julilili42/papers huggingface dataset:
MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy
2017-05-20

1000 Background: Abemaciclib, an oral, selective inhibitor of CDK4 &amp; 6, dosed on a continuous schedule, demonstrated clinical activity as monotherapy in patients (pts) with treatment refractory hormone receptor positive (HR+) metastatic breast cancer (MBC). The tolerability and activity of abemaciclib + fulvestrant (F) supported Phase 3 evaluation. Methods: MONARCH 2 is a double-blind Phase 3 trial of abemaciclib + F vs placebo (P) + F in women with HR+/HER2- advanced breast cancer. Women who progressed on (neo)adjuvant endocrine therapy (ET), ≤12 months from end of adjuvant ET, or on first line ET for MBC and who had not received chemotherapy for metastatic disease were eligible. Pts were randomized 2:1 to receive abemaciclib at 150 mg Q12H (or 200 mg prior to amendment) or P plus F (500 mg, per label) and stratified by metastatic site (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). Pre/perimenopausal pts received a gonadotropin-releasing hormone agonist. The primary objective was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and other efficacy and safety endpoints. Assuming a hazard ratio (HR) of 0.703 in favor of abemaciclib + F, 378 events were needed for 90% power at one sided α=.025. Results: 669 pts were randomized to abemaciclib + F (N=446) and to P + F (N=223). 56% of pts had visceral disease, 72% had measurable disease, 25% had primary ET resistance, and 82% were postmenopausal. In the ITT population 379 PFS events were observed with a median PFS of 16.4 m for abemaciclib + F and 9.3 m for P + F (HR: 0.553; 95% CI: 0.449, 0.681, P&lt;.0000001 by log-rank test). In pts with measurable disease, the ORR was 48.1% (3.5% complete response [CR]) for abemaciclib + F and 21.3% (0% CR) for P + F. The most frequent treatment emergent adverse events for abemaciclib + F vs P + F were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). Conclusions: Abemaciclib + fulvestrant was an effective treatment in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy with significantly improved PFS and ORR. Clinical trial information: NCT02107703.
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.
2017-05-20

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 &lt; 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.
FDG PET scan (PET) positive residual lesions after chemotherapy (chemo) for metastatic seminoma: Results of an International Global Germ Cell Cancer Group (G3) registry.
2017-05-20

4521 Background: Residual disease is a frequent finding after chemo for metastatic seminoma. Watchful waiting is recommended for residual lesions &lt; 3 cm or lesions ≥3 cm with negative PET. Data on the optimal management of PET positive residual lesions is lacking. Methods: A retrospective analysis within the G3 Group identified 91 patients (pts) from 9 countries with metastatic seminoma and residual PET positive lesions after chemo. Pts with elevated AFP ( &gt; 2xULN) or non-seminomatous components at diagnosis were excluded. We analyzed the post PET management chosen and its impact on relapse and survival. Results: Median follow-up was 29 (IQR 10 – 64) months. Median age at diagnosis was 41 (range 19 – 69) years. The primary tumor was gonadal in 68 pts (76%), retroperitoneal in 12 pts (13%) and mediastinal in 10 pts (11%). Prior to chemo the median size of the largest metastasis was 10 (range 1.4 – 23) cm, 67 pts (74%) had elevated LDH and 51 pts (57%) elevated HCG. Median diameter of the largest residual mass was 4.8 (range 1.1 – 14) cm mainly located in the retroperitoneum (77%), pelvis (15%), mediastinum (16%) or lung (4%). Median time from last day of chemo to PET was 7 (IQR 4 – 10) weeks. Post PET management was repeated imaging in 46 pts (51%), resection in 32 pts (35%), biopsy in 9 pts (10%) and radiotherapy in 4 pts (4%). Histology of the resected specimen was necrosis only in 25 (78%) and vital seminoma in 7 cases (22%). No biopsy revealed vital seminoma. Relapses occurred after a median of 3.7 (IQR 2.5 – 4.9) months in 16 pts (18%): 2/9 (22%) after biopsy, 12/46 (26%) on repeated imaging and 2/32 (6%) after resection (one necrosis, one &lt; 10% vital seminoma). Site of relapse was the area of residual disease in 14 pts (88%) and additional distant relapse (one bone, one lung) in 2 pts (12%). All relapsed pts received successful salvage chemo apart from one who died from treatment and two pts who are alive with ongoing treatment. Conclusions: PET positive post chemo residual lesions in seminoma pts are false positive in about 75%. Relapses in PET positive pts occur early and can be salvaged with chemo. Further analysis is needed to identify risk factors for relapse.
Phase 3 ELOQUENT-2 study: Extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).
2017-05-20

8028 Background: Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action: directly activating NK cells and tagging myeloma cells for recognition/death via antibody-dependent cell-mediated cytotoxicity. In a 3-y FU, ELOQUENT-2 (NCT01239797) showed a sustained 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos et al, ASH 2015). Here we present extended 4-y FU data (median FU 46 mo). Methods: RRMM patients (pts) were randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS, ORR. Secondary endpoint: OS. Results: Of 646 RRMM pts, 321 were randomized to ELd, 325 to Ld; ~ twice as many pts remain on therapy in ELd vs Ld (17 vs 9%) at data cut-off (Oct 18, 2016). Discontinuation was mainly due to disease progression (both arms 54%). At 4-y FU, ELd had 29% reduction in risk of progression/death vs Ld (HR 0.71, 95% CI 0.59–0.86) and relative improvement of 50% in PFS (21 vs 14%). Pts with ≥VGPR (ELd 112 [35%], Ld 95 [29%]) had greatest reduction in risk of progression/death (HR 0.65, 95% CI 0.46–0.94). ORR was 79% (ELd) vs 66% (Ld). OS will be presented. G3–4 AEs in ≥5% of pts included second primary malignancies (SPMs), vascular diseases, cardiac disorders and infections (ELd vs Ld: 9 vs 6%, 10 vs 8%, 5 vs 8%, 33 vs 26%). Overall rate (any grade) of infection and SPMs was 84 vs 75% and 17 vs 11% for ELd vs Ld. However, pts had longer exposure to ELd vs Ld (median [Q1, Q3] treatment cycles (19 [9, 42] vs 14 [6, 25]). There were fewer deaths with ELd vs Ld (165 vs 186), mainly due to disease progression and infection in both arms. Conclusions: Elotuzumab in combination with Ld consistently met its efficacy objectives at 4-y FU. ELd showed durable, clinically relevant improvement in PFS, with 29% reduction in risk of progression/death, consistent with 2-y (30%) and 3-y FU (27%). Safety, including rate of SPMs, was consistent with previous findings, with minimal incremental AEs with addition of elotuzumab to Ld. These data represent the longest median FU of an immuno-oncology agent in MM. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01239797.
A randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab, a PD-L1 antibody, to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC).
2017-05-20

3062 Background: Adding an anti-PD-L1 checkpoint inhibitor durvalumab to standard chemotherapy (CT) may increase pathological complete response (pCR) in patients (pts) with TNBC. Methods: GeparNuevo randomizes pts to durvalumab (D) 1.5 g i.v. or placebo (pl) every 4 weeks (wks). D/pl monotherapy (0.75 g i.v.) is given for the first 2 wks (window phase), followed by a biopsy and D/pl plus nab-paclitaxel (nP) 125 mg/m2 weekly for 12 wks, followed by D/pl plus epirubicin/cyclophosphamide (EC) q2 wks for 4 cycles. Randomization is stratified by stromal TILs (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). Pts with primary cT1b-cT4a-d disease, centrally confirmed TNBC, and sTILs status can be included. Primary objective compares pCR (ypT0 ypN0) rates. Secondary objectives are pCR rates in stratified subpopulations and according to other pCR definitions; response rates; breast conservation rate; toxicity; compliance and survival. Change in sTILs, Ki67 and other immune biomarkers before CT, after the window phase and after CT will be correlated with outcome. The first 10, 20 and 30 pts will be included in safety interim analyses (SIA). Sample size was planned assuming a pCR rate of 48% for pl (nP treated TNBC cohort in GeparSepto) and of 66% for D (as clinically meaningful benefit), requiring 158 pts to show superiority of D (2-sided α = 0.2, 80% power). Assuming a 10% drop-out rate 174 pts will be randomized. Results: Since 6/2016, 50 pts were recruited within 16 sites; data are presented as available until 01/2017. Median age is 49 years; 86% NST and G3 tumors; sTILs categories 40% low, 40% intermediate and 20% high. Blinded SIA was performed. No pt interrupted D/pl, one nP and one EC. Treatment delay was observed in 9 pts (20.0%) in D/pl, 18 (41.9%) in nP and 2 (13.3%) in EC; dose was reduced in 10 pts (23.3%) in nP and in 4 (26.7%) in EC. 10 pts (20%) had at least one grade 3-4 AE: 4 haematological and 6 non-haematological AEs. 4 SAEs and 5 immune related AEs were reported. 2 pts discontinued study treatment prematurely in the EC phase. Conclusions: The addition of D to standard nP-EC is feasible and does not result in an increased toxicity. Clinical trial information: NCT02685059.
Health-related quality of life as a marker of treatment benefit with nivolumab in platinum-refractory patients with metastatic or unresectable urothelial carcinoma from CheckMate 275.
2017-05-20

4526 Background: CheckMate 275 (NCT02387996), a phase II, single-arm study of nivolumab (3 mg/kg every 2 weeks) treatment in platinum-refractory patients (pts) with metastatic urothelial carcinoma, showed an objective response rate of 19.6% (95% CI, 15.0%–24.9%) with manageable toxicity. The objective of this analysis was to examine the impact of nivolumab on health-related quality of life (HRQoL) in the study. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and three-level EQ-5D (EQ-5D-3L) and visual analog scale (VAS). Questionnaires were completed at baseline and every 8 weeks thereafter for the first 48 weeks. The analysis cohort included pts with scores recorded at baseline and ≥1 postbaseline assessments while on treatment. Data were analyzed using mixed models, adjusting for baseline score. Results: Of the 270 patients treated with nivolumab, 168 (62%) had an assessment at baseline and ≥1 postbaseline assessment and were included in HRQoL analyses. Completion rates at baseline were 97% for both questionnaires. Statistically significant ( P&lt; 0.05) improvements in mean scores for the EORTC QLQ-C30 subscales measuring role, emotional, and social functioning; global health status/quality of life; nausea/vomiting; pain; dyspnea; insomnia; appetite loss; constipation; and diarrhea were observed at ≥1 time points. With the exception of cognitive functioning, no significant worsening in subscale scores was observed in the EORTC QLQ-C30. Statistically significant and clinically meaningful improvement (based on a minimally important difference of 7) in EQ-5D VAS was noted between weeks 17 and 41. EQ-5D-3L utility index scores based on the UK tariff remained stable during treatment. Conclusions: Results of CheckMate 275 indicate that pts with metastatic or unresectable urothelial carcinoma whose disease progressed or recurred after treatment with a platinum agent exhibited stable, or in some cases statistically significantly improved, HRQoL while being treated with nivolumab, as measured by EORTC QLQ-C30 and EQ-5D-3L. Clinical trial information: NCT02387996.
A randomized, double-blind, multi-center phase III study evaluating paclitaxel with and without RAD001 in patients with gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).
2017-05-20

4027 Background: There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction (EGJ) who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2 nd , 3 rd or 4 th line therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity. Results: 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (Arm A, 150, Arm B, 150). In the intention to treat population, there was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) or median OS (placebo, 5.0 vs. RAD001, 6.1 months, HR 0.93, p = 0.54). For patients with prior taxane use, RAD001 improved PFS (placebo 1.8 vs. RAD001, 2.7 months, HR 0.69, p = 0.03) and OS (placebo 3.9 vs. RAD001, 5.8 months, HR 0.73, p = 0.07). Combination of paclitaxel and RAD001 was tolerable, but the RAD001 arm was associated with significantly more grade 3-5 mucositis (13.3% vs. 0.7%; p &lt; 0.001). Conclusions: The addition of RAD001 to paclitaxel/RAD001 did not improve outcomes in pretreated metastatic gastric/EGJ cancer. Of note, activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit. Clinical trial information: 2009-018092-14.
Towards the assessment of stress and emotional responses of a salutogenesis-enhanced software tool using psychophysiological measurements
2017-05-20

Software development is intellectual, based on collaboration, and performed in a highly demanding economic market. As such, it is dominated by time pressure, stress, and emotional trauma. While studies of affect are emerging in software engineering research, stress has yet to find its place in the literature despite that it is highly related to affect. In this paper, we study stress coping with the affect-laden framework of Salutogenesis, which is a validated psychological framework for enhancing mental health through a feeling of coherence. We propose a controlled experiment for testing our hypotheses that a static analysis tool enhanced with the Salutogenesis model will bring 1) a higher number of fixed quality issues, 2) reduced cognitive load, 3) reduction of the overall stress, and 4) positive affect induction effects to developers. The experiment will make use of validated physiological measurements of stress as proxied by cortisol and alpha-amylase levels in saliva samples, a psychometrically validated measurement of mood and affect disposition, and stress inductors such as a cognitive load task. Our hypotheses, if empirically supported, will lead to the creation of environments, methods, and tools that alleviate stress among developers while enhancing affect on the job and task performance.
Panitumumab in platinum-sensitive epithelial ovarian cancer patients with KRAS wild-type: The PROVE-study, a phase II randomized multicenter study of the North-Eastern German Society of Gynaecologic Oncology.
2017-05-20

5558 Background: For ovarian cancer (OC) patients with platinum-sensitive recurrence the addition of new biologic agents to chemotherapy may improve survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). The purpose of this trial was to investigate the therapeutic efficacy of panitumumab in the combination with carboplatin-based chemotherapy in relation to the respective standard combination in patients with a KRAS wildtype with platinum-sensitive recurrent ovarian cancer (NCT01388621). Methods: Major eligibility criteria were pretreated platinum-sensitive epithelial ovarian/ fallopian/ peritoneal cancer and no more than 2 prior treatments for this disease. Only patients with measurable disease or elevated CA125 and with KRAS wild type were eligible. Patients were treated with Carboplatin AUC4/Gemcitabine 1000 mg/m2 or Carboplatin AUC5/PLD 40 mg/m2 and randomized to panitumumab 6 mg/kg day 1 and day 15, every 3 or 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CT-scan and CA-125 criteria. Results: In this multi-institutional phase II trial 102 patients were randomized and 96 enrolled for the final analysis. Progression-free survival in the intention-to-treat population (N=96) was 9.5 vs. 10.7 months (HR 0.829, 95%CI of 8.5-11.6 months vs 8.5-13.1 months) for the experimental vs. standard arm, p=0.45. Data of overall survival are not jet evaluable. The most common treatment related grade 3+ toxicities included hematologic toxicity (54%), skin reactions (18%) and gastrointestinal events (16%). Conclusions: The addition of panitumumab to platinum-based chemotherapy for recurrent ovarian cancer does not influence efficacy and progression-free survival in platinum sensitive patients, while no new additional toxicity aspects for panitumumab were evaluated. Clinical trial information: NCT01388621.
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.
2017-05-20

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 &lt; 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 &lt; 25% blasts: 15 μg/m 2 /d; ≥ 25% blasts: 5 μg/m 2 /d on d1−7 in cycle 1, then 15 μg/m 2 /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]