bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and toxicity according to hormone therapy used in the CHHiP trial.
Authors: Tree Alison , Griffin Clare , Hall Emma , Dearnaley David P. ,   on behalf of the CHHiP Investigators
Published: February 2020

316 Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial which investigated the use of moderately hypofractionated radiotherapy (RT) dose schedules for treatment of localised prostate cancer. 97% of participants (pts) had concurrent androgen deprivation therapy (ADT). Luteinising Hormone Releasing Hormone analogues (LHRHa) and bicalutamide 150mg (BIC) daily were permitted. This exploratory analysis investigates whether both ADT regimens show similar efficacy and whether BIC has the propensity to preserve erectile function. Methods: In CHHiP, 2700 pts received LHRH and 403 BIC, median duration 5.6 months. The primary endpoint was biochemical or clinical failure (BCF). ADT groups were compared with Cox regression adjusted forage, NCCN risk group, Gleason score,T-stage and stratified by RT dose. A key secondary endpoint was erectile function assessed by clinicians (LENTSOM subjective erectile function for vaginal penetration score) and pts (single items within UCLA-PCI and EPIC-50 questionnaires) at 2 years. 195/875 (22%) pts were excluded from this toxicity analysis as they had erectile dysfunction pre-ADT (grade (G) 3/4 LENTSOM). A chi square trend test compared ADT regimens. Results: Baseline demographics were similar except BIC pts were significantly younger (median 67 years BIC, 69 years LHRHa). With a median follow-up of 9.2 years, there was no evidence of a difference in BCF with an adjusted hazard ratio 0.95 (95% CI 0.75-1.20), p = 0.657. Eight year BCF rates were 80.7% (95%CI 79.0-82.2) and 80.3% (95%CI 75.8-84.0) for LHRHa and BIC pts respectively. At two years, LENTSOM erectile function was significantly worse (p < 0.0001) for LHRHa pts with 93/585 (16%), 95/585 (16%) and 125/585 (21%) G2, G3 and G4, compared to 3/68 (4%), 5/68 (7%) and 9/68 (13%) in BIC. At 2 years, the ability to have an erection, as reported by pts, was graded poor and very poor in 73/278 (26%) and 57/278 (21%) LHRHa pts and 5/23 (22%) and 4/23 (17%) in BIC pts (p = 0.584). Conclusions: There was no evidence of a difference in efficacy according to ADT received. BIC preserved clinician assessed (LENTSOM) erectile function at 2 years but patient reported outcomes did not show statistically significant differences with type of ADT. Clinical trial information: 97182923.
Prognostic factors in advanced seminoma: An analysis from the IGCCCG Update Consortium.
Authors: Beyer Joerg , Collette Laurence , Daugaard Gedske , De Wit Ronald , Tryakin Alexey , Albany Costantine , Stahl Olof , Fizazi Karim , Gietema Jourik A. , De Giorgi Ugo , Hansen Aaron Richard , Feldman Darren R. , Cafferty Fay , Tandstad Torgrim , Garcia del Muro Xavier , Huddart Robert A. , Sweeney Christopher , Necchi Andrea , Assele Samson , Gillessen Silke ,   for the IGCCCG Update Consortium
Published: February 2020

386 Background: Extrapulmonary visceral metastases were the only adverse prognostic factor among 660 advanced seminomas in the original classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) treated between 1975 and 1990 and published 1997. Outcomes may have improved with current era management and additional prognostic factors may exist. Methods: To update the original IGCCCG classification, an international consortium (30 centers/groups) provided data on 2458 advanced seminoma patients treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2015 in prospective cohorts or clinical trials. Progression-free (PFS) and overall survival (OS) probabilities were calculated. CART analysis was used to identify prognostic factors inside original IGCCCG good risk group to further refine the classification. Among eligible 2302 patients with full data, a training set of 1509 patients (1437 good risk and 72 intermediate risk) was used for model building. An independent set of 793 patients was set aside for validation. Primary endpoints were PFS and OS at 5 years. Results: Compared with the 1997 IGCCCG benchmarks, the 5-year PFS rates increased to 88.7% (87.2 - 89.9%) and 78.4% (69.6 - 84.9%) in good and intermediate IGCCCG patients. The corresponding 5-year OS rates were 95.4% (94.4 - 96.2%) and 87.2% (79.2 - 92.2%). CART analysis identified LDH with a cut-point of 2.5 x ULN as the single most significant prognostic factor in good risk patients with 5-y PFS rates of 92.1% (90.3 - 93.6%) and 79.2% (74.2 - 83.4%) in low and high LDH subgroups. (HR = 2.90, P < .0001). Good risk patients with LDH above 2.5 x ULN (313 of 1411 patients) performed similarly to the intermediate IGCCCG patients; hCG was not independently prognostic. Conclusions: In this modern era series, the original IGCCCG still significantly discriminates between "good” and "intermediate" risk metastatic seminoma, but with significantly improved PFS and OS in both risk groups. LDH at a cut-off point of 2.5 x ULN further refines this classification and identifies men with intermediate risk seminoma in the absence of extrapulmonary visceral metastases. This refinement will be relevant to improve future seminoma care.
Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS).
Authors: Grimm Marc-Oliver , van der Heijden Toine , Colombel Marc , Martinez Pineiro Luis , Muilwijk Tim , Babjuk Marek , Turkeri Levent N. , Palou-Redorta Joan , Patel Anup , Bjartell Anders , Caris Christien , Schipper Raymond , Witjes Wim ,   EAU Research Foundation NIMBUS Study Group
Published: February 2020

436 Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.
The National Radium-223 Dichloride Audit Group: Data from patients in United Kingdom oncology centers with metastatic castration-resistant prostate cancer treated with radium-223 dichloride.
Authors: Randhawa Manreet , Stratton Irene , Jones Robert J. ,   National Radium-223 Audit Group
Published: February 2020

59 Background: Clinicians in 20 UK oncology centres comprise the National Radium-223 Dichloride Audit group which is evaluating treatment patterns and outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with Radium-223 dichloride (Xofigo). Methods: Pts first treated with Xofigo from September 2017 were included and demographics, treatment, clinical, biochemical and outcome data collected prospectively. Analysis was carried out using frequency tables, univariate and survival analysis. Results: We report the outcomes on the first 100 pts in 4 centres with good quality data. Median values of each characteristic including 25th and 75th percentiles are as follows: Age at diagnosis = 67 years (62-72), weight = 83.5kgs (73.6-92.8), Hb = 139g/L (118 – 136), WCC = 7.3X109/L (5.7 – 8.7), plt count = 252x109/L (208 – 290), ALP = 128U/L (96-263) and PSA = 42.1ug/L (21.5 – 125.7). A majority of pts had an ECOG PS of 0-1. The number of pts having Xofigo as 1st, 2nd, 3rd and 4th line treatment was 15, 64, 20 and 1 respectively. There was a statistically significant decline in median weight, Hb, WCC, plt count and ALP and a rise in PSA between cycle 1 and cycle 6. Thirty eight pts did not complete 6 cycles with 31 of these (82%) discontinuing due to disease progression. The prevalence of adverse events was 5% (20/100). Twenty nine pts had a skeletal event by 12 months. There was no change in the WHO analgesic score, QOL scores or ECOG PS between treatment 1 and 6. Thirty nine pts had subsequent lines of treatment with 31 of these having only 1 line of treatment. Median overall survival was 363 days (95% CI 312-426 days). Conclusions: The ongoing National Radium-223 Dichloride Audit records data from approximately 600 mCRPC pts treated across the UK in routine clinical NHS care. To our knowledge, it is the first prospective analysis of such pts and the largest in assessing treatment patterns, outcomes and quality of life data in addition to standard biochemical and clinical parameters. Further multivariate analysis will be presented and the implications of the licensing change of Xofigo will be illustrated in the final analysis.
A multicenter retrospective study to evaluate real-world clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) and brain metastasis treated with ipilimumab and nivolumab.
Authors: Brown Landon Carter , Desai Kunal , Kao Chester , Kinsey Emily Noelle , Healy Patrick , Kephart Julie , Harrison Michael Roger , Ramalingam Sundhar , Armstrong Andrew J. , George Daniel J. , Martin Allison , Allman Kimberly D. , Wood Laura S. , Wei Wei , Garcia Jorge A. , Gilligan Timothy D. , Gupta Shilpa , Rini Brian I. , Ornstein Moshe Chaim , Zhang Tian 
Published: February 2020

637 Background: The combination of ipilimumab & nivolumab (I+N) followed by maintenance nivolumab has improved outcomes in patients (pts) with mRCC. Little is known about the outcomes in mRCC pts with brain metastasis. In this multicenter retrospective analysis, we present a real-world experience in pts with brain metastasis treated with I+N. Methods: Pts with mRCC and brain metastases treated with I+N at the Duke Cancer Institute and Cleveland Clinic were identified. Pt characteristics were summarized with descriptive statistics. Fisher’s exact test was used to determine predictors of response (alpha 0.05). Results: From 10/2017 to 2/2019, 17 pts received I+N for mRCC with brain metastases. Median age was 60; 29% were female. IMDC risk was 18%/59%/24% favorable/intermediate/poor, and 77% were clear cell histology. Pts received I+N as either first-line (65%) or ≥ second-line (35%) therapy. Of the pts evaluable for response: objective response rate (ORR) was 42% [0% CR]; with 29% achieving stable disease and 18% progressive disease as their best response. Median duration on therapy was 13 weeks. 59% of pts developed an immune-related adverse event (AE). The most common reason for treatment discontinuation was disease progression (47%) followed by AEs (18%). There were no significant predictors of any radiographic response category (PR, SD, or PD) among variables assessed (gender, IMDC risk, histology, presence of bone metastasis, line of therapy, or presence of irAE). Of note, 50% (3/6) patients treated in the second-line or greater setting experienced a PR. Conclusions: In our real-world cohort of mRCC patients with brain metastasis, I+N is clinically effective. Further investigation is warranted in this population given exclusion from prior clinical trials.
Depth of response (DepOR) analysis and correlation with clinical outcomes from JAVELIN Renal 101.
Authors: Voss Martin H , Motzer Robert J. , Albiges Laurence , Rini Brian I. , Schmidinger Manuela , Larkin James M. G. , Haanen John B. A. G. , Kollmannsberger Christian K. , Campbell Matthew T. , Grimm Marc-Oliver , Pal Sumanta K. , Gravis Gwenaelle , Atkins Michael B. , Huang Bo , Chudnovsky Aleksander , di Pietro Alessandra , Thomaidou Despina , Choueiri Toni K. 
Published: February 2020

690 Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), avelumab + axitinib (A+Ax) significantly improved progression-free survival (PFS) in patients (pts) with advanced renal cell carcinoma (aRCC) compared with sunitinib (S); median PFS (mPFS) in the A+Ax arm was 13.8 mo (95% CI, 11.1 mo, not estimable [NE]) vs 8.4 mo (95% CI, 6.9, 11.1) in the S arm (HR, 0.69; 95% CI, 0.56, 0.84; P < 0.001) (Motzer NEJM 2019). Here, we report on the correlation of PFS with DepOR at early imaging timepoints. Methods: Data from pts in both arms were analyzed based on blinded independent central review (BICR) per RECIST 1.1. Tumor shrinkage or growth was categorized by best percent change in target lesions on imaging obtained up to 13 wk: shrinkage ≥0% to < 30%, ≥30% to < 60%, and ≥60% and growth > 0% to < 20%. Pts without progressive disease and who had not died at or prior to 13 wk after randomization were included in the landmark analysis. PFS data were analyzed for each category. A Cox multivariate landmark analysis was conducted for PFS for pts in the A+Ax arm, with DepOR as a continuous variable. Results: Results are reported on the basis of the first interim analysis, with a minimum follow-up of 6.0 mo in all pts. The table shows the proportion of pts in each shrinkage category and PFS outcomes according to best percent change in target lesions at the 13-wk landmark. After adjusting for prognostic covariates, Cox multivariate analyses showed a meaningful association between DepOR and PFS for pts in the A+Ax arm, consistent with the results observed in each shrinkage category. Conclusions: Greater tumor shrinkage at early imaging timepoints was associated with longer PFS in JAVELIN Renal 101. Clinical trial information: NCT02684006 .[Table: see text]
Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Serritella Anthony , Shevrin Daniel H. , Heath Elisabeth I. , Wade James Lloyd , Martinez Elia , Karrison Theodore , Stadler Walter Michael , Szmulewitz Russell Zelig 
Published: February 2020

91 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.
Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921.
Authors: Petrylak Daniel Peter , Shore Neal D. , Bennamoun Mostefa , Ratta Raffaele , Piulats Josep M. , Li Ben , Schloss Charles , Fizazi Karim 
Published: February 2020

TPS262 Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m2 IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506.
A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.
Authors: Steinberg Gary D. , Palou-Redorta Joan , Gschwend Juergen E. , Tran Ben , Loriot Yohann , Daneshmand Siamak , Roupret Morgan , Santiago-Walker Ademi E. , Switzky Julie C. , Major Christopher , Baig Mahadi , Xia Qi , Catto James WF 
Published: February 2020

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.