bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with hepatocellular carcinoma (HCC) from a phase I study.
Authors: Martell Robert E. , Puzanov Igor , Ma Wen Wee , Santoro Armando , Dy Grace K. , Goff Laura Williams , Fetterly Gerald J. , Michael Shaunita A. , Means-Powell Julie Ann , Chai Feng , Lamar Maria , Simonelli Matteo , Chiang Wendy M. , Jarboe Jamie , Schwartz Brian E. , Adjei Alex A. 
Published: March 2020

4117 Background: The multikinase inhibitor sorafenib is standard of care for pts with advanced HCC. Tivantinib, an oral, selective MET inhibitor, demonstrated synergistic antitumor activity when combined with sorafenib in several tumor models. The phase 1 dose-escalation study assessed the safety profile of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase 2 dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Dose escalation previously established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with HCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. After a safety review in HCC pts in other studies and a report of febrile neutropenia in this study, the tivantinib dose for newly enrolled pts was reduced to 240 mg BID. Results: 20 pts with HCC (mean age, 62 yr; Child-Pugh [CP] A [n = 14], or CP B [n = 6]) were treated at the RP2D (n = 10) or at the reduced tivantinib dose plus sorafenib (n = 10). 10 pts received ≥ 1 previous systemic anticancer treatment (median, 0.5; range, 0-3). The most common adverse events (≥ 25%) were rash (40%), palmar-plantar erythrodysesthesia syndrome (35%), fatigue and diarrhea (30% each), and nausea and anorexia (25% each). Neutropenia was reported in 2 pts. Best response was 1 complete response (CR), 1 partial response (PR), and 12 stable disease (SD). Overall response rate and disease control rate were 10% and 70%, respectively. Median progression-free survival (mPFS) was 3.5 mo (95% CI, 2.8-11.1 mo). Among 8 pts previously treated with vascular endothelial growth factor (VEGF) inhibitors (6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib), best response was 1 CR, 1 PR, and 3 SD, and mPFS was 15.9 mo (95% CI, 1.6-15.9 mo). 2 pts are still on study. Conclusions: The combination of tivantinib (360 mg BID) plus sorafenib (240 mg BID) was well tolerated. Preliminary evidence of antitumor activity indicates that combined inhibition of MET and angiogenic signals may have therapeutic potential in this setting, including pts pretreated with VEGF inhibitors.
PAZONET: Results of a phase II trial of pazopanib as a sequencing treatment in progressive metastatic neuroendocrine tumors (NETs) patients (pts), on behalf of the Spanish task force for NETs (GETNE)—NCT01280201.
Authors: Grande Pulido Enrique , Castellano Daniel E. , Garcia-Carbonero Rocio , Teule Alex , Duran Ignacio , Fuster Jose , Sevilla Isabel , Escudero P. , Sastre Javier , Capdevila Jaume 
Published: March 2020

4119 Background: Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT that has demonstrated clinical activity in NETs. The aims of our study were to assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with NETs who had previously failed to at least one antiangiogenic or mTOR inhibitor treatment. Methods: Pts presented locally-advanced or metastatic gastrointestinal or pancreatic NET disease documented as progressive. Pazopanib 800 mg was given daily until disease progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit Rate (CBR) defined as Complete Response plus Partial Response (PR) plus Stable Disease (SD) at 6 months by RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates waere used for the analysis of time-to-event variables: 95% CI. Results: 33 pts were evaluable for response per protocol. 54.5% males, mean age 60.7±10.3 years. At 6 months, 2 pts had PR (6%), 26 SD (79%), and 5 DP (15%), thus the CBR was 85%. By subgroups, CBR was 100% in pts with no previous targeted therapy (7 pts), 89% in pts with previous mTOR inhibitors (9 pts), 83% in pts with previous antiangiogenics (12 pts), and 60% in pts with previous antiangiogenics and mTOR inhibitors (5 pts). The sum of the longest diameter of target lesions had a decrease over 10% in 22% of pts (29% without previous biological treatment, 22% mTOR without prior multitarget, 18% prior multitarget without mTor, and 20% with previous multitarget and mTOR. Median PFS was only reached in the subgroup of pts (26 pts) with previously treated with antiangiogenics and mTOR inhibitors (20.6 weeks, 95% CI, 10.4-30.8). Most frequent toxicities, any grade: asthenia (75%), diarrhoea (63%), nausea (42%). Translational studies on angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing. Conclusions: Pazopanib at 800 mg daily has promising activity in advanced NET regardless of previous treatment with other targeted therapies. This trial may introduce the concept of treatment sequencing with novel targeted agents in NETs.
Treatment of advanced neuroendocrine tumors: Results of the UKINETS and NCRI randomized phase II NET01 trial.
Authors: Corrie Philippa , Caplin Martyn , Reed Nicholas , Qian Wendi , Lao-Sirieix Si-houy , Hardy Richard , Armstrong Graham , Valle Juan W. , Talbot Denis Charles , Cunningham David , Luong Tu Vinh , Shaw Ashley , Meyer Tim ,   on behalf of all collaborators
Published: March 2020

4121 Background: Chemotherapy is widely used for advanced, unresectable neuroendocine tumours (NETs) but only four randomised trials are published. The first combined streptozocin (strep) and 5fluorouracil (5FU), reporting 63% response rate (RR), but subsequent retrospective studies had lower RRs (6-45%). Cisplatin has been combined with strep+5FU in a retrospective study with promising activity in NETs and capecitabine (cap) has been effectively substituted for 5FU in many tumours. The NET01 trial was designed to investigate whether cap+strep ± cisplatin warrant further evaluation. Methods: Patients (pts) with histologically confirmed, unresectable, advanced and/or metastatic NETs of foregut, pancreatic or unknown primary site were randomised (ratio 1:1) to 6 cycles of 3-weekly cap 625 mg/m2 po bd daily (D1-21), strep 1.0g/m2 IV (D1), with cisplatin 70mg/m2 IV(D1) (Cap-cist) or without (Cap-strep). The primary outcome measure was RR using RECIST criteria (v 1.0). 84 pts were required to test a RR of <40% vs >60% with a significance level of 5% and 80% power in each arm. Central pathology review was performed; retrospective central radiology review was undertaken on 10% of randomly selected cases. Results: 86 pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42 Cap-cist) with primary site – foregut 20%, pancreatic 48% and unknown 33%. The grade was low 8 (11%), intermediate 47 (67%) and high 15 (21%). Baseline characteristics were balanced between the 2 arms. 60% Cap-strep pts received ≥6 cycles compared with 33% Cap-cist pts. 17 Cap-strep and 26 Cap-cist pts experienced grade ≥3 toxicities. Outcome results are summarised in the table. Ki67, mitotic index or primary site of origin did not appear to predict for response. Conclusions: The novel Cap-strep ± cisplatin regimens were associated with overall disease control and survival durations consistent with published studies. Cap-strep was better tolerated than Cap-cist. Further prospective randomised studies are required to determine optimal NET chemotherapy. [Table: see text]
Circulating tumor cells as prognostic and predictive markers in neuroendocrine tumors.
Authors: Khan Mohid Shakil , Tsigani Theodora , Garcia-Hernandez Jorge , Hartley John Anthony , Caplin Martyn E , Meyer Tim 
Published: March 2020

4123 Background: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors with variable survival. While Ki67 in tumour tissue is prognostic, there have been no prospectively validated circulating prognostic or predictive markers. Here we present results from a large prospective study of circulating tumor cells (CTCs) in patients with NETs. Methods: Patients about to commence therapy had a 7.5 ml blood sample taken at baseline with additional samples taken at 3-5 weeks after commencing treatment. CTCs were enumerated using the CellSearch system and counted independently by two observers. Radiological response was classified according to RECIST 1.1. PFS and OS were measured from start date of therapy, to date of progression and date of death, respectively. In order to define a prognostic cut off value for CTCs, 90 patients were enrolled in a training set and 85 patients in a validation set. The optimal cut-off level validated was CTC≥1. Prognostic factors including Ki67 were evaluated using Cox regression. Changes in CTCs after treatment were divided into tertiles. Results: 138 patients with metastatic NET (31 pancreatic, 81 midgut, 12 bronchopulmonary, 11 unknown primary, 3 hindgut) were recruited who were about to undergo treatment with somatostatin analogues(34), chemotherapy(28), PRRT(40), TAE(18), RFA(3), Sunitinib(4), interferon(4) and surgery(7). Median follow-up was 9.7 months (range 5-29). Patients with baseline CTC≥1 had significantly worse PFS (HR 4.3 95%CI 1.8-10.3), and OS (HR 6.1 95%CI 1.8-20.3) than those without CTCs. In multivariate analysis CTC presence was associated with worse PFS (HR 3.7 95%CI 1.5-8.9) and OS (HR 5.1 95%CI1.5-7.3). Changes in CTCs predicted response to therapy (Fisher’s exact p<0.001) and those with increase in CTCs by ≥33% post-therapy had significantly worse PFS (HR 23.1 95%CI 5.37-99.0) and OS (HR18.9 95%CI 2.4-146) than a fall or <33% increase. Conclusions: In metastatic NETs, CTCs are a promising prognostic marker and may be an early marker of response to therapy. Further evaluation of CTCs in the context of therapeutic trials is required.
Prevalence of functional tumors in neuroendocrine carcinoma: An analysis from the NCCN NET database.
Authors: Choti Michael A. , Bobiak Sarah , Strosberg Jonathan R. , Benson Al Bowen , Bloomston Mark , Yao James C. , Zornosa Carrie C. , Bergsland Emily K. , Kulke Matthew , Nakakura Eric K. , Shah Manisha H. 
Published: March 2020

4126 Background: Neuroendocrine tumors (NETs) are increasing in incidence and prevalence. Identification and treatment of specific clinical NET syndromes are established, yet there is uncertainty regarding the prevalence of NET with hormone-related symptoms versus nonfunctional tumors. Methods: The National Comprehensive Cancer Network (NCCN) created a comprehensive database to characterize patients (pts) treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions with a confirmed NET diagnosis: including carcinoid (cNET), pancreatic NET (pNET), NET not otherwise specified (NOS), and pheochromocytoma (PCC) between 2004 and 2010. The primary aim of this analysis was to describe demographic and clinical characteristics of NET pts by functional (fxn) status at diagnosis (dx). Results: Among 1244 NET pts, 26% (n=327) had an fxn tumor. Carcinoid syndrome (CS) occurred in 28% of cNET pts. The most common primary tumor sites among CS pts were small bowel (69%) and unknown (15%). Prevalence of hormonal syndrome (HS) among pNET pts was 22%, 24% among NOS pts and 37% among PCC pts. The majority of CS pts (74%), pNET HS pts (67%), and NOS HS pts (91%) had distant disease at dx, in contrast to 31% of PCC HS patients. Among CS pts with a known histologic grade, 91% were well differentiated (G1). Similarly, 86% of pNET HS and 67% of NOS HS pts with a known histologic grade had G1 NETs. The most common symptoms at dx among pts with CS included abdominal cramping (53%), change in bowel habits (48%), and flushing (40%). Among those tested, 85% of CS pts had a positive 5-HIAA test at dx. Among pNET HS pts, the most common symptoms present at dx were abdominal cramping (39%) and change in bowel habits (46%). The most common symptoms present at dx among NOS HS pts were abdominal cramping (35%), change in bowel habits (47%) and flushing (38%). Conclusions: Prevalence of CS in this NCCN database (28%) was slightly higher than the 10% previously reported in the literature. In contrast, the prevalence of HS among pNET pts (22%) was lower than previously reported. Approximately one quarter of cNET pts without metastatic disease had CS, warranting further analysis as CS most often occurs in the presence of liver metastasis.
Methylguanine DNA methyl transferase (MGMT) expression to predict response to temozolomide (TMZ) in patients with digestive neuroendocrine tumors (NETs).
Authors: Hammel Pascal , Hentic Olivia , Cros Jerome , Rebours Vinciane , Zappa Magaly , Maire Frederique , Ruszniewski Philippe , Couvelard Anne 
Published: March 2020

4133 Background: TMZ is an orally given drug used in patients (pts) with NETs, with encouraging results in pancreatic NETs in a recent study (Strosberg et al, 2011). Higher treatment efficacy seems to be correlated to MGMT tumor deficiency (Kulke et al, 2010). Aim-To assess MGMT expression in digestive NETs and to correlate with the efficacy of TMZ-based therapies. Methods: All pts with well differentiated, progressive, non resectable NETs treated with TMZ-based chemotherapy were included. Treatment efficacy was defined according to RECIST. Pts with progression or only stable disease were considered as “non-responders”. Nuclear expression of MGMT was assessed by immunohistochemistry on primary tumors or metastases and graded according the product of the intensity of staining (0 to 3) and the rate of positive cells (%), leading to a score comprised between 0 and 300. A score ≥ 80 was defined as “high” staining. Results: 22 pts (age 59 years (36-81)) with pancreatic (14 pts), small bowel (5 pts) or other (3 pts) NETs, grade 1 (5 pts) or 2 (17 pts) (WHO 2010 classification) were included. They received TMZ alone (19 pts) or combined with capecitabine (3 pts) as first line (3 pts) or 2+ line (19 pts).After a median of 6 cycles (3-16), objective response, stable disease and progression rates were seen in 32 % (7 pts, all with pancreatic NETs), 41% (9 pts, 5 pancreatic) and 27% (6 pts, 4 small bowel), respectively. Median (range) MGMT score was 10 (0-300). A “High” MGMT score was seen in 36% of pts (small bowel 4, pancreas 3 pts) ; it was correlated with primary tumor location (more frequent in small bowel NETs, p=0.02) and predictive of the absence of response (p=0.02). A “Low “MGMT score tended to be associated with objective response (p=0.06) whereas none of the pts with “high” score had tumor response. Response rate in pts with “low” MGMT score was 50%. Conclusions: MGMT deficiency is more frequent in pancreatic than small bowel NETs. Patients with pancreatic NET and low MGMT score are good candidates for TMZ, whereas those with high score should be treated with other drug in first intention. In patients with small bowel NET with most often high MGMT score, tumor stabilization using TMZ seems to be rare.
Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial.
Authors: Motzer Robert John , Nosov Dmitry , Eisen Tim , Bondarenko Igor N. , Lesovoy Vladmir , Lipatov Oleg N. , Tomczak Piotr , Lyulko Alexey A. , Alyasova Anna , Harza Mihai , Kogan Mikhail , Alexeev Boris Y. , Sternberg Cora N. , Szczylik Cezary , Zhang Joshua , Strahs Andrew Louis , Esteves Brooke , Slichenmyer William J. , Berkenblit Anna , Hutson Thomas E. 
Published: March 2020

4501 Background: Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature. Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.
Randomized phase II trial of gemcitabine/cisplatin (GC) with or without cetuximab (CET) in patients (pts) with advanced urothelial carcinoma (UC).
Authors: Grivas Petros , Agarwal Neeraj , Siefker-Radtke Arlene O. , Daignault Stephanie , Puzanov Igor , MacVicar Gary R. , Levine Ellis Glenn , Srinivas Sandy , Twardowski Przemyslaw , Eisenberger Mario A. , Quinn David I. , Vaishampayan Ulka N. , Yu Evan Y. , Dawsey Scott , Day Kathleen C. , Day Mark L. , Smith David C. , Hussain Maha 
Published: March 2020

4506 Background: In UCpts EGFR over-expression correlates with high grade, stage, progression, short survival. Preclinical data show enhanced anti-tumor effect with CET + chemotherapy (CT). In several solid tumors CET added to CT improved survival. CET is hypothesized to improve UC response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, unresectable, locally recurrent or metastatic UC were stratified by disease state and randomized (1:2) to C 70mg/m2 d1, G 1000mg/m2 d1, d8, d15 (Arm A) or same CT + CET 500mg/m2 d1, d15 (Arm B) q28 days. Due to high thromboembolic events rate in Arm B, G dose was reduced to 800 mg/m2. 6 GC cycles were planned. Arm A pts progressing after 2 GC cycles had CET added. Arm B pts were to continue on CET monotherapy after 4-6 CT cycles. Imaging was q8 weeks. Primary endpoint: RECIST response rate (RR); secondary: safety, PFS, survival. Since E-cadherin impacts UC response to CET in vitro, serum level (sE-cad) was assessed at baseline, after 2 cycles, end of CT and at progression. With 1-stage design, assuming RR 50% (Arm A) and at least 65% (Arm B), planned sample size was 27/54 pts. RR improvement of 5% has 81% probability if true difference is 15%. Results: 88 pts were eligible and randomized, Arm A/B: median age 66/61 years; bladder primary 71.4%/77.2%; metastatic disease 92.9%/89.5%, median CT cycles number 6/5. 28 Arm B pts continued CET (median 3 cycles, range 1-29); 1 Arm A pt had CET added. Most common G3/4 adverse events (AEs) (Arm A, B): neutropenia (34.5%, 33.9%), anemia (10.3%, 5.1%), thrombocytopenia (27.6%, 22%), thromboembolism (6.9%, 18.6%), hyponatremia (3.5%, 10.2%); Arm B only: rash 28.8%, fatigue 11.9%, hypomagnesemia 11.9% and 2 deaths. 84 pts were response evaluable (see table below). sE-cad did not correlate with outcome. sE-cad increased in Arm A, but decreased in Arm B over time. Conclusions: GC/CET was feasible with no outcome improvement but higher AEs. sE-cad did not correlate with outcome. Decreased sE-cad in Arm B suggests potential EGFR-mediated E-cad proteolysis. [Table: see text]
Final analysis of intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110).
Authors: Mason Malcolm David , Parulekar Wendy , Sydes Matthew Robert , Parmar Mahesh , Anderson John , Barber Jim , Brundage Michael Donald , Cowan Richard , Gospodarowicz Mary K. , Hayter Charles , Hetherington John , Hiltz Andrea Clare , Kirkbride Peter , Kostashuk Edward , Sanders Karen , Sathya Jinka , Swanson Gregory P. , Chen Bingshu E , Warde Padraig Richard ,   NCIC-CTG PR3/MRC UK PR07 Investigators
Published: March 2020

4509 Background: Data from the SPCG-7 study and interim analysis of this trial have demonstrated an overall survival (OS) benefit for RT when added to ADT. We present the protocol specified final analysis of PR3/PR07. Methods: Patients with locally advanced (T3/T4, N0/NX, n=1057) or organ-confined prostate cancer (T2,N0/NX, with either PSA > 40 μg/l or PSA > 20 μg/l and Gleason > 8, n=144) were randomized to lifelong ADT (bilateral orchiectomy or LHRH agonist) or ADT + RT (65-69 Gy to prostate + seminal vesicles with or without 45Gy to pelvic nodes). The primary outcome measure was OS; secondary outcomes included disease-specific survival (DSS), time to disease progression and quality of life. Final analysis was planned after 421 deaths. Results: 1,205 patients were randomized from 1995-2005, 602 to ADT alone and 603 to ADT+RT (well balanced with respect to baseline characteristics). The median follow-up is 8.0 years and 465 patients have died (260 ADT, 205 ADT+RT). Adding RT to ADT significantly reduced the risk of death (Hazard Ratio 0.70, 95% CI 0.57-0.85, p=0.001). 199 patients died of disease and/or treatment (134 on ADT alone and 65 on ADT+RT). Competing risk analysis demonstrated that patients on the ADT alone arm had a significantly higher chance of dying of disease related causes than those treated with ADT+RT (10 year cumulative disease specific death rates 15% with ADT+ RT, 26% with ADT alone, p<0.0001). The addition of RT to ADT had a small detrimental effect on late gastrointestinal toxicity and health-related quality-of-life (> grade II proctitis, 0.3% ADT alone, 1.0% ADT+RT; mean change EORTC Rectal symptoms -0.3 ADT vs 1.7 ADT + RT, p=0.54). Conclusions: Mature data indicate a sustained and substantial overall survival and disease specific survival benefit for ADT+RT in the management of patients with locally advanced prostate cancer with minimal increase in late treatment toxicity. The benefits of combined modality treatment should be discussed with all patients. Supported by NCI-US Grant CA077202, CCSRI Grants #14469 and # 015469, UK Medical Research Council Grant G9805643, UK National Cancer Research Network.