bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of JASPAC05: Phase II trial of neoadjuvant S-1 and concurrent radiotherapy followed by surgery in borderline resectable pancreatic cancer.
Authors: Takahashi Shinichiro , Ohno Izumi , Ikeda Masafumi , Konishi Masaru , Kobayashi Tatsushi , Akimoto Tetsuo , Kojima Motohiro , Morinaga Soichiro , Toyama Hirochika , Shimizu Yasuhiro , Miyamoto Atsushi , Hishinuma Shoichi , Takakura Norihisa , Takayama Wataru , Hirano Satoshi , Otsubo Takehito , Nagino Masato , Kimura Wataru , Sugimachi Keishi , Uesaka Katsuhiko ,   JASPAC Group
Published: May 2019

4127 Background: Borderline resectable pancreatic cancer (BRPC) is frequently associated with positive surgical margins and a poor prognosis when treated with upfront surgery. This study was designed to assess whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate. Methods: This was a multicenter, single-arm, phase II study. Patients with BRPC received S-1 (40 mg/m2 bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of the superior mesenteric vein or portal vein; and (2) tumor contact ≤180° with the superior mesenteric artery, common hepatic artery, or celiac axis. The primary endpoint was the R0 resection rate in BRPC confirmed by central review. Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (RECISTv1.1), pathological response rate, surgical morbidity (Clavien–Dindo classification), and toxicity (CTCAEv4.0). At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and threshold value for the primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible, of whom 41 had BRPC by central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% (95% CI, 37.6%–66.0%) in 52 eligible patients and 63% (95% CI, 46.9%–77.9%) in 41 patients with BRPC. The radiological response rate was 5.8%, while destruction of > 50% of tumor cells was shown microscopically in 32% of patients. Postoperative grade III/IV adverse events were observed in 7.5% of operated patients. Among the 52 eligible patients, the 2-year OS rate, median OS, and median PFS were 51%, 25.8 mo, and 6.7 mo. Of the 41 patients with BRPC, the 2-year OS rate, median OS, and median PFS were 58%, 30.8 mo, and 10.4 mo. Conclusions: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate with encouraging survival rates in BRPC. A phase II/III trial evaluating this treatment is ongoing. Clinical trial information: NCT02459652.
Relacorilant (RELA) with nab-paclitaxel (NP): Safety and activity in patients with pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA).
Authors: Munster Pamela N. , Sachdev Jasgit C. , Fleming Gini F. , Borazanci Erkut Hasan , Grabowsky Jennifer A. , Sharma Manish , Custodio Joseph , Greenstein Andrew , Lu Lawrence , Nguyen Dat , Shepherd Stacie Peacock 
Published: May 2019

4130 Background: Glucocorticoid receptor (GR) pathway activation has been linked with chemotherapy resistance (CTR). RELA (formerly CORT125134, Corcept Therapeutics), a potent selective GR modulator, in combination with paclitaxel reduced CTR and enhanced activity against tumor growth in preclinical models of solid tumors. Methods: Patients (pts) with advanced solid tumors, ≤3 prior lines of cytotoxic therapy, ECOG status 0-1, and adequate marrow function received RELA (100, 150, or 200mg) + NP (60, 80, or 100mg/m2). Once daily RELA was given either continuously (CON) or intermittently (INT) (day before, of, and after NP). NP was dosed weekly for 3 of 4 weeks (wks) of a 28-day cycle. Prior NP therapy was allowed. Results: 72 pts have been enrolled [mean age 60 (range 18-81), mean number of prior therapies 3, prior taxane (TXN) treatment 54/72 (75%)]. 61 pts received ≥1 dose of RELA. Grade ≥3 AE ≥10% for CON: neutropenia (6/43, 14%); INT: neutropenia (6/18, 33%), anemia (2/18, 11%), and mucosal inflammation (2/18, 11%). Prophylactic G-CSF became mandatory in later cohorts. Recommended Phase 2 Dose: RELA 100mg-CON/150mg-INT + NP 80mg/m2 (exposures similar to NP 100mg/m2 due to CYP3A4 inhibition by RELA). Disease control (DC) > 24 wks was noted in 5/27 (19%) PDAC pts: 3 PR, 2 SD (27-50 wks). 3 pts achieved benefit despite progression on prior TXN with time to progression (TTP) 1.9-3.6x longer than prior TXN. 4/13 (31%) OvCA pts had DC > 24 wks: 1 CR, 1 PR, 2 SD (33-54+ wks). 1 pt had TTP 4.4x longer than prior TXN. 3 additional PRs were observed: acinar pancreatic cancer, TTP 31 wks (4.4x prior TXN); vulvar SCC HPV+, TTP 55 wks (3.9x prior TXN); cholangiocarcinoma, DC 29+ wks. Expression of GR-regulated genes involved in inflammation, apoptosis, and CTR distinguished pts with DC from pts without DC, providing proof of mechanism. Conclusions: RELA+NP resulted in durable disease control in pts with metastatic PDAC, OvCA, and other solid tumors, including those that have progressed on prior TXN. TTP was often several-fold longer than previously achieved on TXN therapy. Toxicities are manageable with prophylaxis for neutropenia. Further evaluation in OvCA NCT03776812, PDAC, and others are planned. Clinical trial information: NCT02762981.
Methylated circulating tumor DNA (Met-DNA) as an independent prognostic factor in metastatic pancreatic adenocarcinoma (mPAC) patients.
Authors: Pietrasz Daniel , Wang-Renault Shufang , Dahan Laetitia , Taieb Julien , Le Malicot Karine , Rinaldi Yves , Doat Solene , Phelip Jean-Marc , Taly Valerie , Bachet Jean-Baptiste , Laurent-Puig Pierre 
Published: May 2019

4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.
SWOG S1314: A randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer.
Authors: Flaig Thomas W. , Tangen Catherine M. , Daneshmand Siamak , Alva Ajjai Shivaram , Lerner Seth P. , Lucia M. Scott , McConkey David James , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Bangs Richard Carlton , MacVicar Gary R. , Bastos Bruno R. , Gustafson Daniel , Plets Melissa , Thompson Ian Murchie 
Published: May 2019

4506 Background: Both dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). We investigated COXEN, a gene expression model, as a predictive biomarker. Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective was to assess whether the pre-specified dichotomous treatment-specific COXEN gene expression profile is prognostic of pT0 rate or ≤ pT1 at surgery, and to assess whether COXEN score is a predictive factor between regimens and response. Logistic regression was used to model response, adjusting for stratification factors. Results: 167 patients were included; the ddMVAC/GC arms had a median age of 65/64, PS = 0 in 80%/75%, Male proportion of 88%/79% and T2 stage of 87%/92%. All had at least 3 cycles of chemo and surgery/progression within 100 days of last chemo. There were favorable COXEN ddMVAC scores in 32% and GC score in 26%. The pT0 rates for ddMVAC and GC were 32% and 35%; the rates of ≤ pT1 were 55% and 49%, respectively. Conclusion: The COXEN scores were not significantly prognostic for response in their individual arms; The COXEN GC score was significant predictor for downstaging in pooled arms. There was no evidence of an interaction between COXEN score and regimen in predicting response. The prospective data and samples from this study will allow for further development of COXEN and other predictive biomarkers. Clinical trial information: NCT02177695. [Table: see text]
Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Zaghloul Tarek , Smith Andrew , Abdalla Ahmed , William Hany , Hwang Wei-Ting , Baumann Brian Christopher 
Published: May 2019

4507 Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemotherapy or decline it, even though such treatment may be warranted. There is no clear alternative adjuvant therapy for these patients, who are usually observed. In this study, we compare post-op radiotherapy (PORT) vs. adjuvant chemotherapy in a randomized clinical trial. We hypothesized that PORT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. In 2007, a third arm comparing adjuvant chemo was added. Herein, we report the results of PORT vs. adjuvant chemo. Patients ≤70 y/o with ≥1 of the following factors (≥pT3b/T4a, grade 3, or positive nodes) with negative margins after RC + pelvic node dissection were eligible. Routine follow-up & pelvic CT q6 months were performed. PORT included 3D conformal pelvic RT (45Gy/1.5Gy BID). Chemo included gemcitabine/cisplatin x 4. Post-hoc non-inferiority exploratory analysis was performed. Results: The PORT arm accrued 78; the chemo arm accrued 45. 51% had urothelial carcinoma; 49% had squamous cell carcinoma/other. The two arms were well-balanced except for gender (p = 0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for PORT vs. chemo alone were 54% vs. 47% (HR 0.65(95%CI 0.35-1.19, p = 0.16) for DFS; 92% vs. 69% (HR 0.28(95%CI 0.10-0.82), p = 0.02 for LRFS; 75% vs. 79% (HR 2.39(95%CI 0.94-6.09), p = 0.07) for DMFS; 61% vs. 60% (HR 0.94(95%CI 0.52-1.69), p = 0.83) for OS. Late grade ≥3 GI toxicity was observed in 6 PORT patients (8%) & 1 chemo patient (2%). Based on our data, there is a greater than 90% probability that the true difference in 2 yr DFS is less than 10%, the pre-specified non-inferiority margin. Conclusions: This randomized study demonstrates superior local control with PORT vs. adjuvant chemo with no significant differences in DFS, DMFS or OS. Results suggest that PORT could be an option for patients with LABC after RC who are medically unfit for adjuvant chemo or who decline it. Clinical trial information: NCT01734798.
FIERCE-22: Clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis.
Authors: Siefker-Radtke Arlene O. , Currie Graeme , Abella Esteban , Vaena Daniel A. , Rezazadeh Kalebasty Arash , Curigliano Giuseppe , Tupikowski Krzysztof , Andric Zoran Gojko , Lugowska Iwona , Kelly William Kevin 
Published: May 2019

4511 Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. Reported response rates to immune checkpoint inhibitors (ICI) are approximately 20%. 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), which may result in lower sensitivity to ICI. V (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of both the wildtype and genetically activated receptor. This is a Phase 1b/2 study designed to evaluate V monotherapy window followed in combination of V with P(VP) (NCT03123055). Methods: This trial enrolled mUC pts with failure to ≥ 1 prior line of chemotherapy or recurrence ≤ 12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG <2. Treatment consisted of v at 25 mg/kg alone for 2 week monotherapy window followed by combination with P 200 mg q3w.during the V window paired tumor biopsy were obtained. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity [ORR]). Results: 35 pts have received treatment (Ph1b:8, WT:20, M/F+: 7). WT patients were unselected for PD-1 status, predominately male (55%) white (95%), all had received at least 1 line of prior chemo and 60% had Bellmunt scores of > 1. The safety profile is consistent with previously reported data for P. TEAE occurring in >20% of patients were nausea, anemia, diarrhea and fatigue. Six WT patients (30%) had responses (4 confirmed responses, 1 unconfirmed), and an additional patient with an iRECIST response. Responses occurred at a median of 3.5 months. At 4+ months of follow up, 13(65%) remain on treatment @ a median of 8 cycles (range: 1-13). At 5+ months the median PFS has not been reached. Conclusions: VP combination therapy is well tolerated with an encouraging ORR and prolonged PFS in the WT cohort; greater than one would anticipate from P alone based upon historical data. We will be reporting 9+ month preliminary PFS/OS and updated OOR/DOR data. Clinical trial information: NCT03123055.
Efficacy of immune checkpoint inhibitors (ICI) and genomic characterization of sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC).
Authors: Bakouny Ziad , Vokes Natalie , Gao Xin , Nassar Amin , Abou Alaiwi Sarah , Flippot Ronan , Bouchard Gabrielle , Steinharter John A. , Nuzzo Pier , Pan Wenting , Flaifel Abdallah , Lee Gwo-Shu Mary , Braun David A. , Wei Xiao X. , Signoretti Sabina , McGregor Bradley Alexander , Harshman Lauren Christine , Van Allen Eliezer Mendel , Choueiri Toni K. 
Published: May 2019

4514 Background: S/R mRCC are poorly characterized rapidly progressing tumors associated with poor prognosis. Although conventional therapies are less effective for these tumors, emerging data suggests that ICIs may be especially effective. Our aim was to characterize the genomic alterations (GA) in S/R mRCC tumors and evaluate their response to ICIs. Methods: We retrospectively compared the activity of first-line ICIs to non-ICI-based therapies for S/R mRCC patients (pts) treated at DFCI and analyzed sequencing data from an NGS panel (275-447 genes) on a subset of these patients (matched by histology to non-S/R mRCC). For S/R mRCC pts treated with ICI vs non-ICI therapies, overall survival (OS) and time to treatment failure (TTF) were compared by Cox regression and objective response rate (ORR) by logistic regression. GA frequencies were compared by Fisher’s test and tumor mutational burden (TMB) by Mann Whitney U between S/R and non-S/R mRCC. Results were considered statistically significant if p < 0.05 or q < 0.10. Results: 125 S/R mRCC pts were included (88 S, 23 R, 14 S&R) among which 103 were clear cell and 48 had sequencing data. GA in BAP1 were significantly more frequent in S/R vs non-S/R (25% vs 4.3%; q = 0.096) while other GA had similar frequencies and TMB (median [IQR]) was similar (7.2 [5.2-8.4] vs 6.8 [5.3-9.1] mut/Mb; p = 0.98). Median follow-up was 35.4 (95% CI = 24.9 – 46.0) months (m). On multivariable analysis, S/R mRCC pts treated with ICI had significantly better clinical outcomes (Table). Conclusions: Pts with S/R mRCC have a higher frequency of BAP1 GA and better outcomes on ICIs compared to non-ICI-based therapies. Future studies should determine the molecular mechanisms underlying the improved response to ICIs in S/R mRCC. [Table: see text]
Patient-reported outcomes (PROs) in IMmotion150: Atezolizumab (atezo) alone or with bevacizumab (bev) versus sunitinib (sun) in first-line metastatic renal cell carcinoma (mRCC).
Authors: Pal Sumanta K. , McDermott David F. , Atkins Michael B. , Escudier Bernard , Rini Brian I. , Motzer Robert J. , Fong Lawrence , Joseph Richard Wayne , Oudard Stephane , Ravaud Alain , Bracarda Sergio , Suarez Rodriguez Cristina , Lam Elaine Tat , Choueiri Toni K. , Ding Beiying , Quach Caroleen , Hashimoto Kenji , Schiff Christina , Piault Elisabeth , Powles Thomas 
Published: May 2019

4515 Background: The phase 2 IMmotion150 study showed improved PFS with atezo + bev vs sun in patients (pts) whose tumors were PD-L1+ and corroborated the activity of atezo monotherapy in previously untreated mRCC. This study offers an opportunity to evaluate PROs with immunotherapy and VEGF-directed therapy alone and in combination. Methods: Pts randomized to atezo 1200 mg IV q3w alone or with bev 15 mg/kg IV q3w, or sun 50 mg po qd for 4 wk on/2 wk off completed the MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) q3w of each 6-wk cycle until progression (RECIST 1.1). Time to deterioration (TTD; first ≥ 2-point score increase over baseline [BL]) and change from BL (effect size [ES] ≥ 0.2 suggests a clinically important difference vs sun) in MDASI symptom severity and interference and BFI fatigue severity and interference scores are reported for all-comers. Results: Completion rates were > 90% at BL and ≥ 80% at most visits across arms. BL PRO scores indicating mild symptoms and interference were similar across arms. Delayed TTD of symptom severity and interference with daily life was seen with atezo vs sun and atezo + bev vs sun and was longest with atezo alone (Table). Pts reported milder symptoms and less interference during the first 6 cycles with atezo vs sun: ES mean (range) was 0.36 (0.07-0.68) for core symptom severity and 0.36 (0.04-0.83) for symptom interference. The 5 worst pt-reported symptoms during tx (dry mouth, fatigue, rash, drowsiness, lack of appetite) were all in the sun arm; all 16 symptoms measured were milder with atezo vs sun. Conclusions: PROs suggest that atezo alone or with bev maintained daily function with minimal symptom interference vs sun. Clinical activity, safety and PRO data for atezo support its investigation in adjuvant tx of high-risk RCC pts (IMmotion010; NCT03024996). Clinical trial information: NCT01984242. [Table: see text]
Phase II study of nivolumab and ipilimumab for advanced bladder cancer of variant histologies (BCVH).
Authors: McGregor Bradley Alexander , Campbell Matthew T , Xie Wanling , Siefker-Radtke Arlene O. , Shah Amishi Yogesh , Venkatesan Aradhana M. , Kilbridge Kerry L. , Sonpavde Guru , Bubley Glenn , McKay Rana R. , Choueiri Toni K. 
Published: May 2019

4518 Background: Patients with BCVH have poor outcomes and data regarding the management of this heterogeneous group of patients is limited. Nivolumab and ipilimumab has demonstrated safety and efficacy in urothelial carcinoma and other malignancies. In this multicenter, single arm, multi-cohort phase II trial we evaluate the efficacy of nivolumab and ipilimumab in patients with BCVH and other advanced rare genitourinary cancers (NCT 03333616). Herein, we report the preliminary results of the fully accrued BCVH cohort. Methods: Eligible patients had metastatic BCVH, ECOG performance status of 0-2 and were either untreated or had received any number of lines of prior therapy excluding prior immunotherapy. Patients underwent a baseline biopsy and blood collection for correlative studies and received treatment with nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 cycles with continued maintenance of nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 19 BCVH patients were enrolled at 4 institutions between 4/2018 and 1/2019: squamous cell (n = 6), small cell (n = 3), adenocarcinoma (n = 3), urachal (n = 5), plasmacytoid (n = 1), and spindle cell (n = 1). 13 (68%) patients had received prior systemic therapy including platinum-based chemotherapy in 92% patients. Median number of cycles of ipilimumab plus nivolumab received was 3 (range 1-8) and median follow-up was 3.6 (0.3-8.8) months. 13 patients had undergone at least one scan; ORR was 31% (4/13, 80%CI: 14-52%), with partial responses seen in small cell carcinoma (n = 2), urachal (n = 1) and a complete response in 1 patient with plasmacytoid carcinoma. 3 patients (16%) developed treatment-related grade 3 toxicities with 1 (5%) grade 4 toxicity. Conclusions: Nivolumab and ipilmumab resulted in objective responses in a subset of patients with BCVH with manageable toxicities. Updated clinical and correlative data will be presented. This combination may warrant further investigation in patients with BCVH, which has substantial unmet needs. Clinical trial information: NCT 03333616.