bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20.
Authors: Du Bois Andreas , Vergote Ignace , Ferron Gwenael , Reuss Alexander , Meier Werner , Greggi Stefano , Jensen Pernille Tina , Selle Frédéric , Guyon Frederic , Pomel Christophe , Lecuru Fabrice , Zang Rongyu , Avall-Lundqvist Elisabeth , Kim Jae Weon , Ponce Jordi , Raspagliesi Francesco , Ghaem-Maghami Sadaf , Reinthaller Alexander , Harter Philipp , Sehouli Jalid 
Published: September 2018

5501 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were randomized to 2nd-line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2nd-line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI 0.52-0.83, p<0.001). Median time to start of first subsequent therapy (TFST) was 21 vs 13.9 mos in favor of the surgery arm (HR 0.61, 95%CI 0.48-0.77, p=p<0.001). PFS-2 between 1st and 2nd relapse equaled or even exceeded PFS-1 before 1strelapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT01166737.
A novel genomic rearrangement signature to predict poor survival among women with high grade serous ovarian cancer.
Authors: Hillman Robert Tyler , Lu Karen H. , Futreal Phillip Andrew 
Published: September 2018

5509 Background: Resistance to platinum-based chemotherapy is a major cause of disease progression and mortality among women with high grade serous ovarian cancer (HGSOC). It is not known whether patterns of genomic rearrangement are predictive of clinical outcome in HGSOC. Methods: This was a retrospective cohort analysis of whole genome sequences from 80 HGSOC tumors. Genomic rearrangements were identified and categorized by size and type (inversion, duplication, deletion, or translocation). Non-negative matrix factorization was then used to extract rearrangement signatures. Wilcoxon rank-sum test was used for comparison of continuous variables. Univariate and multivariate analyses were performed using Cox proportional hazards models. Results: A rearrangement signature characterized by 10 kilobase to 10 megabase duplications and deletions was identified. The median overall survival (OS) was 22.5 months (95% CI, 20.1 to 33.5 months) in the Sig-High group versus 46.0 months (95% CI, 27.7 to 80.6 months) in the Sig-Low group (hazard ratio, 2.13; 95% CI, 1.27 to 3.55; P=0.004). Exploration of clinical variables showed a significantly higher median signature contribution in platinum-resistant disease than platinum-sensitive disease (20.0% vs 9.1%, p=0.007). Multivariate analysis showed a hazard ratio for death of 2.1 associated with the Sig-High group (Table). Validation of this signature was performed using HGSOC copy number data from the Cancer Genome Atlas. In this cohort, the median OS was 38.8 months (95% CI, 36.7 to 44.5 months) in the Sig-High group versus 49.5 months (95% CI, 45.2 to 56.3 months) in the Sig-Low group (hazard ratio, 1.44; 95% CI, 1.14 to 1.82; P=0.024). Conclusions: A genomic rearrangement signature is associated with chemoresistance and poor prognosis in HGSOC. Prediction of poor survival outcomes could allow early identification of women who may be candidates for clinical trials. [Table: see text]
Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary results from the phase 2 KEYNOTE-158 study.
Authors: Schellens Jan H.M. , Marabelle Aurelien , Zeigenfuss Susan , Ding Jie , Pruitt Scott Knowles , Chung Hyun Cheol 
Published: September 2018

5514 Background: In the phase 1b KEYNOTE-028 study, pembrolizumab showed promising activity as monotherapy in patients with advanced cervical cancers that expressed PD-L1. As part of the ongoing, multicohort, phase 2 KEYNOTE-158 study (NCT02628067), we assessed the antitumor activity of pembrolizumab in a larger cohort of patients with previously treated, advanced cervical squamous cell cancer who were enrolled without regard to tumor PD-L1 or other tumor biomarker expression. Methods: Key eligibility criteria for this cohort included age ≥18 years, histologically or cytologically confirmed advanced cervical squamous cell cancer, progression on or intolerance to ≥1 line of standard therapy, ECOG PS 0 or 1, and provision of a tumor sample for biomarker analysis. Patients received pembrolizumab 200 mg Q3W for 2 years or until progression, intolerable toxicity, or physician or patient decision. Clinically stable patients with progression could remain on treatment until progression was confirmed on subsequent assessment. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. PD-L1 positivity was evaluated retrospectively by IHC and was defined as a combined positive score ≥1%. Primary end point was ORR assessed per RECIST v1.1 by independent central radiologic review. Planned enrollment is ~100 patients. This efficacy analysis includes patients who had ≥18 weeks of follow-up as of Oct 19, 2016. Results: Among the first 47 patients with advanced cervical cancer who enrolled, ORR was 17% (95% CI, 8%-31%), with 3 confirmed and 5 unconfirmed responses. 41 (87%) patients had PD-L1–positive tumors, and ORR was independent of PD-L1 status. Among the 15 patients who had ≥27 weeks of follow-up, ORR was 27% (95% CI 8%-55%), with 3 confirmed responses and 1 unconfirmed response. Safety and updated efficacy data for 83 patients with ≥27 weeks of follow-up will be available for presentation. Conclusions: Preliminary data from KEYNOTE-158 suggest that pembrolizumab has promising antitumor activity in patients with previously treated advanced cervical squamous cell cancer. The observed ORR with pembrolizumab appears to increase with longer follow-up. Clinical trial information: NCT02628067.
Evaluating the cost-effectiveness of current FDA-approved PARP inhibitors for the treatment of recurrent ovarian cancer.
Authors: Wolford Juliet Elizabeth , Bai Jiaru , Eskander Ramez Hassef , Keller Robin , Minion Lindsey E , Chan John K. , Monk Bradley J. , Tewari Krishnansu Sujata 
Published: September 2018

5516 Background: Unlike approved IV administered therapies, Medicare is under no obligation to cover prescription medicines. We sought to evaluate the cost-effectiveness of the two FDA-approved orally administered PARP inhibitors (PARPi), olaparib and rucaparib. Methods: A Markov model was created in TreeAge Pro 2015 with nodes in the chain allowing patients to transition through response, hematological complications, non-hematological complications, progression, and death. Separately, the PARP inhibitors were compared with IV administered drugs approved for recurrent ovarian cancers including platinum-based, non-platinum, and bevacizumab-based regimens. Toxicity and mean PFS rates for the different agents were obtained from registration trial data. Costs of IV chemotherapy, managing toxicities, infusions, and supportive care were estimated using 2015 Medicare data. Incremental cost-effectiveness ratios (ICER) were calculated and survival was reported in quality adjusted life months. Results: Platinum-based combinations were the most cost-effective at $1,672/PFS mo as compared to non-platinum agents ($6,688/mo), bevacizumab-containing regimens ($12,482/mo), olaparib ($13,3731/mo), and rucaparib ($14,034/mo). Considering a cost of $114,478 for olaparib and $137,068 for rucaparib prior to progression, costs associated with PARPi were 7.1 to 8.3X more than platinum combinations. To better compare the registration trial data to PARPi data, probability was adjusted to 2nd line for rucaparib, revealing it’s ICERs’ of per month of life added to be $26,997 for bevacizumab, $17,757 for non-platinum, and $79,585 for platinums. Using the adjusted-to-2nd-line probabilities for olaparib, exhibited ICERs were $16,549 for bevacizumab, $25,637 for non-platinums and $72,083 for platinums. Conclusions: The high costs of PARPi were not balanced by costs of infusion and managing toxicities of IV drugs typically associated with lower response rates and shorter PFS in the recurrent space. Balancing incremental clinical benefit with novel therapies remains problematic and could widen disparities among those with limited access to care.
Phase II clinical and molecular trial of oral ENMD-2076 in clear cell ovarian cancer (CCOC): A study of the Princess Margaret phase II consortium.
Authors: Lheureux Stephanie , Burnier Julia V. , Tan Qian , Kanjanapan Yada , Clarke Blaise , Tinker Anna , Ghatage Prafull , Dhani Neesha C. , Butler Marcus O. , Welch Stephen , Weberpals Johanne Ingrid , Tan David Shao Peng , Brooks Kelly , Ramsahai Janelle , Wang Lisa , Shaw Patricia Ann , Tsao Ming Sound , Garg Swati , Stockley Tracy , Oza Amit M. 
Published: September 2018

5522 Background: CCOC is a rare chemoresistant subtype of OC. ENMD-2076 is an oral multi-target kinase inhibitor with antiangiogenic/antiproliferative profile; selective activity against the mitotic kinase Aurora A and VEGFRs, FGFRs. Methods: This is a multi-center Phase II study of ENMD-2076 in pts with recurrent CCOC and prior platinum. Primary endpoints were ORR and 6-m PFS rate. Correlative analyses include ARID1A, PTEN expression by IHC and genome sequencing by custom capture library of 555 genes. Results: Completed study enrolled 40 pts – 37 evaluable, median age of 54 (39-78). 12 pts (31%) received prior radiation and 24 (62%), 11 (28%), 4 (10%) had 1, 2 or 3 lines of chemotherapy. Archival tissue was available for 36/37 pts. Best response was PR for 2 pts (1 unconfirmed), SD for 25 (68%) and PD for 10 (26%) pts. Median PFS was 3.7 months (m) (95%CI: 3.4-4.4). ENMD was well tolerated with main related AE: hypertension (21 pts - 8 G3), nausea (18 pts -1 G3) and diarrhea (17 pts - 4 G3). By IHC, median PFS (95%CI) in ARID1A loss (19 pts) was 4.1m (3.5-10.3) vs 3.6m (1.7-3.9) in ARID1A positive (17 pts) (p = 0.024). Whilst, by IHC, PTEN was loss in 20 pts; intact in 10 and heterogeneous in 6 pts; no difference in PFS was observed. By PI3KCA mutation status, median PFS (95%CI) in wild-type (WT) (12 pts) was 5m (3.4-19.3) vs 3.7m (167-4.4) in mutated group (20 pts) (p = 0.038). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), TP53 (7%), BRIP1 (7%), ATM (11%), BRCA1 (5%), BRCA2 (3%), RAD50 (3%), PABL2 (1%), RAD51C (1%), FANCA (1%), CTNNB1 (3%).The patient with the longest treatment duration (22m) was PTEN WT, diploid PTEN, putative bi-allelic inactivation of ARID1A. Conclusions: The PFS at 6 months was 20% for the evaluable patients, 31% in ARID1A loss and 12% in ARID1A positive patients. Loss of ARID1A, a known negative prognostic factor, was correlated with better PFS on ENMD-2076. Additional molecular profiling of the baseline biopsy material is underway. Clinical trial information: NCT01914510.
A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929.
Authors: Mayadev Jyoti , Brady William E. , Lin Yvonne Gail , Da Silva Diane M , Lankes Heather A. , Fracasso Paula M. , Ghamande Sharad A. , Moore Kathleen N. , Pham Huyen Q. , Wilkinson Kelly Jeanes , Kennedy Vanessa Amy , Aghajanian Carol , Koh Wui-Jin , Monk Bradley J. , Schilder Russell J. 
Published: September 2018

5526 Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m2) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ↓ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4+- and CD8+- T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations. Clinical trial information: NCT01711515.
Treatment and outcomes of small cell neuroendocrine carcinoma of the cervix (SCCC).
Authors: Schlappe Brooke , Jordan Emmet , Zhou Qin , Iasonos Alexia , Leitao Mario M. , Park Kay J. , Alektiar Kaled M. , Zivanovic Oliver , Sabbatini Paul , Aghajanian Carol , O'Cearbhaill Roisin Eilish 
Published: September 2018

5531 Background: Extrapulmonary small cell carcinoma is rare. SCCC represent 2% of cervical cancers and can portend a poor prognosis. Treatment standardization is challenging given its rarity. We describe management of limited stage (LS; disease could be encompassed within one radiation port) at a large tertiary referral center and the characteristics and outcomes in a cohort of patients (pts) with LS and extensive stage (ES) SCCC. Methods: Pts with SCCC diagnosed from 1/1990-1/2016 were identified following IRB approval. Clinicopathologic, treatment, and follow-up data were recorded. Descriptive statistics were provided. Median PFS/OS or PFS/OS rate were estimated using Kaplan-Meier method. Results: 39 pts were identified, 29 with LS. Select characteristics are shown in table. Tumor molecular profiling revealed MYC amplifications, TP53 mutations, PIK3CA mutation among the small subset of pts who had this performed. LS SCCC was treated with whole pelvic radiation therapy (RT) (4500-5040cGy) and concurrent IV cisplatin (60mg/m2) on day 1 and etoposide (120mg/m2) on days 1, 3, and 5 during RT and days 1-3 post RT to complete a total of 4 cycles. 26 pts, all had LS, underwent initial surgical management. No pt had prophylactic cranial RT. 3 pts (8%), all had LS, developed brain metastases. Median follow-up was 59.5 months (1.9-234.1). Median PFS (95%CI) for LS pts was 39.2 months (15.1-not estimable) vs 2.9 months (0.9-4.6) for ES. Median OS(95%CI) was 31.8 months (16.3-56.0) for the whole cohort, 52.8 months (31.8-not estimable) for LS and 5.9 months(1.8-16.3) for ES. Conclusions: In the LS SCCC cohort treated with concurrent cisplatin/etoposide chemo/RT and outback cis/etoposide +/- post initial radical hysterectomy the 5-year PFS (95%CI) was 37.5% (19.2-55.9%). Clinicopathologic characteristics and risk factors for SCCC appear distinct to cervical cancers and lung small cell cancers. Further investigation of molecular alterations and treatment of this rare tumor is needed to improve pt outcomes. [Table: see text]
A multicenter phase II study of the efficacy and safety of quisinostat (an HDAC inhibitor) in combination with paclitaxel and carboplatin chemotherapy (CT) in patients (pts) with recurrent platinum resistant high grade serous epithelial ovarian, primarily peritoneal or fallopian tube carcinoma cancer (OC).
Authors: Tjulandin Sergei , Fedyanin Mikhail , Vladimirov Vladimir Ivanovich , Kostorov Vladimir , Lisyanskaya Alla Sergeevua , Krikunova Ludmila , Cakana Andrew , Azarova Valeria , Karavaeva Oksana , Vostokova Natalia , Baranovsky Sergey 
Published: September 2018

5541 Background: Quisinostat is an orally bioavailable potent pan-histone deacetylase inhibitor. Combinations of HDAC inhibitors with paclitaxel or cisplatin demonstrate promising results in preclinical models with cisplatin and paclitaxel resistant OC. In phase Ib study the dosage of Quisinostat in combination of paclitaxel and carboplatin recommended for the phase II study was 12 mg. We report results of the phase II study of Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistantOC. Methods: the main inclusion criteria was tumor progression observed not less than 1 month and no more than 6 months after completion of the planned number of cycles of 1st line platinum/paclitaxel based CT. Quisinostat was administered at dose 12 mg p.o. each 3 week cycle on Days 1, 3, 5, 7, 9, 11 with of paclitaxel (175 mg/m2) and carboplatin (AUC5) on Day 7 of each cycle, for 2ndline. Pts received up to 6 cycles. The primary efficacy endpoint is the objective response rate (ORR) verified by the ICR. The secondary endpoints include safety, progression free survival (PFS) and overall survival. The study design implies the use of the two-stage Simon model: 29 patients who underwent treatment would provide 80% power for hypothesis testing in order to frequency of the ORR 30% (α = 0.05). Results: 31 pts were enrolled (30 pts evaluated). Median age was 57 years. Twenty one pts (67.7%) received all 6 cycles of therapy. ORR was 50.0% (15 pts). Median duration of response was 5 months (4.2-5.7). Median PFS - 6 months (95%CI 4.4-7.6). Any SAE were seen in 16.1% pts, AE of grade 3 and 4 – in 71% and 48.4% pts temporarily discontinued therapy due to AE. Dose reduction of CT due to AE was performed in 22.6% pts. The most common adverse events were neutropenia – 67,7%, nausea – 61.3%, weakness – 29%, thrombocytopenia – 22.6%, neuropathy – 19.4%, vomiting – 19.4%. Conclusions: Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistant ovarian cancer showed high efficacy and good tolerability Clinical trial information: NCT02948075.
A phase II clinical trial of metformin as a cancer stem cell targeting agent in stage IIc/III/IV ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Buckanovich Ronald J. , Brown Jason , Shank Jessica , Griffith Kent A. , Reynolds R. Kevin , Johnston Carolyn , McLean Karen , Uppal Shitanshu , Liu J. Rebecca , Cabrera Lourdes , Mehta Geeta 
Published: September 2018

5556 Background: Epidemiologic and preclinical studies suggest that Metformin has antitumor effects which may be due to an impact on cancer stem-like cells (CSC). We present a phase II trial of metformin administered in combination with chemotherapy for patients with advanced stage epithelial ovarian cancer (EOC). Primary endpoints were 18 month progression free survival (PFS) and CSC number in Metformin treated tumors. Methods: Thirty-eight patients with confirmed stage IIC(n=1)/III(n=25)/IV(n=12) EOC were treated with either neoadjuvant metformin followed primary debulking surgery and adjuvant Metformin+chemotherapy, or neo-adjuvant metformin+chemotherapy, followed by interval debulking and adjuvant chemotherapy+Metformin. Patients were evaluated for side effects, PFS and overall survival (OS). Metformin treated tumors were evaluated for the presence of CSC via FACS and sphere assays. Results: Thirty-two patients (84%) completed at least six cycles of metformin+chemotherapy. Metformin was well tolerated with only one grade III/IV treatment-related adverse event (3%) noted. Common adverse effects were diarrhea (18%) and nausea (16%). Eighteen month PFS was 65.4% (95% confidence interval 47.9-78.3), Median PFS was 21.7 months (CI-17-26.7). Estimated three year OS was 73.5% (CI-54.7-84.3) with median OS not reached after a media follow-up of 33 months. Finally, tumors treated with metformin were noted to have a 3-fold decrease in ALDH+ CSC at baseline, increased sensitivity to Cisplatin in vitro, and a reduced ability to amplify ALDH+ CSC with passage in vitro. Conclusions: This is the first prospective study of Metformin in EOC patients. Translational studies confirm an impact of metformin on CSC. Metformin was well tolerated and outcome results were favorable, supporting the use of Metformin in phase-III studies. Clinical trial information: NCT01579812.