bluuebunny/crossref_metadata_2025 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.
An in-depth multicentered population-based analysis of outcomes of patients with metastatic renal cell carcinoma (mRCC) that do not meet eligibility criteria for clinical trials.
Authors: Heng Daniel Yick Chin , Choueiri Toni K. , Lee Jae-Lyun , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Vaishampayan Ulka N. , Yuasa Takeshi , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Pal Sumanta Kumar , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Wood Lori
Published: March 2020

4536

Background: Clinical trials have strict eligibility criteria that exclude many patients to whom the trial results are later extrapolated to in clinical practice. Methods: mRCC patients treated with VEGF targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky Performance Status (KPS) <70%, brain metastases, non-clear cell histology, hemoglobin<=9 g/dL, creatinine >2x the upper limit of normal, platelet count of <100x103/uL, neutrophil count <1500/mm3 or corrected calcium>=12 mg/dL. Results: 894/2076 (43%) patients were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression free survival (PFS) and median overall survival of first-line targeted therapy were 21% vs 29%, 5.2 vs 8.8 months and 14.5 vs 28.8 months (all p<0.0001), respectively. Second-line PFS (if applicable) was 3.2 months in the trial ineligible vs 4.4 months in the trial eligible patients (p=0.0074). Patients who were excluded due to KPS<70, hemoglobin<=9 g/dL, calcium >=12, brain metastases, and non-clear cell histology, had a hazard ratio (HR) for death of 2.8 (95%CI 2.4-3.4), 1.8 (95%CI 1.4-2.2), 1.8 (95%CI 1.2-2.7), 1.4 (95%CI 1.1-1.8), and 1.4 (95%CI 1.1-1.7), respectively (all p<0.01). When adjusted by the Heng et al prognostic categories, the HR for death between trial ineligible vs trial eligible patients was 1.511 (95%CI=1.335-1.710, p<0.0001). Conclusions: The number of patients that are ineligible for clinical trials is high and their outcomes are inferior. Specific trials addressing the needs of protocol ineligible patients and assessing OS are required. [Table: see text]
Phase III randomized sequential open-label study to evaluate efficacy and safety of sorafenib (SO) followed by sunitinib (SU) versus sunitinib followed by sorafenib in patients with advanced/metastatic renal cell carcinoma without prior systemic therapy (SWITCH Study): Safety interim analysis results.
Authors: Michel Maurice Stephan , Vervenne Walter , Goebell Peter J. , Von Weikersthal Ludwig Fischer , Freier Werner , De Santis Maria , Zimmermann Uwe , Bos Monique M.E.M. , Trojan Lutz , Lerchenmuller Christian A. , Schenk Marcus , Staehler Michael D. , Flörcken Anne , Pahernik Sascha , Los Maartje , Van Arkel Cornelis , Schirrmacher-Memmel Silke , Eichelberg Christian
Published: March 2020

4539

Background: Several retrospective studies have investigated the sequential use of SO and SU. Some smaller trials support the use of SO followed by SU forming the rationale for this study. Methods: Pts with metastatic RCC unsuitable for cytokines without prior systemic therapy, ECOG PS 0/1, MSKCC score low or intermediate, and ≥1 measurable lesion (CT/MRI every 12 weeks) were randomized to SO->SU or SU->SO in standard dosage (primary endpoint total PFS from randomization to event during 2nd line therapy). Treatment continues until progression or intolerability. Monitoring includes echocardiography and NT pro-BNP. Results: Baseline characteristics of 361 randomized pts (116 completed) are balanced between arms. Safety data of 333 pts are evaluable. AE occurring in >10% of pts are listed in tab. 1. Left-ventricular ejection fraction (LVEF) at screening, switch of treatment, and end of study are given in tab. 1. AE occurred in 93.4% and 92.8%; grade 3/4 AE in 59.9% and 50%; and SAE in 46.7% and 42.2% in the SO->SU and SU->SO arm, respectively. Updated results will be presented. Conclusions: AE frequencies are higher in 1st than in 2nd line treatments. Typical AE profiles for SO and SU are observed. LVEF values are in a similar range. [Table: see text]
The use of tumor growth rate (TGR) in evaluating sorafenib and everolimus treatment in mRCC patients: An integrated analysis of the TARGET and RECORD phase III trials data.
Authors: Ferte Charles , Albiges Laurence , Soria Jean-Charles , Loriot Yohann , Fizazi Karim , Escudier Bernard J.
Published: March 2020

4540

Background: RECIST criteria may not be sufficient to evaluate targeted therapies in mRCC. TGR includes the time between each evaluation and is expected to overcome some of the RECIST pitfalls. How TGR is modified under targeted therapies and how it correlates with outcome in mRCC remains unknown. Methods: Medical records from all patients (pts) prospectively treated at Institut Gustave Roussy (IGR) in the TARGET (n=84) and in the RECORD (n= 52) phase III trials were extracted. Results were subsequently validated in the entire TARGET cohort (TARGET) (n=902). TGR was computed by dividing tumor shrinkage by the time between the two related evaluations (% RECIST x 100 / days). Typical treatment periods were assessed: BEFORE treatment (wash-out), UNDER treatment (first cycle), at PROGRESSION (pts still receiving the drug) and AFTER treatment interruption (wash-out). Results: As compared to placebo, TGR UNDER was significantly decreased following sorafenib (-23.6 vs. 20 (IGR) and -19 vs. 22 (TARGET)) and everolimus (-5.2 vs. 30 (IGR)). The great majority of pts (IGR) had a decrease in the TGR UNDER vs. BEFORE, regardless of the RECIST evaluation, both with sorafenib (28/29) or everolimus (36/37). TGR AFTER sorafenib or everolimus interruption was significantly higher than TGR at PROGRESSION in both settings (IGR) (14.6 vs. 31 and 17.9 vs. 32.1 respectively). No significant difference was observed between TGR AFTER vs. BEFORE either in sorafenib or in everolimus pts (IGR). High TGR UNDER is associated with poor progression free survival (HR= 2.6) and overall survival (HR= 2.3) in sorafenib-treated pts (multivariate analysis, trained in IGR and validated in TARGET cohorts) and with poor overall survival in everolimus-treated pts (IGR)(HR= 1.2). Conclusions: Adding TGR assessment in mRCC unravels interesting traits that make it potentially adaptable for clinical practice: (i) better evaluation of the tumor response, regardless of RECIST criteria, (ii) independent prognosis value, (iii) it suggests that maintaining sorafenib or everolimus after disease progression might benefit to patients and should be prospectively evaluated.
Phase II trial of RAD001 in renal cell carcinoma patients with non-clear cell histology.
Authors: Koh Youngil , Kim Ji Yeon , Lim Ho Yeong , Ahn Jin-Hee , Lee Jae-Lyun , Rha Sun Young , Kim YuJung , Kim Tae Min , Lee Se-Hoon
Published: March 2020

4544^

Background: In non-clear cell renal cell carcinoma (ncRCC), the efficacy of VEGF tyrosine kinase inhibitor (TKI) is controversial. In the while, a mTOR inhibitor, temsirolimus showed a promising efficacy in ncRCC patients in ARCC trial. Hence, we investigated the role of everolimus in ncRCC with this phase II trial. Methods: ncRCC patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. We included patients who had received VEGF TKI previously, while excluded patients who received previous mTOR inhibitor. The primary end point was progression free survival (PFS). Results: A total of 49 patients were enrolled from 5 centers. Their median age was 57 years (range 24-75 years) and male to female ratio was 37:12. Histology of the patients included papillary (n=29), chromophobe (n=8), collecting duct (n=2), sarcomatoid (n=4), and unclassifiable (n=6) RCC. Twenty-three patients had been treated with VEGF-TKI prior to the study enrollment. Among 49 patients, 46 patients underwent radiologic response assessment after everolimus treatment. Partial response was observed in 5 patients (10.2%) and stable disease in 25 patients (51.0%). Diseases of 16 patients (32.7%) progressed despite of everolimus administration. Histology of 5 patients who showed objective response to everolimus included chromophobe carcinoma (n=2), papillary carcinoma (n=2) and unclassifiable carcinoma (n=1). During the study period, 34 patients experienced PFS events and median PFS was 5.2 months. Patients with chromophobe histology showed longer PFS than patients with the other histologies (median PFS 18.8 months vs. 3.5 months, p=0.027). Estimated median PFS were not significantly different between patients VEGF-TKI treatment and patients without previous VEGF-TKI treatment (median PFS 7.1 vs. 3.7 months, p=0.110). Toxicity profiles were commensurable with previous reports. Conclusions: Everolimus shows considerable efficacy in ncRCC. Patients with chromophobe histology might earn benefit from everolimus treatment especially. Previous treatment with VEGF-TKI seems not to significantly influence outcome of everolimus therapy in these patients. (ClinicalTrials.gov number, NCT00830895)
Phase I trial of ASG-5ME in metastatic castration-resistant prostate cancer (CRPC).
Authors: Morris Michael J. , Bruce Justine Yang , Reyno Leonard M. , Anand Banmeet , Hartford Alan , Jelaca-Maxwell Kathy , Lackey Jacqueline , Eisenberger Mario A.
Published: March 2020

4568

Background: SLC44A4 is a 710 amino acid protein that is expressed on prostate, pancreas and other cancers. SLC44A4 is found in 95% of primary prostate tumors (75% express moderate to high levels). ASG-5ME is an antibody drug conjugate (ADC) comprised of a fully human antibody targeting SLC44A4, conjugated to the microtubule-disrupting agent monomethyl auristatin E. ASG-5ME has dose-dependent cytotoxic effects in vitro and significant anti-tumor activity in xenograft models. We report results of a phase I study to establish the maximum tolerated dose (MTD) of ASG-5ME for CRPC, conducted by the Prostate Cancer Clinical Trials Consortium. Methods: Patients (pts) had progressive metastatic CRPC. Prior chemotherapy was allowed. Treatment cohorts were 0.3, 0.6, 1.2, 1.8, 2.4, and 3.0 mg/kg. ASG-5ME was given IV q3 weeks. Safety, pharmacokinetic properties, anti-tumor effects, circulating tumor cell (CTC) enumeration, and CTC molecular profiles were assessed. Pts were treated until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined by cycle 1 toxicity. Results: 20 pts have been treated (3, 3, 3, 3, 6, and 2 pts per respective cohort). Mean age was 69 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA 225 (5-1987). Pts received an average of 4 doses (1-12). 2 DLTs occurred in Cycle 1 in the 3 mg/kg cohort: DLT 1: Grade (Gr) 3 troponin elevation and DLT 2: Gr3 maculopapular rash, hypoxia, constipation, and Gr4 neutropenia. Common Gr 1 and 2 adverse events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr3 events included: fatigue (2 pts),peripheral neuropathy (1), dyspnea (1) and nausea (1). Serum concentrations of ASG-5ME decreased multi-exponentially and the exposure was dose-proportional. The half-life of intact drug was calculated as 7.01 days (range-3.93-15.9, n=17) after the first dose and 11.2 days ( range-7.75-19.1 days, n=10) after the last dose. PSA declines of >50% were seen in 3/8 pts treated in the last two cohorts and one unconfirmed >50% decrease in retroperitoneal nodes. Conclusions: DLT events observed at 3 mg/kg exceeded the MTD; the MTD is 2.4 mg/kg of doses tested in pts with metastatic CRPC. The drug appears to have anti-cancer activity at 2.4 and 3 mg/kg.
Intravesical sequential BCG and electromotive mitomycin versus BCG alone in high risk non-muscle invasive bladder cancer.
Authors: Di Stasi Savino Mauro , Verri Cristian , Liberati Emanuele , Zampa Germano , Masedu Francesco , Valenti Marco
Published: March 2020

4572

Background: In 2006, we reported that intravesical sequential bacillus Calmette-Guérin (BCG) and electromotive mitomycin in high risk non-muscle invasive bladder cancer leads to higher disease-free interval, lower recurrence and progression, and to improved overall survival and disease-specific survival compared with BCG alone. After an additional 6 years of follow-up, we now report estimated 16-year results. Methods: From 1994 through 2002, we randomly assigned 212 patients with high risk non.muscle invasive bladder cancer to 81 mg BCG infused over 120 min once a week for 6 weeks (n=105) or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval. Analyses were done by intention to treat. Results: Median follow-up was 121 months (IQR 70.5–163.5). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (79 months [95% CI 27–139] vs 26 months [11–113]; difference between groups 53 months [39–67], log-rank p=0.0002). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (45% [35–55] vs 62% [50–72], difference between groups 17% [6–28], log-rank p=0.0002); progression (12% [3–21] vs 28% [17.5–38.5], difference between groups 16% [5–27], log-rank p=0.003); overall mortality (44% [33–55] vs 59% [43–75], difference between groups 15% [2–28], log-rank p=0.01); and disease-specific mortality (9% [2.5– 15.5] vs 23% [11–34], difference between groups 14% [4–24], log-rank p=0.0055). Conclusions: In patients with high risk non-muscle invasive bladder cancer intravesical BCG combined with electromotive mitomycin provided better results than BCG alone in terms of higher remission rates and longer remission times.
Results of a phase II study of pralatrexate in patients with advanced/metastatic relapsed transitional cell carcinoma of the urinary bladder.
Authors: Loriot Yohann , Fizazi Karim , Carles Joan , Weems Garry Alan , Chance Lacey , Agarwal Neeraj
Published: March 2020

4574

Background: Antifolate agents have demonstrated activity in transitional cell carcinoma (TCC), a disease with very poor outcomes in advanced stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster, CO), a folate analogue targeting dihydrofolate reductase, is designed for enhanced uptake and accumulation in tumor cells. The objective of this study was to examine the activity and safety of pralatrexate in patients (pts) with advanced/metastatic TCC of the urinary bladder after failure of prior chemotherapy. Methods: Pts with histologically confirmed TCC (>50% TCC in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15 of a 28‑day cycle supplemented with vitamin B12 and folic acid. Included pts had Eastern Cooperative Oncology Group performance status of 0–1, measurable disease, and prior treatment with ≤1 platinum- and/or methotrexate-based regimen in the recurrent/metastatic setting. Results: Thirty pts were enrolled and treated. All pts received prior platinum-based therapy, and 7 pts (23%) received methotrexate in a multidrug regimen. One pt had a confirmed partial response (PR); 4 additional pts had unconfirmed PRs. Twelve pts had stable disease. The median number of cycles received was 2 (range, 1–24), and median time on treatment was 56 days (range, 1–714). The median progression-free survival (PFS) and overall survival for all pts was 4.0 months (95% confidence interval [CI], 2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts (27%) had PFS >6 months and 3 pts (10%) had PFS >12 months. Eight pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%) discontinued the study due to treatment-related adverse events (AEs)—mainly mucositis. The most frequent treatment-related AEs were stomatitis (77%), asthenia (30%), vomiting (27%), and anemia, nausea, and neutropenia (23% each). Conclusions: Pralatrexate showed evidence of activity and durable disease control when used as a single agent in pts with advanced bladder cancer, although the overall response rate was modest. Further study of pralatrexate in this setting should focus on improving drug delivery and evaluation of novel combination approaches.
Long-term progression-free survival (PFS) and overall survival (OS) to pemetrexed (P) as single agent in metastatic urothelial carcinoma (MUC): A Spanish Oncology Genitourinary Group (SOGUG) systematic review.
Authors: Cervera Grau J. M. , Gonzalez-Billalabeitia Enrique , Ayala Francisco , Ballester Navarro Inmaculada , Lopez Antonio , Garde Javier , Juan Vidal Oscar , Satre Jose Manuel , Barrajon Enrique , Esquerdo Gaspar , Molins Carmen , Maciá Sonia , Rolfo Christian Diego , Espinoza Venegas Macarena Paz
Published: March 2020

4587

Background: The effect of pemetrexed in MUC is not well characterized. Vinflunine is the standar second-line in MUC with adjusted benefits and no more drugs have been aproved. SOGUG reports a systematic review of MUC patient series with high activity of P in monotherapy. Methods: Patients with locally advanced urothelial carcinoma and/or MUC whom received P 500 mg/m(2) every 21 days with folic acid and vitamin B12 supplementation, were elected. These patients received P in second, third or fourth-line of chemotherapy. Results: 44 patients have been reported (39males), median age 62 [41-82]. Of all 44 patients; 21, 22, and 1 patients received P as second-line, third and fourth-line respectively. A median of 4 courses were administered [1-12] and disease control (SD+PR+CR) was achieved in 19 patients for an overall control rate of 43.2%. Four groups with significant differences in PFS (p=.033) were established (1.bone-metastasis, 2.visceral-metastasis, 3. nodal-visceral-metastasis and 4.nodal-metastasis). OS was significant between 2nd and 4th group (p=.036) . Mean PFS and OS were 125days [17-606] and 219days [17-1168] respectively for all 44 patients. Mean PFS and OS of 8 patients with bone metastasis were 75 days and 134 days. Mean PFS and OS of 10 patients with visceral metastasis were 65 days and 144 days. Mean PFS and OS of 8 patiens with nodal+visceral metastasis were 154 and 228 days. Mean PFS and OS of 18 patients with nodal metastasis were 166 days and 299 days. Conclusions: Our longer and multicenter follow-up shows that single agent P in monotherapy as second, third and fourth line in MUC is associated with high activity and long-time survival specially in metastatic nodal MUC. These results suggest that P as monotherapy requires to be further studied, more patients are being collected.
Correlation of chromosome (Chr) 14 loss and 5q gain with outcomes of pazopanib treatment in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC).
Authors: Hudes Gary R. , Pei Jianming , Liu Yuan , Gagnon Robert C. , Carpenter Christopher , Pandite Lini , Testa Joseph
Published: March 2020

4605

Background: The identification of molecular prognostic and/or predictive determinants of outcome in pts with mRCC is an important challenge. We hypothesized that specific tumor DNA copy number alterations (CNAs) - loss of chr 14 or 14q (14/14q-), and gain of chr 5q (5q+) may predict likelihood of pazopanib treatment benefit in pts with mRCC. Methods: Pts DNA samples from the Phase II (VEG102616) pazopanib trial were analyzed by using Affymetrix OncoScan. Copy no. data were moving smoothed and normalized. The copy no. and allele difference were profiled according to their chromosome locations to interrogate CNA and LOH. Objective response (OR, RECIST) and progression free survival (PFS) were determined by investigators (IN) and an independent review (IR) committee. OR and PFS data were analyzed using exact and Kaplan-Meier tests. Results: Tumor DNA samples from 75 pts were adequate for CNA analysis. 14/14q- was found in 35/75 pts (46.7%), and 5q+ was found in 37/75 (49.3%). 14/14q- was present in the tumors of 12/31 pts (39%) with OR by IR compared with 23/44 (52%) nonresponding pts (p=0.347). 14/14q- did not affect PFS. 5q+ was present in tumors of 17/31 pts (55%) with OR and 20/44 (45%) nonresponding pts (p=0.486). PFS was longer in pts with 5q+ tumors compared with those without 5q+ (log rank p=0.026), with median PFS of 66 vs 35 wks, respectively. The odds of achieving OR decreased as the total number of chromosomal gains/losses increased (p=0.032, odds ratio 0.49), but this had no effect on PFS. In exploratory analysis, we examined the combined effect of both 14/14q- and 5q+ on PFS (Table). Conclusions: Pts with 5q+ tumors have significantly longer PFS, with no effect on OR rate. While 14/14q- alone had no effect on outcomes, the combination of 5q+ and no 14/14q- was associated with significantly greater PFS. Pts with more genetically complex tumors were less likely to obtain OR with pazopanib. [Table: see text]
Selecting renal cell carcinoma therapy: Ranking of patient perspective on toxicities.
Authors: Wong Michael K.K. , Mohamed Ateesha F , Hauber A. Brett , Yang Jui-Chen , Liu Zhimei , Rogerio Jaqueline Willemann , Garay Carlos A.
Published: March 2020

4608

Background: Oral therapies (angiogenesis inhibitors and mammalian target of rapamycin (mTOR) inhibitors) for renal cell carcinoma (RCC) have demonstrated significant improvements in progression-free survival but also possess toxicities. The objective of this study was to evaluate whether different toxicities of oral RCC therapies had equal importance to patients. Methods: US adults from the Kidney Cancer Association with a self-reported diagnosis of RCC completed a web-enabled survey. Respondents were asked to select the 3 most and 3 least troublesome toxicities from a list of 20 common RCC therapy toxicities. For each respondent, a value of 1 was assigned to each of the 3 most troublesome toxicities, a value of -1 was assigned to each of the 3 least troublesome toxicities, and a value of 0 was assigned to the remaining toxicities. A straight count method was applied to estimate the mean relative importance of each toxicity. Respondents also answered 10 treatment-choice questions, each of which included a pair of hypothetical RCC medication profiles described by survival, toxicities, and serious adverse events. Four toxicities including fatigue, mouth sores, hand-foot syndrome, and stomach problems were included in both exercises. Results: 264 of the 272 respondents completed the entire ranking exercise. Among the 20 toxicities, stomach problems was the most troublesome and was assigned an importance of 10. Changes in hair color was the least troublesome and was assigned an importance of 0. Patients ranked fatigue (8.2), mouth sores (7.7), hand-foot syndrome (6.6) by order of importance. When given choices among eliminating severe toxicities, fatigue was as important as stomach problems, both fatigue and stomach problems were more import than mouth sores, and mouth sores was more important than hand-foot syndrome; although not statistically significant. Conclusions: This statistical approach offers insight into those toxicities important to patients on chronic RCC therapies.