bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC).
Authors: Yau Thomas Cheung , Sukeepaisarnjaroen Wattana , Chao Yee , Yen Chia-Jui , Lausoontornsiri Wirote , Chen Pei-Jer , Sanpajit Theeranun , Lencioni Riccardo , Camp Aaron C , Cox Donna S , Kallender Howard , Ottesen Lone Harild , Poon Ronnie Tung-Ping 
Published: March 2020

4108 Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting.
Updated results from a phase III trial of sunitinib versus placebo in patients with progressive, unresectable, well-differentiated pancreatic neuroendocrine tumor (NET).
Authors: Vinik Aaron , Van Cutsem Eric , Niccoli Patricia , Raoul Jean-Luc , Bang Yung-Jue , Borbath Ivan , Valle Juan W. , Metrakos Peter , Smith Denis , Chen Jen-Shi , Hoersch Dieter , Castellano Daniel E. , Kennecke Hagen F. , Picus Joel , Van Hazel Guy , Patyna Shem , Lu Dongrui (Ray) , Chao Richard C. , Raymond Eric 
Published: March 2020

4118 Background: In a double-blind phase III trial, sunitinib (Sutent; SU) improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5 mos; HR: 0.42, 95% CI: 0.26–0.66; P=0.0001) and was well tolerated in patients (pts) with unresectable, well-differentiated pancreatic NET that had progressed ≤12 mos before baseline. Initial overall survival (OS) revealed a benefit for SU vs PBO, although median OS had not been reached. We now report PFS assessed by blinded independent central review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU 37.5 mg or PBO on a continuous daily dosing schedule, each with best supportive care. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95% of pts had died. Additionally, BICR was performed retrospectively; baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from Jun 2007 to Apr 2009. The trial ended when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure; pts were offered open-label SU and followed for survival. Median PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI: 0.18–0.55; P=0.00001). At study closure, there were 9 and 21 deaths in the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P=0.02). By Apr 2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%), median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P=0.11 [Table]). 69% of pts crossed over to SU on progression. Conclusions: BICR confirmed investigator assessment of PFS and demonstrated a 6.8-mo improvement in median PFS with SU. Updated OS favors SU, although this result is non-significant for reasons that may include crossover of treatment and limited statistical power. [Table: see text]
RAMSETE: A single-arm, multicenter, single-stage phase II trial of RAD001 (everolimus) in advanced and metastatic silent neuro-endocrine tumours in Europe.
Authors: Pavel Marianne E. , Wiedenmann Bertram , Capdevila Jaume , Reed Nicholas , Valle Juan W. , Caglio Silvia , May Christoph , Comis Silvia , Castellana Ramon , de Herder W.W. , Metzner Cornelia , Salazar Ramon , Hörsch Dieter , Oberg Kjell E. 
Published: March 2020

4122 Background: The mammalian target of rapamycin (mTOR) signaling pathway is involved in the pathogenesis of neuroendocrine tumors (NET). Everolimus (RAD001), an oral mTOR inhibitor, has antitumor activity in patients (pts) with advanced NET. In this open-label, multicenter, phase II study (RAMSETE), the safety and efficacy of everolimus monotherapy was evaluated in pts with advanced nonsyndromic, nonpancreatic NET. Methods: Pts with advanced (unresectable or metastatic), progressive, nonsyndromic, nonpancreatic NET received everolimus (10 mg/day) as monotherapy. The primary endpoint was objective response rate (proportion of pts with best overall complete response [CR] or partial response [PR] per RECIST v1.0) by central radiologic review. A secondary endpoint included progression-free survival (PFS). Results: By database soft lock (December 1, 2011), 73 pts from 16 European clinics received everolimus (median duration of treatment: 193 days). Fifty-five (75%) pts discontinued; reasons included disease progression (n=23), adverse events (AEs [n=23]), withdrawal of consent (n=4), death (n=3), and protocol deviation (n=2). In the per protocol population (N=60), 32 (53%) pts received prior antineoplastic therapy. The best response by central review was stable disease in 55%. By local review, 3 (5%) pts had a PR, with SD in 39 (65%) pts. Median PFS by central review was 185 days (95% CI: 158-255). Median PFS by local investigator review was 285 days (95% CI: 231-not estimable). 69 (95%) pts reported treatment-related AEs of any grade, including rash (n=28; 38%), diarrhea (n=20; 27%), mucosal inflammation (n=18; 25%), and decreased appetite (n=17; 23%). Treatment-related grades 3 and 4 AEs and serious AEs were reported by 27 (37%) and 18 (25%) pts, respectively. Conclusions: In this open-label trial of everolimus in pts with advanced, nonsyndromic, extrapancreatic NET, a high rate of disease stabilization was achieved after prior tumor progression with favorable median PFS. This study further supports efficacy of everolimus in types of NET other than those studied in RADIANT-3 (pancreatic NET) and RADIANT-2 (NET associated with carcinoid syndrome).
Well-differentiated grade 3 digestive neuroendocrine tumors: Myth or reality? The PRONET study group.
Authors: Scoazec Jean-Yves , Couvelard Anne , Monges Genevieve , Leteurtre Emmanuelle , Belleannee Genevieve , Guyetant Serge , Duvillard Pierre , Danjoux Marie , Parot Xavier , Lepage Come 
Published: March 2020

4129 Background: In contrast to the 2000 World Health Organization (WHO) classification of digestive neuroendocrine tumors (NET) in which morphologic differentiation was the first criterion, the 2010 WHO classification of NET is based mostly on histologic grade. NET are now classified into three main categories: NET G1 (mitotic count <2/10 HPF and/or ≤2% Ki67 index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine carcinoma (NEC) of small or large cell type. While NET G1 and G2 are well-differentiated tumors, NEC are considered poorly differentiated G3 tumors. We looked at the agreement between grade and differentiation to determine whether all NET can be readily classified according to the 2010 WHO classification. Methods: We designed a 1-year prospective, epidemiologic study to assess the characteristics of newly diagnosed NET, including diagnostic pathology. From August 2010 to July 2011, all pathology laboratories in France were invited to register all incident cases of gastroenteropancreatic (GEP) and thoracic NET, excluding small cell carcinoma. For GEP-NET, investigators were asked to indicate morphologic differentiation (according to WHO 2000) and elements of histologic grade (mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited centers, 80 participated; 1417 incidental cases were included and 77 excluded (duplicates or exclusion criteria), totaling 1340 cases; 778 (58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%) poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and 32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were described as poorly differentiated, 21 (20%) as well differentiated (mean Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid. Conclusions: In this prospective, epidemiologic study, overall agreement between grade and differentiation was good. However, a significant proportion of G3 NET were classified as well differentiated and thus unclassifiable by 2010 WHO classification. This group of tumor deserves to be included in future classifications to help the clinician decide whether they should be treated as NET G1/G2 or NEC G3.
Bilateral testicular cancer within two prospective, population-based SWENOTECA protocols in clinical stage I nonseminoma.
Authors: Tandstad Torgrim , Solberg Arne , Hakansson Ulf , Angelsen Anders , Haugnes Hege Sagstuen , Oldenburg Jan , Kjellman Anders , Dahl Olav , Cohn-Cedermark Gabriella ,   SWENOTECA
Published: March 2020

4508 Background: Contralateral tumor (CLT) occurs in 3.5-5% in men diagnosed with testicular cancer. The precursor lesion, ITGCNU, transforms into invasive germ cell cancer in 50-100%. Although radiotherapy eradicates ITGCNU effectively, mandatory biopsy of the contralateral testis to detect ITGCNU is controversial. Whether, adjuvant chemotherapy (ACT) reduces the incidence of bilateral cancer is also uncertain. Methods: 988 patients with clinical stage 1 nonseminoma were included in two prospective, population-based SWENOTECA protocols. Thirteen patients were excluded due to previous contralateral biopsy, synchronous bilateral cancer or protocol violations. Treatment was either adjuvant chemotherapy (n=490), or surveillance (n=485). Contralateral testicular biopsy was recommended, but performed only in 283 patients. In case of ITGCNU radiotherapy to 16 Gy was recommended.The estimated cumulative incidence of CLT was calculated using the Kaplan-Meier method. Results: With a median follow-up of 6.3 years, twenty-nine (3.9%) patients developed CLT including five patients with synchronous cancer. Biopsies showed ITGCNU in 3.2%. The incidence of CLT was similar following ACT, 3.7 % (11/490), and surveillance, 3.1% (12/485), p=0.99. Biopsied patients had a risk of developing CLT of 4.3% (9/283), and seven patients treated for CIS never developed CLT. Unbiopsied patients had a risk of 3.0 % (14/668). The proportion of bilateral cancers was similar in biopsy negative patients 3.6% (7/274) and unbiopsied patients 3.0 % (14/668). Young age at orchiectomy was a significant risk factor for metachronous cancer, HR 0.94 (CI: 0.89-0.99), p=0.04. All patients with ITGCNU were offered RT. One irradiated patient developed CLT cancer, and one developed CLT before RT was given. Conclusions: In this selected population ACT did not reduce the incidence of CLT. There was a high proportion of false negative biopsies, which might explain why biopsy negative patients had the same risk of CLT as patients not undergoing biopsy. Young patients had the highest risk of developing contralateral cancer, the risk of CLT decreased by 6% yearly.
Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.
Authors: Saad Fred , Smith Matthew Raymond , Shore Neal D. , Oudard Stephane , Miller Kurt , Tombal Bertrand , Sieber Paul , Fizazi Karim , Van Veldhuizen Peter , Damião Ronaldo , Marx Gavin M. , Morote Juan , Ye Zhishen , Dansey Roger D. , Goessl Carsten Dietrich 
Published: March 2020

4510 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT ≤6 months (previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when >660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT ≤6 months. Results: Median BMFS in the placebo group of men with PSADT ≤6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT ≤6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]
Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).
Authors: Smith Matthew Raymond , Sweeney Christopher , Rathkopf Dana E. , Scher Howard I. , Logothetis Christopher , George Daniel J. , Higano Celestia S. , Yu Evan Y. , Harzstark Andrea Lynne , Small Eric Jay , Sartor A. Oliver , Gordon Michael S. , Vogelzang Nicholas J. , Smith David C. , Hussain Maha , De Bono Johann Sebastian , Haas Naomi B. , Scheffold Christian , Lee Yihua , Corn Paul G. 
Published: March 2020

4513 Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of bone scan resolution, pain relief and overall disease control, independent of PSA changes, were previously reported in a phase II study in mCRPC patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a novel primary endpoint of bone scan response based on computer-aided quantitative assessment of bone scan lesion area (BSLA) and a double-reader, independent, blinded review (Nucl Med Commun, in press). Methods: D-pretreated (≥225 mg/m2) CRPC pts with bone metastasis were required to have progressed in soft-tissue or bone within 6 months of last dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 wks. Bone scan response (BSR) was defined by a ≥30% decline in BSLA. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and interference with sleep and daily activity were prospectively assessed using an IVR system. Analgesic use was collected by diary. Bone turnover markers and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89 evaluable with ≥6 wks f/u). Median age was 67, 46% received cabazitaxel and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18% had anemia. 44% had worst pain ≥4 of which 95% were taking narcotics. Median CTC count was 49 and 80% had ≥5. Median f/u was 125 days (range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24 (28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%) had reduction of measurable disease.16/33 pts (49%) with BPI ≥4 and ≥12 wks f/u had pain reduction durable for ≥6 wks; 46% had decreased narcotic use, including 27% who discontinued use. Sleep and daily activity were improved in pts with pain relief. Among pts with elevated serum levels, 74%, 67% and 47% had declines on treatment of ≥30% in CTx, NTx and bALP, respectively. In 59 pts with CTCs ≥5, 92% had a decrease of ≥30% and 39% converted to <5 CTCs at weeks 6 or 12. 12% discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue (19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment resulted in high rates of bone scan response, durable pain relief, and reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts with bone metastases.
Prognostic model for overall survival in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy.
Authors: Galsky Matt D. , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Moshier Erin L. , Sonpavde Guru , Godbold James H. , Oh William K. , Bamias Aristotelis 
Published: March 2020

4524 Background: Patients with metastatic urothelial cancer (UC) treated with cisplatin-based chemotherapy have heterogeneous clinical outcomes. Pretreatment prognostic variables have previously been defined (Bajorin, JCO, 1999) but have not been extensively validated or expanded upon. Methods: Pretreatment clinical parameters from 400 international patients with metastatic UC treated on phase II and III first-line clinical trials with cisplatin-based chemotherapy from 11/1997 to 10/2011 were evaluated (cisplatin + gemcitabine +/- paclitaxel or +/- antiangiogenic agent = 235; MVAC = 83; cisplatin + 5FU +/- paclitaxel = 79). Parameters were subjected to multivariable regression analysis to determine which patient characteristics had independent prognostic significance for survival. Results: Complete data were available on 361 patients, median survival was 13.9 months (95% CI 12.4, 16.5); 247 have died. In multivariable analysis, ECOG performance status (≥1), visceral metastases (lung, liver, bone), and white blood count (WBC, continuous variable) were significantly associated with poor survival (P < .05), whereas perioperative chemotherapy, hemoglobin, platelets, creatinine clearance, site of primary tumor, and number of metastatic sites were not (Table). The cut-off for WBC was established at 10. Median survival times for patients with 0, 1, 2, or 3 risk factors were 26.9, 16.8, 12.8, 9.7 months (log rank p value < 0.0001). When subjected to internal validation, the model achieved a bootstrap-corrected c-index of 0.60. External validation is ongoing utilizing data from a phase III trial (n=186) of MVAC versus docetaxel plus cisplatin. Conclusions: A model derived from pretreatment parameters from an international cohort of patients was constructed that confirmed, and expanded upon, known prognostic factors in metastatic UC. This model may be useful for patient counseling and clinical trial design. Better predictions require the identification of additional factors that affect survival. [Table: see text]
Accelerated BEP for metastatic germ cell tumors: Combined analysis of Australian and U.K. phase I/II trials.
Authors: Grimison Peter S. , Chatfield Mark D. , Mazhar Danish , Toner Guy C. , Chester John D. , Stockler Martin R. , Stark Daniel P. , Thomson Damien B. , Shamash Jonathan , Friedlander Michael , White Jeff , Gebski Val , Wason James , Boland Amy L , Rimmer Yvonne L. , McDonald Angus , Gurney Howard , Rosenthal Mark , Singhal Nimit , Williams Michael V. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group; West Anglia Cancer Research Network
Published: March 2020

4531 Background: Standard chemotherapy for advanced germ cell tumors is 3-weekly BEP (bleomycin, etoposide, cisplatin). 5-year overall survival is > 90% in good risk disease, but only ~80% in intermediate and ~ 60% in poor risk disease. Accelerated versions of standard regimens have proven more effective in other malignancies. We aimed to determine tolerability and activity of accelerated (2-weekly) BEP by combining data from two single arm, multi-center, phase I/II trials. Methods: The UK trial (n=16) included patients with intermediate and poor risk metastatic germ cell tumours. The Australian trial (n=45) also included patients with radiologically measurable good risk disease. BEP chemotherapy was repeated every 2 weeks for 4 cycles (3 cycles for good risk). The Australian and UK regimens differed for cisplatin (20mg/m2 D1-5; 50mg/m2 D1-2), etoposide (100mg/m2 D1-5; 165mg/m2 D1-3), bleomycin (30kIU weekly x 12 or 9; 30kIU at 4-6 day intervals x 12), and pegylated G-CSF (6mg D6; 6mg D4) respectively. Primary endpoint for combined analysis was 2-year progression-free survival. Results: 61 patients were enrolled from 2004-09 (UK) and 2008-10 (Australia). 17 had poor risk, 28 intermediate risk, 16 good risk disease. Median follow-up is 27 months (range 6 to 81). Adverse events are presented in the table. 45 of 61 patients (74%) achieved a complete response to chemotherapy +/- surgery (9 of 17 poor risk (53%), 20 of 28 intermediate risk (71%), 16 of 16 good risk disease (100%)). 11 of 61 patients have relapsed. 2 patients have died of disease (both intermediate risk). 2 year overall survival is 98%. 2 year progression-free survival is 65% for poor risk, 86% for intermediate risk, and 92% for good risk disease. Conclusions: Efficacy data are promising, particularly for intermediate and poor risk disease. Adverse events appear comparable to standard BEP. These results provide the rationale for an international trial randomised trial comparing accelerated and standard versions of BEP. [Table: see text]