bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma.
Authors: Liu Joyce F. , Xiong Niya , Campos Susana M. , Wright Alexi A. , Krasner Carolyn N. , Schumer Susan T. , Horowitz Neil S. , Veneris Jennifer Taylor , Tayob Nabihah , Morrissey Stephanie , West Gabriela , Quinn Roxanne , Matulonis Ursula A. , Konstantinopoulos Panagiotis A. 
Published: May 2020

6009 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by TP53 mutations ( > 90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. As such, USC may therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This two-stage single arm Phase 2 study was conducted to assess the activity of the Wee1 inhibitor adavosertib as monotherapy in recurrent USC. Methods: Women with recurrent USC (defined as non-carcinosarcoma uterine cancers with any serous component) were eligible. Patients (pts) were required to have had at least one prior platinum-based chemotherapy regimen; those with known MSI-H/MMRd disease were required to have received prior PD1/PDL1 therapy or to be ineligible for such therapy. There was no upper limit on the number of prior lines pts could have received. All pts were required to have RECIST measurable disease. Pts received adavosertib 300mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Coprimary endpoints were objective response and progression-free survival at 6 months (PFS6). Results: Between OCT-11-2018 and SEP-30-2019, 35 pts enrolled on study. Median follow-up is 4.6 months. The median number of prior lines was 3 (range 1-8). 34 pts were considered evaluable for response. In these pts, 9 confirmed and 1 unconfirmed responses were observed, for an ORR of 29.4% (95% CI 15.1-47.5%). The PFS at 6 months was 58.7% (95% CI: 39.5-73.7%). The median PFS is 6.1 months and the median duration of response is 9.0 months. Frequently observed Grade 3 or higher related adverse events included neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%). Immunohistochemistry and targeted next-generation sequencing were performed to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in women with USC. The observed monotherapy activity is higher than in other diseases, and additional exploration of the biology of Wee1 inhibition in USC is needed. Further studies of adavosertib in this patient population are planned. Clinical trial information: NCT03668340.
Impact of chemotherapy alone or in combination with an anti-angiogenic on the immune tumor microenvironment (TME) of ovarian cancer: Data from the randomized CHIVA trial (a GINECO –GINEGEPS study).
Authors: Yaniz Elisa , Genestie Catherine , Klein Christophe , Salviat Flore , Ray-Coquard Isabelle Laure , Joly Florence , Ferron Gwenael , Pujade-Lauraine Eric , Pautier Patricia , Leary Alexandra 
Published: May 2020

6011 Background: The neoadjuvant setting is an excellent opportunity to study ‘ in vivo’ the biological impact of treatment on tumor cells and the immune TME. Both chemotherapy and anti-angiogenics may have immunomodulatory properties which could prime the TME and increase effectiveness of immunotherapeutic agents. We performed comprehensive multiplexed immune biomarker analyses on paired tumor samples at diagnosis and after 3 cycles of neoadjuvant carboplatin+paclitaxel (CP) +/- the anti-angiogenic tyrosine kinase inhibitor nintedanib (N) in the randomized CHIVA trial. Methods: Patients were randomized 2:1 to CP + N or placebo for 3 cycles prior to interval debulking, samples were evaluable for immune profiling for 124 pts at diagnosis and 107 at surgery from the CHIVA trial. For 86 patients matched paired samples were available. Multiplexed IF or IHC panels were performed for CD4, CD3, CD8, CK, Granzyme B, FOXP3, CD68, CD163 and DC-Lamp. Wilcoxon tests were used to compare measurements. Results: At diagnosis the most abundant cells were CD8+ and CD4+ cells (median=118 and 119cells/mm2, respectively) compared to Foxp3+ TRegs (median=30/mm2). Among the myeloid lineage, the proportion of CD68+ (M1) and CD163+ (M2) macrophages was balanced, while mature dentritic cells (DC) represented <5% of myeloid cells. In the whole population, regardless of arm, neoadjuvant platinum-based treatment significantly increased CD4+ (p=0.03) and CD8+ infiltration (p=0.009), decreased FOXP3+ cells (p=0.01), and these differences pre- and post-treatment remained significant when analysis was restricted to pts with paired samples. Mature DC also increased significantly with neoadjuvant treatment (p=0.0003), there was no significant modification in CD68+ or CD163+ macrophages. Changes in immune parameters did not differ significantly between the CP+B vs CP+placebo arms. Conclusions: Neoadjuvant treatment has a profound impact on the immune cell composition of the TME in advanced OC. However this change seems to be mainly mediated by platinum+paclitaxel chemotherapy rather than the anti-angiogenic tyrosine kinase inhibitor nintedanib.
A Big Ten Cancer Research Consortium phase II trial of pembrolizumab with carboplatin and paclitaxel for advanced or recurrent endometrial cancer.
Authors: Pineda Mario Javier , Schilder Jeanne , Hill Emily K. , Teoh Deanna Gek Koon , Barber Emma Longley , Robertson Sharon E. , Strohl Anna Everett , Xu Jiahui , Kocherginsky Masha , Matei Daniela 
Published: May 2020

6022 Background: There are limited chemotherapeutic options for patients (pts) with advanced or recurrent endometrial cancer (EC). Reported objective response rates (ORR) for first-line doxorubicin/cisplatin/ paclitaxel combination therapy was 57%; with a median progression-free survival (PFS) of 8.3 months. The goal of this phase II study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in pts with measurable advanced or recurrent EC. Methods: This was a single-arm, open-label, multi-center phase II study for pts with RECIST measurable advanced or recurrent EC coordinated by the Big Ten Cancer Research Consortium. Patients may have had received 1 prior platinum-based regimen, with a platinum free interval > 6 months, < one non-platinum chemotherapy, or prior hormonal therapy. Pts received carboplatin AUC 6, paclitaxel 175mg/m2 (CT) and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles; with dose reduced for prior radiation. The primary endpoint was ORR per immune-related RECIST. Planned sample size of 46 subjects provided 77% power to detect 15% ORR improvement compared to historical controls, with one-tailed test and 10% type I error rate. Results: 46 pts were enrolled. Median age was 67 (range: 43-86). 32 pts had recurrent and 14 had primary metastatic EC. Histological types were: 26 endometrioid, 11 serous, 3 clear cell, 6 other. 19 patients had received prior carboplatin/paclitaxel, 23 pelvic EBRT, 14 brachytherapy, 1 adriamycin and 1 hormonal therapy. Grade 3-4 adverse events (AEs) included: laboratory abnormalities (20), hematological (8), metabolism (6), nervous system (4), gastrointestinal (2), and others (6). There were 15 grade 3-4 SAEs occurring in 7 pts: vomiting (1), anaphylaxis (3), fever (2), dehydration (1), syncope (2), vascular (2), fatigue (1), neurological (2), thrombocytopenia (1), and no grade 5 SAEs. 36 patients were evaluable for response at the time of abstract submission. ORR was 77.8% (28/36) and median PFS was 10.55 months. Conclusions: The addition of pembrolizumab to standard of care CT chemotherapy for advanced or recurrent EC induced a clinically significant improvement in ORR compared to historical outcomes and toxicity did not exceed anticipated toxicity with standard treatment, supporting further testing in a phase III trial. Clinical trial information: NCT02549209.
Genome-wide association analysis in host genetic characteristics of progression to high-grade cervical intraepithelial neoplasia or higher for women with human papillomavirus infection and normal cytology.
Authors: Lai Chyong-Huey , Chang Su-Wei , Yang Lan-Yan , Hung Shuen-Iu , Lin Chiao-Yun , Chao Angel , Lee Yun-Shien , Huang Huei-Jean , Wu Ren-Chin , Chang Ting-Chang , Chang Chee-Jen , Fann Cathy S. J. 
Published: May 2020

6033 Background: Human papillomavirus (HPV) testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in HPV-positive/ normal cytology women is 20–34 fold as compared to those with HPV-negative/normal cytology. HPV-positivity would cause substantial anxiety. Apart from viral factors such as high-risk (hr) types, it is important to identify host characteristics for predicting outcome. Methods: An initial genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) by Affymetrix Axiom™ Genome-Wide Human Arrays was conducted on 505 cases with histological diagnosis of CIN2+ (group D1) versus 920 female controls. An additional set of 2315 female controls from the Taiwan Biobank genotype array were added in the discovery stage. The identified 29 CIN2+ -associated SNPs from GWAS (p < 5 x 10−6) were verified in an independent cohort (group D2 [n = 306] versus group N [n = 600]). Group N were HPV-negative/normal cytology women from a population-based cervical cytology and HPV co-test study. A cohort with HPV-positive/normal cytology (group P, n = 755) underwent follow-up and was served as the prediction set. The predictive validity was analyzed by logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Thirty-three individuals of the group P progressed to CIN2+ (median follow-up: 23.7 months, range 4.0–122.1). A risk-predictive panel of 8 SNPs rs3097662, rs35979982, rs7763822, rs4282438, rs3128927, rs7759943, rs213194, rs17835649 which were significant in the replication (p < 0.05) was used to train models for disease risk prediction using the combination of GWAS and verification sets. Two prediction models were finalized and determined using 7 SNPs for hr- and low-risk (lr) HPV groups respectively (sensitivity 0.72 and 0.75, specificity 0.651 and 0.884, area under the ROC curve 0.703 and 0.701). Among group P with hr-HPV, those carried < 6 risk-alleles had significantly decreased hazard (log-rank p < 0·001) of progression to CIN2+ than those with ≧6 risk-alleles, while among group P with lr-HPV, those with predictive probability of ≥ 0·095 had a cumulative risk of progression of 10% at 3 years. Conclusions: Two risk-predictive SNP panels including 7 SNPs with hr- or lr-HPV groups can assist risk stratification among HPV-positive/ normal cytology women. These panels could be further tested in other ethnic populations.
Low rates of BRCA1 and BRCA2 testing for patients with ovarian cancer in ASCO's CancerLinQ, a real-world database.
Authors: Dewdney Summer , Potter Danielle , Larsen Haidle Joy , Hulick Peter J , Riffon Mark , Monzon Federico A. , Keole Sameer R. , Miller Robert S. 
Published: May 2020

6041 Background: Ovarian cancer is the deadliest gynecological cancer and has limited screening options for early stage diagnosis. Genetic mutations in genes such as BRCA1 and BRCA2 increase the risk of ovarian cancer, and if identified, patients can undergo risk-reducing surgery. It is recommended and well accepted to test any new ovarian cancer patient for genetic mutations, particulary BRCA1 and BRCA2. If a BRCA1/2 mutation is found in a patient (somatic or germ line), this information can be used to guide therapy. We sought to analyze the characteristics of genetic testing in a real-world database, ASCO’s CancerLinQ. Methods: We performed a retrospective cohort study using the CancerLinQ Discovery database. Women with ovarian, fallopian tube, or primary peritoneal cancer were identified using ICD9 and ICD10 codes. We included patients diagnosed between 1/1/11 to 12/31/18 and age >18. We included all epithelial histologies including carcinosarcomas and excluded patients without a known histology. Results: Of the 2654 patients meeting inclusion criteria, 600 had been tested for a BRCA1/2 mutation (22.6%). Of those tested, 63% were stage III/IV, 14% stage I/II, and 21.8% an unknown stage. The majority of the histologies were serous (76%), followed by undifferentiated (21.2%). The majority of patients tested were white (69.9%), with 18.8% unknown, and 9.9% black. The rate of a positive BRCA1 or BRCA2 mutation in this population was 17.2%. Of the patients with a BRCA1/2 mutation, the majority had serous histology (87%), followed by 18.5% undifferentiated, and 3.9% transitional cell. The majority of the patients found to have a BRCA1/2 mutation were age >50 (57.3%). Conclusions: Since 2008 evidence-based guidelines have recommended that all ovarian cancer patients be tested for BRCA1 and BRCA2 mutations, but in this real-world database only 22.6% have a recorded test. Of those tested, we found a BRCA1 or BRCA2 mutation rate of 17.2%. Our data is limited by what is recorded in the database and may not represent the true number of patients tested because of data missing from the EHR; however, these percentages appear similar to previous studies. Not only is testing important for cancer prevention for family members of patients, it now impacts the type of treatments for which these patients are eligible. Since genetic testing remains low at only 22.6% in this population, significant opportunities exist to impact cancer prevention and treatment.
Evaluation of an individualized starting-dose of niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.
Authors: Mirza Mansoor Raza , Gonzalez Martin Antonio , Graybill Whitney , O'Malley David M. , Gaba Lydia , Yap Oi Wah S. , Guerra Eva M. , Rose Peter Graham , Baurain Jean-Francois , Ghamande Sharad A. , denys Hannelore , Prendergast Emily , Pisano Carmela , Follana Philippe , Baumann Klaus , Calvert Paula , Korach Jacob , Li Yong , Gupta Divya , Monk Bradley J. 
Published: May 2020

6050 Background: Niraparib is approved at a fixed starting dose (FSD) of 300 mg QD for maintenance treatment of patients (pts) with recurrent ovarian cancer (OC) achieving a complete or partial response to platinum-based chemotherapy based in the ENGOT-OV16/NOVA study. A post-hoc analysis of NOVA showed baseline bodyweight (BW) and platelet count (PC) were predictive for hematologic toxicities and dose reductions. Following this analysis, the PRIMA/ENGOT-OV26/GOG-3012 study was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen. Methods: This double-blind, placebo-controlled, phase III study randomized 733 pts with newly diagnosed advanced OC with a complete or partial response to first-line (1L) platinum-based chemotherapy. The protocol was amended to change the dose from 300 mg FSD for all patients to an ISD regimen: 200 mg QD in pts with BW <77 kg and/or PC <150,000/µL or 300 mg QD in pts with BW ≥77 kg and PC ≥150,000/µL. Exposure, efficacy, and safety data were compared between patients treated with FSD vs ISD. Results: Efficacy in the ISD subgroup was comparable to the FSD subgroup relative to placebo (Table). An interaction test showed no treatment difference between ISD and FSD at the pre-specified 0.10 significance level ( p=0.30). Medians for dose intensity and relative dose intensity in pts who received niraparib were similar. The overall safety profile among pts in the niraparib arm (n=484), including grade ≥3 hematologic toxicities, improved with the ISD. Conclusions: The ISD in the 1L maintenance setting provides comparable efficacy to the FSD while reducing the risk of hematologic toxicities. No new safety signals were identified. Clinical trial information: NCT02655016. [Table: see text]
Niraparib exposure-response relationship in patients (pts) with newly diagnosed advanced ovarian cancer (AOC).
Authors: Monk Bradley J. , Romero Ignacio , Graybill Whitney , Churruca Cristina , O'Malley David M. , Lund Bente , Yap Oi Wah S. , Baurain Jean-Francois , Rose Peter Graham , denys Hannelore , Ghamande Sharad A. , Pisano Carmela , Fabbro Michel , Braicu Elena Ioana , Calvert Paula , Amit Amnon , Prendergast Emily , Milton Ashley , Zhang Zhi-Yi , Gonzalez Martin Antonio 
Published: May 2020

6051 Background: Niraparib improves progression-free survival (PFS) in pts with newly diagnosed AOC after complete or partial response to first-line, platinum-based chemotherapy. In the PRIMA/ENGOT-OV26/GOG-3012 (PRIMA) trial, pts were treated with a fixed starting dose (FSD) of 300 mg QD until a protocol amendment introduced the individualized starting dose (ISD) regimen: 200 mg QD for pts with baseline bodyweight (BW) < 77 kg and/or platelet count (PC) < 150,000/µL, or 300 mg QD for pts with baseline BW ≥77 kg and PC ≥150,000/µL. Here, we developed a population pharmacokinetic (PopPK) model for niraparib and evaluated exposure-response relationships for pts receiving niraparib using safety and efficacy data from PRIMA. Methods: The PopPK model for niraparib was developed based on 7418 plasma samples from 1442 pts from 4 studies: PN001, NOVA, QUADRA, and PRIMA. PRIMA PK samples were collected on cycle 1, day 1 (C1D1), C2D1 pre-dose and 2 h post-dose, C4D1, and C8D1 pre-dose (or EOT if patient discontinued before C8D1). The relationship between PopPK model-based prospective exposure (average concentration [ Cave] until progression/death) and efficacy (PFS) were evaluated in pts receiving niraparib in both the homologous-recombination deficient (HRd) and overall population. The relationship between model-predicted exposure metrics and incidence of clinically relevant adverse events (AEs) was analyzed using univariate logistic regression in pts receiving niraparib. Results: Of 484 pts receiving niraparib in PRIMA, 480 had PK data and were included in the efficacy and safety analysis. The safety exposure-response showed significant associations ( p≤0.0128) between increasing niraparib exposure and increasing probability of experiencing any-grade and grade ≥3 AEs, except grade ≥3 hypertension. The incidence of AEs, including thrombocytopenia, was lower in pts who received a 200-mg ISD. Efficacy was not compromised in these pts. Conclusions: Niraparib exposure was associated with increased risk of select AEs. However, the ISD regimen decreased AE risk without compromising efficacy. Clinical trial information: NCT02655016.
Cediranib in combination with olaparib in patients without a germline BRCA1/2 mutation with recurrent platinum-resistant ovarian cancer: Phase IIb CONCERTO trial.
Authors: Lee Jung-min , Moore Richard G. , Ghamande Sharad A. , Park Min S. , Diaz John Paul , Chapman Julia A. , Kendrick James Erasmus , Slomovitz Brian M. , Tewari Krishnansu Sujata , Lowe Elizabeth S. , Milenkova Tsveta , Kumar Sanjeev , Dymond Mike , Kozarewa Iwanka , Liu Joyce F. 
Published: May 2020

6056 Background: A Phase I trial (NCT01116648) of cediranib (cedi) in combination with olaparib (ola) (cedi + ola) demonstrated an overall response rate of 44% in patients (pts) with recurrent ovarian cancer (OC), including pts without a deleterious or suspected deleterious gBRCAm (non-gBRCAm; Liu et al. Eur J Cancer 2013). The subsequent Phase II trial (NCT01116648) showed significant improvement in progression-free survival (PFS) with cedi + ola versus ola monotherapy in recurrent platinum-sensitive OC pts, notably in non-gBRCAm pts (Liu et al. Lancet Oncol 2014). We report data from the Phase IIb, single-arm, open-label CONCERTO study investigating cedi + ola in non-gBRCAm pts with recurrent platinum-resistant OC who had received ≥3 previous lines of therapy for advanced OC (NCT02889900). Methods: Pts with disease progression <6 months from the last receipt of platinum-based chemotherapy received cedi tablets (30 mg once daily) plus ola tablets (200 mg twice daily) until progression or unacceptable toxicity. gBRCAm pts were ineligible. Primary endpoint: objective response rate (ORR) by independent central review (ICR; RECIST 1.1). Key secondary endpoints: PFS and safety. Results: 60 pts from the USA were included (median age: 64.5 years; median number of previous systemic treatment regimens: 4 [range: 2–9]; previous bevacizumab: 53). All pts had high-grade OC (90% serous; 3.3% clear cell; 3.3% endometrioid; 3.3% other). 7% of pts had tumor BRCA2 (confirmed somatic) mutations, 80% of pts had no tumor BRCA mutation (non-tBRCAm) and 13% of pts were not evaluable for tBRCAm. Five (8%) pts who were non-tBRCAm carried somatic homologous recombination repair gene mutations (FoundationOne Clinical Trial Assay, Foundation Medicine, Inc). The Table shows results of key endpoints. Most common grade ≥3 adverse events (AEs) that occurred in pts were hypertension (30%), fatigue (22%) and diarrhea (13%). 37% of pts reported serious AEs, of which nausea (7%) was most common. Dose interruptions, reductions and discontinuations were caused by AEs in 55%, 18% and 18% of pts, respectively, who received cedi + ola. Conclusions: Cedi + ola showed evidence of antitumor activity in heavily pretreated non-gBRCAm pts with recurrent platinum-resistant OC. Toxicity was manageable with dose modifications. Clinical trial information: NCT02889900. [Table: see text]
The safety and efficacy of weekly paclitaxel and cisplatin chemotherapy for patients with ovarian cancer who developed carboplatin hypersensitivity reaction in previous chemotherapy.
Authors: Nishikimi Kyoko , Tate Shinichi , Matsuoka Ayumu , Shozu Makio 
Published: May 2020

6058 Background: Carboplatin (CBDCA) hypersensitivity reactions (HSR) often occur in patients with ovarian cancer. Once CBACA HSR occurs, it is difficult to use platinum even though the patients had platinum-sensitive disease and consequently the survival of the patients cannot be prolonged. We had administered weekly paclitaxel and cisplatin (CDDP) chemotherapy (wTP) for patients with ovarian cancer who developed CBDCA HSR in previous chemotherapy. We investigated the safety and efficacy of wTP. Methods: We investigated 86 patients with ovarian, fallopian tube, and peritoneal carcinoma who developed CBDCA HSR in previous chemotherapy (paclitaxel/CBDCA) at our institution between 2011 and 2019. After premedication was administered, paclitaxel and sequentially CDDP were administered as one hour infusion, respectively (paclitaxel 80 mg/m2, CDDP 25 mg/m2; 1, 8, 15 day/4 weeks). Results: The median cycle of the previous chemotherapy of CBDCA was 8 (interquartile range [IQR], 6–11). The grade of CBDCA HSR was 1 in 57 (66%), 2 in 26 (30%), and, 3 in 1 (1%) patient(s). WTP was administered for the first line in 21 (24%), second line in 35 (41%) and third or more line in 30 patients (34%). The median cycles of wTP administration was 4 (IQR, 3–7). We observed that severe CDDP HSR did not occur in any patients and 15 patients (17.4%, grade 1, 10 patients; grade 2, 5) developed CDDP HSR. All CDDP HSR were successfully managed with infusion interruption and Hydrocortisone Sodium Phosphate administration. There was no relation between the grade of CBDCA HSR in the previous chemotherapy and the rate of CDDP HSR (p = 0.363). Progression-free survival and overall survival after administration of wTP were 10.9 months (95% CI: 7.7–17.7) and 25.9 months (95%Ci: 19.0–50.2), respectively. Conclusions: 71 patients (82%) who developed CBDCA HSR in previous chemotherapy were able to continue administration of wTP without CDDP HSR. WTP was safe and effective for the patients who developed CBDCA HSR. [Table: see text]