bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing adipose burden in young men with metastatic testicular cancer following front-line cytotoxic chemotherapy.
Authors: Arora Karan Kumar , Kato Caroline , Batra Kunnal , Mullane Michael Russell , Lad Thomas E. , Master Viraj A. , Psutka Sarah P. 
Published: March 2019

525 Background: Exposure to cytotoxic chemotherapy (CC) has been observed to be associated with significant changes in body composition, namely marked lean muscle mass losses, with implications for treatment-related toxicity and oncologic outcomes. However, prior studies predominately include elderly patients who, a priori, are at risk for sarcopenia or severe skeletal muscle deficiency. To date, the impact of CC on body composition in young men with testicular cancer remains undefined. Methods: A retrospective analysis of 19 patients with metastatic testicular cancer treated with CC was performed (2015-17). Lumbar skeletal muscle index (SMI), visceral (VAI), subcutaneous (SCAI), and intramuscular adipose (IMAI) indices (cm2/m2), as well as fat-free mass (FFM, kg) and fat mass (FM, kg) were calculated using cross-sectional soft tissue area measurements on pre- and post-CC computed tomography (CT) axial scans and compared using paired Wilcoxon Signed Rank Tests. Results: Median age was 29 years. According to the NHANES FMI-based classification, 5 (26.3%), 9 (47.4%), 4 (21.1%), and 1 (5.3%) patients had normal, excess, class I, and class II obesity, respectively. Median pre- and post-CC BMI was 27.7 vs. 29.6 kg/m2(p = 0.03). Median pre- and post-CC SMI, VAI, SAI, and IAI were 63.5 vs 57.8 (p = 0.14), 19.9 vs 30.8 (p = 0.01), 47.9 vs 58.2 (p = 0.03), and 3.0 vs 5.2 (p = 0.002), respectively. Median muscle density pre- and post-CC were 47.0 vs 43.6 HU (p = 0.002). Pre- and post-chemotherapy FFM were 21.5 vs 19.5 kg, representing an overall median loss of 2.8%, (IQR -10.1, +4.7; Range -49.5 - +16.3; p = 0.14). Conversely, pre- and post-CC FM were 6.6 vs 7.5 kg, representing an overall median gain of 13.3% (IQR -3.3, +17.0; -24.9 - +50; p = 0.01). Median time between imaging assessments was 121 days. Specific median measures of adiposity each increased significantly, such that VIA increased by 29% (p = 0.01), SCAI increased by 39.7% (p = 0.03), and IMIA increased by 39.7% (p = 0.002). Conclusions: While lean muscularity remained stable, we observed significant increases in total body adipose mass with decreased muscle density in this consecutive case series of testicular cancer patients following CC.
Clinical outcomes of minimally invasive retroperitoneal lymph node dissection and single dose carboplatin for clinical stage IIa seminoma.
Authors: Huddart Robert A , Reid Alison Helen , Mayer Erik , Sohaib Syed A , Nicol David 
Published: March 2019

530 Background: Standard management of Stage 2 seminoma (SEM) is 3 cycles of cisplatin based multi-agent chemotherapy or paraaortic/pelvic radiotherapy. Both treatments have potential short and long term toxicity. We report the use of minimally invasive (robotic or laparoscopic) retroperitoneal lymph node dissection (MI-RPLND) and adjuvant carboplatin. Methods: From 01/2013-04/2017, patients (pt) with SEM and Stage 2a disease on computed tomography (CT) staging scan were considered for MI-RPLND included the radiologically enlarged lymph nodes for Stage 2a SEM. Adjuvant carboplatin (AUC 7) x 1 cycle was administered after confirmation of nodal involvement. Post-operative outcomes including length of stay, Clavien-Dindo 1 complications and pathological staging were recorded. CT was performed at 3 months to verify nodal clearance and then pts monitored with a standard surveillance protocol. Results: Twenty modified unilateral templates were performed. Median and mean post-operative stay was 1 and 1.5 days. One pt required conversion to open surgery and two experienced Clavien-Dindo 1 complications. All pts had preserved ejaculation. Mean number of nodes removed per pt 14.3 (range 5-31) with average 1.75 nodes involved (range 0-5). In 2 pts the enlarged nodes were pN0; they were surveyed and are relapse free at 44+ months. In one case the enlarged lymph node contained embryonal carcinoma (EC) despite primary histology of pure SEM. The remaining 17 pts had confirmed pathological stage 2 SEM. The pt with EC and one pt who had adjuvant carboplatin for stage 1 disease received (B) EP x 2 cycles. 16 patients received a single cycle of adjuvant carboplatin (AUC 7). After median follow-up of 41 months (range 22-70), one patient has relapsed. This occurred at 18 months outside the template of dissection. This patient initially had multifocal disease with 3 pathologically involved nodes. He received BEP X 3 with complete radiological resolution of disease and remains disease free. Conclusions: MI-RPLND in conjunction with a single dose of carboplatin may potentially be an option for the management of Stage 2a SEM. In this series, a subset of pts were overstaged using standard CT imaging.
TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Rini Brian I. , Pal Sumanta K. , Escudier Bernard , Atkins Michael B. , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Needle Michael N. , McDermott David F. 
Published: March 2019

541 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-1 trial in treatment naïve or prior cytokine-treated subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 11.9 months (mos) for T compared to 9.1 mos for sorafenib (S) (p = 0.042, HR = 0.797). However, overall survival (OS) favored sorafenib, likely due to imbalanced crossover to active treatments. TIVO-3 was conducted to confirm the PFS results from TIVO-1. Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. 350 subjects were enrolled to yield 244 events with ~88% power to detect a difference of 6 mos vs. 4 mos with a two-sided p-value of 0.05 by the log-rank test. Secondary endpoints were OS, safety, objective response rate (ORR), and duration of response. Results: The two arms were well balanced for demographics and prior cancer history.60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 28% had prior treatment with a checkpoint inhibitor. T demonstrated a statistically significant improvement in mPFS compared to S, 5.6 (95% CI 7.3-5.3) v. 3.9 mos (95% CI 5.6-3.7; HR 0.73; p=0.02). PFS rate at 2 years was 18% for T compared to 5% for S. ORR was 18% for T compared to 8% for S. 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. Subjects on T were less likely to require a dose reduction (24% v. 38%), interruption (48% v. 63%), or discontinuation (21% v. 29%) due to an adverse event than subjects on S. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this pre-treated population and is better tolerated than S. OS data will be updated prior to presentation. Clinical trial information: NCT02627963.
A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO).
Authors: Powles Thomas , Larkin James M. G. , Patel Poulam , Pérez-Valderrama Begoña , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Liu Wing-Kin , Prendergast Aaron , Vosper Laura , Mousa Kelly , Suárez Cristina 
Published: March 2019

545 Background: Metastatic papillary renal cancer (PRC) has poor outcomes and there is need for new treatments. There is a strong rationale for investigating MET and PD-L1 inhibition in this disease. In this study, we investigate savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Methods: This single arm phase I/II trial explored durvalumab and savolitinib at starting doses of 1500mg Q4W and 600mg OD respectively, with a 4wk savolitinib run-in. Treatment naïve or previously treated patients with metastatic PRC were included. Response rate (RR) (RECIST v1.1) was the primary endpoint. Progression free survival (PFS), tolerability (CTCAE v4) and overall survival were secondary endpoints. Biomarkers were explored from archived tissue. Results: Dose escalation work identified a dose of durvalumab of 1500mg Q4W and savolitinib 600mg OD to take forward to phase II. Between Jan 2017 and Jul 2018, 42 patients were enrolled at this dose. 1 patient did not receive study treatment. The following analyses were performed on the remaining 41 patients. 12% of patients did not receive the combination (3 PD, 1 death, 1 PS deterioration). The median follow up was 8.9 months (95% CI: 6.9-10.9 months). IMDC good, intermediate and poor risk disease occurred in 29% (n=12), 63% (n=26), and 7% (n=3) patients respectively. Overall RR was 27% (11/41), while median PFS was 3.3 months (95% CI: 1.5-NR months). RR and median PFS in the previously untreated cohort (N=28) were 29% (8/28) and 12.0 months (95% CI: 1.5-NR months) respectively. Grade 3/4 toxicity occurred in 15 patients. Discontinuation for toxicity occurred in 3 patients, all due to liver toxicities. Biomarker work including PD-L1 and MET expression will be included in the analysis. Conclusions: The combination of savolitinib and durvalumab appears safe and associated with clinical activity in PRC. Clinical trial information: NCT02819596.
Alterations in DNA damage repair (DDR) genes and outcomes to systemic therapy in 225 immune-oncology (IO) versus tyrosine kinase inhibitor (TKI) treated metastatic clear cell renal cell carcinoma (mccRCC) patients (pts).
Authors: Ged Yasser , Chaim Joshua , Knezevic Andrea , Carlo Maria Isabel , Foster Ashley , Feldman Darren R. , Teo Min Yuen , Riaz Nadeem , Lee Chung-Han , Patil Sujata , Chan Timothy An-thy , Hakimi A. Ari , Motzer Robert J. , Voss Martin Henner 
Published: March 2019

551 Background: Loss of function alterations in DDR genes including core components of mismatch repair and homologous recombination deficiency pathways are associated with tumorigenesis and may determine benefit from IO therapies as shown in colon cancer. The significance for standard IO and TKI treatments in mccRCC is unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for two large cohorts of mccRCC: pts treated with pure IO therapy (cohort 1); and pts receiving first-line TKI (cohort 2). Tumor and germline DNA was subject to targeted panel testing across >400 genes of interest, including 34 DDR machinery genes. Presence of truncating mutations, deletions and functionally validated missense mutations identified individual patient as ‘DDR altered’ (DDRa). Tumor mutational burden (TMB) was inferred for all pts. Non-parametric tests were applied to determine association between DDR status, TMB and treatment outcomes. Results: 225 pts were included (cohort 1=107, cohort 2=118), 37 (16%) were DDRa. Most commonly altered genes were ATM (n=8, 4%) and CHEK2 (n=8, 4%). DDR germline alterations were seen in 12 pts (5%). Median TMB was 4.1 per megabase (range: 0-21.7), and higher TMB (≥ median) was associated with being DDRa (Fisher’s exact, p=0.03). DDRa status correlated significantly with longer overall survival (OS) in the IO cohort (HR 0.29, logrank p=0.04) but not in the TKI cohort (HR 0.74, logrank p=0.44). We found no interaction between objective response and DDR status in either cohort. Conclusions: Loss of function in DDR genes was associated with superior OS in IO-treated but not in TKI-treated RCC pts. Possible underlying mechanisms beyond increase in TMB observed here deserve further study. [Table: see text]
Axitinib versus sunitinib as first-line therapies for metastatic renal cell carcinoma: A multicenter retrospective analysis.
Authors: Hatakeyama Shingo , Tanaka Toshiaki , Ikehata Yoshinori , Fujita Naoki , Masumori Naoya , Kitamura Hiroshi , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara 
Published: March 2019

555 Background: No previous study has compared the efficacy and safety of first-line axitinib and sunitinib. We aimed to compare oncological outcomes and safety of axitinib and sunitinib in patients with treatment-naïve metastatic renal cell carcinoma (mRCC). Methods: We retrospectively evaluated 169 patients with mRCC who were treated with axitinib or sunitinib as the first-line therapy in five hospitals between October 2008 and August 2018.Oncological outcomes and safety were compared between axitinib (n = 68) and sunitinib (n = 101) groups. Inverse probability of treatment weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate effects of first-line therapies on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: Patients in the axitinib group were significantly older (66 vs 72 years) than those in the sunitinib group. Median relative dose intensity was significantly higher in the axitinib group (94 ± 62%) than in the sunitinib group (65 ± 20%; P = 0.001). Objective response rate was significantly higher in the axitinib group (21%) than in the sunitinib group (10%; P = 0.042). IPTW-adjusted Cox regression analysis revealed significant differences in CSS and OS but not in PFS between the two groups. Safety in terms of grade ≥3 adverse events was significantly different between the axitinib (34%) and sunitinib (55%) groups ( P = 0.006). Conclusions: Compared with sunitinib, axitinib significantly prolonged CSS and OS and showed a safer profile as the first-line therapy for treatment-naïve mRCC.
Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC.
Authors: Rini Brian I. , Appleman Leonard Joseph , Figlin Robert A. , Plimack Elizabeth R. , Merchan Jaime R. , Wang Keshi , Thamake Sanjay , Zojwalla Naseem J. , Choueiri Toni K. , McDermott David F. 
Published: March 2019

558 Background: The transcription factor hypoxia-inducible factor (HIF)-2α has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) due to underlying VHL deficiency. Activation of HIF-2α can also promote immunosuppression. In preclinical models, HIF-2α inhibition demonstrated increased efficacy in combination with checkpoint inhibitors (Han et al. AACR 2016). In a Phase 1 dose escalation/expansion trial in heavily pre-treated advanced ccRCC patients, PT2385 monotherapy was associated with variability in drug exposure with higher therapeutic exposure associated with improved anti-tumor activity (Courtney et al. JCO 2018). Methods: In the current Phase 1 expansion cohort, patients with advanced ccRCC who had received 1-3 prior therapies (including at least one VEGF(R)-targeting agent) were treated with PT2385 (800 mg PO BID) in combination with nivolumab (3 mg/kg IV Q2Weeks) to evaluate safety, efficacy, and pharmacokinetics. Results: 50 patients were enrolled. Median age was 62 with 58% ECOG 1 and 42% ECOG 2. Median number of prior therapies was 1; 42% of patients received ≥2 prior lines of therapy. The most common all-grade AEs were anemia (46%), fatigue (46%), nausea (36%), and arthralgia (30%). The most common Grade 3 AE’s were anemia (4%), fatigue (4%), and hypoxia (4%). Two Grade 4 events of elevated ALT and increased lipase/amylase were observed. As of August 31, 2018, ORR = 22% (1 CR, 10 PR). At a median follow up of 12.4 months (m), median PFS was 7.3 m for all patients. Patients who had sub-therapeutic exposures ( < 300 ng/ml) of PT2385 (n = 17) had a median PFS of 4.7 m compared to patients with therapeutic exposures of PT2385 (n = 33), who had a median PFS of 10.0 m. Conclusions: The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients, most notably in patients who achieved therapeutic exposure of PT2385. Single agent and combination studies with PT2977, a second-generation HIF-2α inhibitor with an improved PK profile, are ongoing. Clinical trial information: NCT02293980.
A phase I/II trial of pazopanib alternating with bevacizumab in treatment-naïve metastatic clear cell renal cell carcinoma (CCRCC) patients: Phase I results.
Authors: George Saby , Herbst Laurie , Sikorski Marcus , Diraddo Ann Marie , Azabdaftari Gissou , Roche Charles , Kauffman Eric , Li Qiang , Schwaab Thomas , Levine Ellis Glenn , Pili Roberto , Chatta Gurkamal S. , Appleman Leonard Joseph , Groman Adrienne , Parikh Rahul Atul , Hutson Alan 
Published: March 2019

561 Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]
A phase II study of cabozantinib as first-line treatment in metastatic collecting ducts carcinoma: The BONSAI trial.
Authors: Procopio Giuseppe , Ratta Raffaele , Colecchia Maurizio , Sensi Marialuisa , Sepe Pierangela , Claps Melanie , Rivoltini Licia , De Braud Filippo G. , Pagani Filippo , Verzoni Elena 
Published: March 2019

578 Background: Metastatic collecting ducts carcinoma (mCDC) is a rare and aggressive disease, characterized by a poor prognosis; its treatment represents an unmet medical need. We aimed to evaluate the activity and safety of cabozantinib (cabo) in mCDC. Methods: This is a prospective, monocentric, single-arm phase II trial evaluating cabo in patients (pts) with untreated mCDC. Cabo was administered at the dose of 60 mg orally once daily until disease progression (evaluated by RECIST 1.1 criteria) or unacceptable toxicity. Primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival and safety profile. Exploratory objectives include the identification of somatic mutations and the mutational load on tissue samples; plasma and viable peripheral blood mononuclear cells were studied for immune related biomarker profiling. Results will be crossed with clinical data in terms of response rate, to detect any predictive value of blood immune cell profiling. A central pathological review before study entry is mandatory. The study design is based on a Simon’s two stage optimal design: in the first step at least 2 responses in 9 pts enrolled are needed to go to the second stage of the study (14 additional pts). Results: From January 2018 to September 2018, 11 pts with mCDC have been so far enrolled, nine of which started study treatment. Median age was 58 years, 8 pts were male and 1 female, 7 pts received a previous nephrectomy. The most common metastatic sites were bone and abdominal lymphnodes (5 pts each), followed by liver and lung (2 pts each). Two pts had a partial response as best response, 2 had a stable disease, 3 had a progressive disease and 3 pts died for early progression. Treatment was feasible and well tolerated. All pts reported at least one grade (G) 1-2 adverse events (AEs): the most common were asthenia, diarrhea, anorexia and nausea, hand-foot syndrome, hypertension and dysgeusia. No G3-4 AEs were reported. Genetic and immunological essays are ongoing to assess the immunomodulatory properties of cabozantinib and potential predictive factors. Conclusions: Cabo was safe and active in CDC. The second stage and biomarkers analyses are ongoing. Clinical trial information: NCT03354884.
Outcomes in patients (pts) with advanced renal cell carcinoma (aRCC) who discontinued (DC) first-line nivolumab + ipilimumab (N+I) or sunitinib (S) due to treatment-related adverse events (TRAEs) in CheckMate 214.
Authors: Tannir Nizar M. , Motzer Robert J. , Plimack Elizabeth R. , McDermott David F. , Barthelemy Philippe , Porta Camillo , George Saby , Powles Thomas , Donskov Frede , Kollmannsberger Christian K. , Gurney Howard , Amin Asim , Grimm Marc-Oliver , Rini Brian I. , Tomita Yoshihiko , McHenry M. Brent , Mekan Sabeen Fatima , Escudier Bernard , Hammers Hans J. 
Published: March 2019

581 Background: The phase 3 CheckMate 214 trial demonstrated superior efficacy for N+I vs S in aRCC, although more patients discontinued N+I compared with S due to TRAEs. This is a post hoc analysis of outcomes in pts who DC N+I or S due to TRAEs. Methods: Untreated pts with clear cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg Q3Wx4 (induction) and then N 3 mg/kg Q3W (maintenance), or S 50 mg daily for 4 wk on, 2 wk off (6-wk cycles). This analysis includes all pts who DC due to TRAEs reported during extended follow-up (≤100 d after last study dose). Results: Of 550 N+I randomized pts, 135 (25%) DC due to TRAEs, most commonly increased ALT, diarrhea, and increased AST (all 3%); 64 (12%) of 535 S randomized pts DC due to TRAEs, most commonly increased ALT, diarrhea, and pancreatitis (all 1%). In N+I pts who DC due to TRAEs, 47% DC during N+I induction, 7% completed induction but no N maintenance, and 46% completed induction and received N maintenance (median [range] 8 [1–47] doses). At 30-mo minimum follow-up, ORR per investigator, CR rate, and 24-mo OS rate were higher in pts who DC N+I vs S due to TRAEs. Outcomes in pts who DC S due to TRAEs were similar to those in all S ITT pts and worse than in N+I pts who DC due to TRAEs (Table). At 24 mo, 42% of pts who DC N+I due to TRAEs were alive and free from second-line therapy. Consistent outcomes were seen in pts who DC N+I due to TRAEs across IMDC risk groups (data to be presented). Pts who DC N+I due to TRAEs experienced more immune-related select TRAEs and received more high-dose steroids (≥40 mg prednisone daily or equiv.), but times to onset and resolution and resolution rates of select TRAEs were similar vs all treated N+I pts. Conclusions: Discontinuation of first-line N+I due to TRAEs did not result in impaired outcomes, and a high proportion of pts remain alive and free from second-line therapy. Clinical trial information: NCT02231749. [Table: see text]