vs 1.7%. p = 0.001) and occurred in all phases pre-maintenance. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to non-DS, with increased relapse and toxicities. Less toxic approaches such as immunotherapies and targeted therapies hold promise to improve outcomes in both these areas.