bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer.
Authors: Chelariu- Raicu Anca , Levenback Charles F. , Slomovitz Brian M. , Bodurka Diane C. , Gershenson David Marc , Coleman Robert L. 
Published: May 2020

6059 Background: The epidermal growth factor receptor (EGFR) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian can overexpress EGFR, and its expression has been correlated with poor prognosis features in many cases. While these tumors are chemosensitive to platinum-based therapy, chemoresistance often develops. We conducted a phase I/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with EGFR receptor positivity (1+ or greater). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study (n = 19). We first used “run-in” dose escalation, in which a conventional 3+3 algorithm was used. Initial treatment was gefitinib 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. Next, an additional 10 patients with refractory or progressive ovarian cancer were enrolled in the phase II study. Results: 19 patients received a total of 61 cycles. Median age was 60 years. Histological types of treated patients included 73% serous (n = 14), 12.5% mixed (n = 2), 12.5% transitional (n = 2) and 6.3% clear cell (n = 1). There were 3 patients treated at dose level 1, 3 patients at dose level 2, and 3 patients treated at dose level 3. The maximum tolerated dose was topotecan 4.0mg/m2 IV days 1, 8 and 15, and gefitinib 250mg p.o. QD x28 days. Therefore, dose level 3 was used for the Phase II portion of the trial. Of the 19 patients included in the phase I/II, 3 patients were inevaluable for response to therapy due to toxicity, missed therapy or decline in performance status. Of the 16 patients, 81% patients (n = 13) had progressive disease, 12.5% stable disease (n = 2), and 6% partial response (n = 1). We assessed all 19 patients for adverse events; 60% had treatment-related grade 3 events, primarily blood disorders such as anemia (n = 3, 16%), neutrophil count decrease (n = 4, 21%). Conclusions: This prospective phase I/II clinical trial failed to show sufficient clinical activity of topotecan in combination with gefitinib in patients with EGFR-positive recurrent ovarian, fallopian tube, or peritoneal cancers. The drug combination was relatively well-tolerated in this cohort. As such, the study did not proceed to the next accrual goal secondary to the lack of response. Clinical trial information: NCT00317772.
Effect on response to neoadjuvant chemotherapy in high-grade serous ovarian cancer by inhibiting the GAS6/AXL pathway and inducing homologous recombination deficiency.
Authors: Mullen Mary M , Lomonosova Elena , Toboni Michael Driscoll , Noia Hollie M , Wilke Danny , Oplt Alyssa , Guo Lei , Kuroki Lindsay M , Hagemann Andrea R. , McCourt Carolyn K , Thaker Premal H. , Mutch David Gardner , Powell Matthew A. , Fuh Katherine Cynthia 
Published: May 2020

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.
Sacituzumab govitecan (SG) in patients (pts) with previously treated metastatic endometrial cancer (mEC): results from a phase I/II study.
Authors: Santin Alessandro , Komiya Takefumi , Goldenberg David M. , Sharkey Robert M. , Hong Quan , Wegener William A. , Goswami Trishna , Bardia Aditya 
Published: May 2020

6081 Background: Unselected pts with EC who progressed on prior chemotherapy have a poor prognosis with limited treatment options. SG is a novel antibody-drug conjugate that targets Trop-2, a cell surface glycoprotein highly expressed in many epithelial tumors. It is conjugated to deliver SN-38, the active metabolite of irinotecan, via a proprietary hydrolyzable linker. Preclinical studies show SG has activity against chemotherapy-resistant EC and significant bystander effect against EC with heterogenous Trop-2 expression (Perrone E. Mol Oncol. 2019). Methods: The phase I/II basket study (NCT01631552) evaluated pts unselected for Trop-2 with advanced solid tumors who received intravenous SG (days 1 and 8 of 21-day cycles), until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment by RECIST 1.1. We report results for mEC pts who progressed after ≥1 prior systemic therapy and were treated with SG 10 mg/kg. Endpoints include safety, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 18 mEC pts (all women; 17 white and 1 black; median age 69 years [range, 41–76]) had a median 3.5 (range 2–6) prior lines of therapy. All pts received prior treatment with platinum therapies. At a median follow-up of 12.7 months, the ORR (95% CI) was 22.2% (6.4–47.6), with 4 partial responses. CBR (95% CI) was 44.4% (21.5–69.2), with 8 of 18 pts having either an objective response or stable disease ≥6 months. The DOR of responders ranged from 9.1 to 26.6 months, with 2 of 4 responders having a duration of ≥18 months. Median PFS (95% CI) was 3.2 months (1.9–9.4), and median OS (95% CI) was 11.9 months (4.7–not calculable). Key grade ≥3 TRAEs in the overall basket study safety population (n=495) included neutropenia (28%), neutrophil count decrease (14%), anemia (10%), diarrhea (8%), fatigue (6%), and febrile neutropenia (5%). A similar safety profile was seen in the mEC cohort. Conclusions: Median OS in unselected pts with mEC who progressed on prior platinum therapy is ~10 months with an ORR of ~10%. SG monotherapy showed clinical activity in pts with relapsed/refractory mEC, consistent with previous preclinical findings, and support further clinical investigation (NCT04251416). The phase II TROPiCS-03 (NCT03964727) study in pts with metastatic solid tumors selected based on elevated Trop-2 expression by a validated IHC assay will also provide further insights. Clinical trial information: NCT01631552.
Clinical outcomes of MSI-high (MSI-H) versus stable (MSS) endometrial carcinoma (EC) after front-line platinum chemotherapy and subsequent matched therapy.
Authors: Ngoi Natalie , Sachdeva Manavi , Haran Prevathi , Lim Diana , Heong Valerie , Lim Yi Wan , Eng Lim Siew , Tham Kah Wieng , Wong Andrea , Zhong Sophia , Nathan Santhiay , Tong Pearl , Low Jeffrey , Ng Joseph , Arunachalam Ilancheran , Tan David Shao Peng 
Published: May 2020

6086 Background: Precision oncology approaches in EC patients (pts) are evolving with emerging targeted therapy. We reviewed the effect of genomic findings on treatment choice and outcome in an Asian EC cohort. Methods: Recurrent or metastatic ECs were prospectively profiled with next-generation sequencing (NGS) and relevant immunohistochemistry. Clinical data were collected to assess outcomes. Results: Between 12/2014 to 12/2019, 51 Asian EC pts of endometrioid (26/51), serous (7/51), carcinosarcoma (4/51), clear cell (4/51) and mixed (10/51) histology were enrolled. 35/51(69%) of tumors were high grade. The median age at diagnosis was 56 (range 37-77), and the median lines of treatment received was 3 (range 1-8). 45/51(88%) of pts had successful NGS profiling, 31/45(69%) using FoundationOne CDx, and 14/45 (31%) on an in-house platform. Frequent mutations (>20%) occurred in PTEN (60%), PIK3CA (49%), TP53 (46%), ARID1A (27%), CTNNB1 (24%) and KRAS (22%). There were 12/51(24%) MSI-H, 25/51(49%) MSS, and 14/51(27%) MSI-unknown tumors. The 6 mth progression free survival (PFS) rate for MSS versus MSI-H pts treated with front-line carboplatin+paclitaxel (CP) was 83% versus 50% (RR 1.67, fisher’s exact 2-sided p=0.09), with a shorter median PFS after 1st line CP for MSI-H versus MSS pts (median 5.2 mth vs. 8.3 mth, not sig). Upon progression, 29/51(57%) of pts were matched to therapy based on tumor profiles. Of these, 7/29(24%), 13/29(45%) and 9/29(31%) matched to anti-PD1/PD-L1, endocrine therapy and other targeted therapy, respectively. Among 7 MSI-H pts matched to anti-PD1/PD-L1 therapy, median PFS was 14.6 mth (95% CI 0.4-29), and objective response rate was 57%(4/7). In subsequent-line, matching to endocrine therapy (HR 4.3 95% CI 0.95-19.0, p=0.06) or other targeted therapy (HR 5.1, 95% CI 1.1-24.5, p=0.04) was associated with worse PFS compared to anti-PD1/PD-L1 therapy. Despite a short median PFS after front-line CP, median overall survival (OS) was not reached for MSI-H pts, compared to 38 mth (95% CI 30.7-46.0) for MSS and MSI-unknown pts. Conclusions: MSI-H EC pts appear to have shorter PFS to front-line CP chemotherapy compared with MSS pts, but may derive durable responses from immunotherapy in subsequent-line therapy. Early use of immunotherapy in advanced MSI-H EC pts should be considered. Further optimisation of therapy is urgently needed in advanced MSS EC.
Combination immunotherapy with ipilimumab and nivolumab in patients with rare gynaecological malignancies.
Authors: Klein Oliver , Kee Damien , Gao Bo , Markman Ben , Mileshkin Linda R. , Scott Clare L. , So Yeojeong , Linklater Richelle , Behren Andreas , Palmer Jodie , Carlino Matteo S. , Cebon Jonathan S. 
Published: May 2020

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]
Genomic and transcriptomic profiles of gynecologic neuroendocrine carcinoma are distinct from pulmonary neuroendocrine small cell carcinoma.
Authors: Mahdi Haider , Joehlin-Price Amy , Dowlati Afshin , Abbas Ata 
Published: May 2020

6093 Background: High-grade neuroendocrine carcinoma (NEC) of the cervix and other gynecologic origins are rare and aggressive cancers that unfortunately affect young women with high mortality. Treatment recommendations are often extrapolated from their counterpart, small cell carcinoma of the lung (SCLC). In the present study, we have performed comprehensive genomic and transcriptomic analyses in a cohort of patients with NEC of the cervix and other gynecologic origins and compared them to SCLC. Methods: We have identified 27 patients diagnosed with NEC of gynecologic origin from 1998-2019. Of them, we were able to obtain archival tissue from 14 patients (17 samples), including seven cervical NEC, three ovarian NEC, and two endometrial NEC. Two ovarian and one cervical patient have recurrent tumors. Whole exome sequencing (WES) and RNA-seq were successfully performed in 14 and 13 samples, respectively. BWA-MEM was used for mapping (hg38), and GATK Haplotype Caller was used for WES analysis. Ensemble-VEP was used for variant annotation, and SIFT and PolyPhen-2 were used for pathogenic prediction of missense mutations. Stranded pair-end RNA-seq data were analyzed using STAR and DESeq2. SCLC data from cBioPortal and EBI (accession number EGAS00001000334) were used to compare mutation and transcriptomic profiles. Results: We found that TP53 is not mutated in our cohort, and RB1 is mutated only in 1 (7%) tumor. TP53 and RB1 are the most frequently mutated genes in small cell lung carcinoma. However, LRP1B, the third most mutated gene in SCLC was also mutated in 4 (29%) tumors. We observed that WNT, RTK-RAS, NOTCH, and MYC are among the top mutated pathways in our cohort. Among the top 20 mutated genes, only four genes, MUC4, KMT2C, MAP3K1, and HLA-A, were common in cervical, ovarian, and endometrial tumors suggesting a high diversity within the NEC of gynecologic origin. Our RNA-seq analysis revealed a distinct transcriptional signature when compared to SCLC, especially the expression pattern of SCLC molecular subtypes defining ASCL1, NEUROD1, POU3F2, and YAP1 genes. Surprisingly, we observed a high expression of the YAP1 gene in all of the 13 tumors. However, the YAP1+ subtype represents a minority in SCLC and known to predict chemotherapy resistance and lower survival. Conclusions: Our results suggest a unique mutational profile and transcriptional signature that are distinct compared to SCLC tumors. Therefore, there is an urgent need to re-evaluate the therapeutic options and targets for NEC of gynecologic origin.
Randomized phase II study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma.
Authors: Keam Bhumsuk , Kang Eun Joo , Ahn Myung-Ju , Ock Chan-Young , Lee Keun Wook , Kwon Jung Hye , Yang Yaewon , Choi Yoon Hee , Kim Min Kyoung , Ji Jun Ho , Yun Tak , Nam Byung-Ho , Kim Sung-Bae 
Published: May 2020

6503 Background: Adenoid cystic carcinoma (ACC) does not respond to cytotoxic chemotherapy. Several anti-angiogenic agents were evaluated in single arm phase II trials. However, the role of chemotherapy is still controversial, because of natural stable disease course without chemotherapy and lack of randomized trial. We firstly conducted a randomized trial to evaluate the efficacy of axitinib compared to observation. Methods: In this multicenter, prospective phase II trial, we enrolled recurred, metastatic ACC patients who progressed within 9 months. Patients were randomly assigned either axitinib (5mg twice daily) or observation arm with 1:1 ratio. Crossover to the axitinib arm was permitted for patients in the observation arm who had disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), overall survival (OS), PFS, duration of response and adverse events. Results: A total of 60 patients randomly allocated to axitinib (N=30) and observation arm (N=30) and response evaluation was conducted in 57 patients. With a median follow-up of 25.4 months, the 6-month PFS rate was 73.2% (95% confidence interval [CI], 54.8 to 88.1%) in the axitinib arm and 23.2% (95% CI, 9.3 to 41.1%) in the observation arm (hazard ratio, 0.19; 95% CI, 0.08 to 0.45; P < 0.001). Median PFS was 10.8 months in axitinib arm and 2.8 months in observation arm ( P < 0.001). The ORR was 3.3% (95% CI, 0.1 to 17.2%) in the axitinib arm, and 0% (95% CI, 0 to 12.8%) in the observation arm. The disease control rate was 100% (95% CI, 88.4 to 100%) in the axitinib arm and 51.9% (95% CI, 32.0 to 71.3%) in the observation arm. After crossover, ORR of axitinib in the observation arm was 11.1% (95% CI, 2.4 to 29.2%). Median OS was not reached in axitinib arm, 28.5 months in observation arm ( P = 0.688). The most frequently reported adverse events of axitinib were grade 1 or 2 oral mucositis and fatigue. Detailed data of adverse events and mutational profile data will be presented. Conclusions: In this first randomized trial in patients with recurred or metastatic ACC, axitinib significantly increased 6-month PFS rate compared to observation. Clinical trial information: NCT02859012 .
Low-cost oral metronomic versus intravenous chemotherapy in recurrent, inoperable and metastatic head and neck cancer: Phase III Metro-CIS study.
Authors: Menon Nandini Sharrel , Noronha Vanita , Patil Vijay Maruti , Dhumal Sachin Babanrao , Joshi Amit , Sable Nilesh , Kumar Suman , Mahajan Abhishek , Bhattacharjee Atanu , Banavali Shripad Dinanath , Prabhash Kumar 
Published: May 2020

6506 Background: The NCCN preferred regimens for palliation in head and neck cancer, either EXTREME or KEYNOTE-048 are the only two regimens which have improved outcomes over chemotherapy, but they have limited applicability (1-3%) in low and middle-income countries due to the cost. Oral metronomic chemotherapy (OMC) has shown better outcomes than intravenous cisplatin; these results were obtained with a low incidence of adverse events and the cost of 1/100th of NCCN-preferred regimens in a Phase II study. Methods: This was a randomized Phase III non-inferiority open-label study. Adult patients with relapsed-recurrent or metastatic upfront palliatively treated squamous cell carcinoma of head and neck and ECOG PS 0-1 were eligible. Patients were randomized 1:1 between OMC (oral methotrexate 15 mg/m2 weekly with celecoxib 200 mg once daily or intravenous cisplatin (IVC) 75 mg/m2, 3-weekly for 6 cycles. CTCAE version 4.0 was used for adverse event recording. Response assessment (RECIST version 1.1) was performed every 2 months. EORTC QLQ-C 30 and EORTC QLQ -H&N 35 questionnaires were self-administered at baseline and 2-monthly thereafter. The primary endpoint was overall survival (OS) and was measured from the date of randomization to death. Assuming a 6-month OS in IVC arm of 40%, the non-inferiority margin of 13%, type 1 error of 5% (2-sided), type 2 error of 20% and lost-to-follow up rate of 20%, a total sample size of 422 subjects was required. Kaplan Meier method was used for the estimation of OS and progression-free survival (PFS). To determine non-inferiority the upper limit of 95% CI of difference between 6 months OS of the 2 arms had to be below 13%. Results: In the intention to treat analysis, the 6-months OS was 50.89% (95% CI, 43.3-57.97) and 62.26% (95% CI, 54.72-68.9) in the IVC and OMC arm respectively. The difference in 6-months OS between the 2 arms was - 11.37% (95% CI, -20.77 to -0.97). The median OS was 6.1 (95% CI, 5.33-6.93) versus 7.5 (95% CI, 6.5-8.8) months in IVC arm and OMC arm respectively ( P= .026). The unadjusted hazard ratio for death was 0.773 (95% CI, 0.615-0.97, P= .026). The median PFS was 1.67 (95% CI, 1.47-2.03) versus 3.23 (95% CI, 2.57-4.13) months in IVC and OMC arms respectively ( P< 0.001). Any grade 3 or above adverse events were seen in 61 (30.2%) versus 37 (18.9%) patients in IVC and OMC arm respectively ( P= .01). Conclusions: OMC improves outcomes in palliatively treated head and neck cancer and is a new standard of care in this setting, in addition to the EXTREME and KEYNOTE-048 regimen. Clinical trial information: CTRI/2015/11/006388 .