bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).
Authors: Basch Ethan M. , Scholz Mark C. , De Bono Johann Sebastian , Vogelzang Nicholas J. , De Souza Paul L. , Marx Gavin M. , Vaishampayan Ulka N. , George Saby , Schwarz James K. , Antonarakis Emmanuel S. , O'Sullivan Joe M. , Rezazadeh Kalebasty Arash , Chi Kim N. , Dreicer Robert , Hutson Thomas E. , Mangeshkar Milan , Holland Jaymes S. , Weitzman Aaron , Scher Howard I. 
Published: February 2017

141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in pain, bone scans, measurable disease, and circulating tumor cells. COMET-2 compared the effects of Cabo versus MP on pain palliation in men with progressive mCRPC. Methods: In this double-blind, controlled phase 3 study (NCT01522443), pts with moderate to severe pain and disease progression following D, and A and/or E were randomized 1:1 to receive Cabo (60 mg qd) or MP (12 mg/m2 q3wk and 5 mg bid, resp). All pts were required to have a 7-day average of 4+ pain per Brief Pain Inventory (BPI) item 3 while on an optimized narcotics regimen at baseline. Randomization was stratified by prior cabazitaxel and ECOG performance status. The primary endpoint was pain response (≥30% reduction in BPI item 3) at week 6, confirmed at week 12, without increase in narcotics. The original sample size (N = 246) was selected to achieve at least 90% power to detect an increase in pain response with Cabo (25%) vs. MP (8%) using a two-sided α = 0.05 chi-squared test. The secondary efficacy endpoints were bone scan response (BSR) and overall survival (OS). Results: 119 pts were randomized between March 2012 and July 2014. Randomization was concluded prior to reaching the planned sample size because the companion study COMET-1 did not show a significant OS benefit compared to P in a similar population. Pain response rates were 15% for Cabo vs 17% for MP (P = 0.773). BSR rates were 31% for Cabo vs 5.2% for MP. Median OS was 9 months for Cabo vs 7.9 months for MP. Most frequent G3/4 AEs in the Cabo arm were anemia (22% vs 26% MP), hypertension (22% vs 0% MP), fatigue (18% vs 8.8% MP), and AST increased (10% vs 1.8% MP), with fewer pts discontinuing study treatment for AEs in the Cabo arm (16% vs 26% MP). Conclusions: The primary endpoint of improving pain response was not achieved in this heavily pretreated population. The key secondary endpoints of BSR and OS showed trends favoring the Cabo arm, and no new safety signals were observed at the dose of 60 mg. Clinical trial information: NCT01522443.
Antigen-specific immune responses through 24 months in the STAND trial: A randomized phase 2 study evaluating optimal sequencing of sipuleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC).
Authors: Antonarakis Emmanuel S. , Kibel Adam S. , Adams George W. , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Vogelzang Nicholas J. , Corman John M. , Tyler Robert Claude , McCoy Candice , DeVries Todd , Sheikh Nadeem A. , Drake Charles G. 
Published: February 2017

171 Background: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP), approved for treatment of asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. STAND evaluates sequencing of sip-T and ADT in men with BRPC at high risk of metastases. Here we report interim assessments of cellular and humoral responses through 24 mos. Methods: Men (n=68)were randomized 1:1 to sip-T followed by ADT (2 wks after 3rd infusion; Arm 1) or ADT (3-mo lead-in) followed by sip-T (Arm 2). Product parameters (total nucleated cell [TNC] count, antigen presenting cell [APC] count, APC activation) were determined with each product manufacture. Cellular and humoral immune responses were analyzed through 24 mos with a repeated measures statistical model. Results: Sample size ranged 8–28 for cellular responses and 34–64 for humoral responses. PA2024 ELISPOT count increased vs baseline at most timepoints (p<0.05) and was lower in Arm 2 vs Arm 1 (p=0.015). PA2024 antigen-specific T-cell proliferation increased from baseline at all timepoints (p≤0.001) and was lower in Arm 2 vs Arm 1 (p<0.001). PA2024 antibody titers were similar between treatment arms (p=0.976). PA2024 antibody titer was significantly higher at the 3rd sip-T infusion visit and remained elevated at 24 mos (23 times higher on average vs baseline; p<0.001). A similar antibody titer profile was reported for PAP but of lesser magnitude. The number of immune responders (post-baseline antibody titer ≥25,600) was similar at any timepoint between arms (Arm 1: 30/34, 88.1%; Arm 2: 32/34, 94.1%; p=0.673). Higher cumulative TNC and baseline hemoglobin positively correlated with maximum PA2024 antibody titer response (p<0.05). Conclusions: Sip-T induced a robust immune response sustained to 24 mos in men with BRPC. Cellular response appeared to differ according to treatment sequence; humoral response was similar between treatment arms. Given its consistent association with the humoral response, cumulative TNC count may be a potential biomarker of response to sip-T. Clinical trial information: NCT01431391.
Development of intermediate and high-risk prostate cancer after testicular cancer.
Authors: Riggin Andrew John , Siddiqui Mohummad Minhaj 
Published: February 2017

177 Background: Men with a history of testicular cancer are known to have an increased risk of developing prostate cancer (PCa) in epidemiologic studies. We hypothesized they may also have an increased risk of developing intermediate to high-risk PCa. Herein, we present a case-control study to assess the association of a history of testicular cancer and intermediate to high-risk PCa. Methods: We used the eighteen Surveillance, Epidemiology and End Results (SEER) registries to compare men with a history of testicular cancer to a control population of men with a history of melanoma. Melanoma was used as a control group because, to our knowledge, there is no association of melanoma and PCa. Men were excluded if they were not 60 years of age or older to allow for sufficient PCa diagnosis. PCa incidence was only counted if it occurred at least 5 years after the diagnosis of their primary cancer to allow for possible temporal effect of the primary malignancy. Incidence of total and intermediate to high-risk PCa(Gleason score ≥ 7) was compared using Kaplan-Meier (KM) curves. Cox proportional hazards models were utilized to assess for associations of PCa (JMP 10, SAS Inc). Results: 119,781 men with melanoma and 10,365 men with testicular cancer were identified. The incidence of all PCa by age 80 was 2.7% in the control melanoma cohort and 12.3% in the case cohort of men with history of testicular cancer (p<0.0001 for KM survival curves). For intermediate/high-risk disease, the incidence was 1.1% versus 5.7% for each cohort respectively (p<0.0001 for KM survival curves). Testis cancer (versus the control melanoma cohort) was associated with an increased risk of all PCa (HR 4.7, p<0.0001) and intermediate/high-risk PCa (HR 5.5, p<0.0001). These associations persisted even when controlling for race. Conclusions: A history of testicular cancer is associated with a significantly increased risk of developing both PCa and intermediate/high risk PCa.
Contemporary use of radium-223 (Ra-223) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Feasibility and safety.
Authors: Emamekhoo Hamid , Chowdry Rajasree Pia , Elson Paul , Ledet Elisa M. , Martin Allison , Cotogno Patrick , Beach Jennifer , Steinberger Allie E. , Allman Kimberly D , Stolten Michael , Garcia Jorge A. , Sartor Oliver 
Published: February 2017

210 Background: Ra-223 is an α-emitter that binds to the newly formed bone matrix and targets osteoblastic metastatic lesions. Treatment with Ra-223 delays symptomatic skeletal-related events (SREs) and improves overall survival (OS) in men with mCRPC. Concerns about the efficacy and safety of Ra-223 in the pre-chemotherapy space, given alone or in combination with Abiraterone Acetate (AA) or enzalutamide (ENZ), have been raised. Methods: To determine the feasibility, efficacy and safety profile of Ra-223 given alone or in combination with AA or ENZ to men with docetaxel-naïve mCRPC a retrospective study was conducted. PSA decline, rPFS and safety data for patients (pts) treated at Cleveland Clinic (CC) and Tulane University (TU) were analyzed. Results: Fifty-one (27 CC and 24 TU) chemo-naïve mCRPC pts with bone metastases were identified. The median age was 63 (46-87). Testosterone suppression was maintained during treatment. Pre-treatment alkaline phosphatase (ALP) was elevated in 16 pts (33%). In addition to bone, 24 pts (47%) had soft-tissue metastases. While 23 pts received Ra-223 alone, 22 pts (43%) received concomitant AA or ENZ therapy. To date, the median number of Ra-223 cycles received is 5 (1-6) with 39% of pts (20/51) receiving all 6 cycles. PSA declines >30% were observed in 31% of pts. All but one pt had at least some decline in ALP. ALP decline >30% was observed in 68% of pts. Reasons for treatment discontinuation included; completion of 6 cycles 39% (20/51); PD 35% (18/51); AEs 8% (4/51) and pt choice 4% (2/51). Grade (G) 3/4 AEs were observed in 4 pts; G3 anemia (n=3) and G4 thrombocytopenia (n=1). The vast majority of pts had PSA progression (81%) and 42% of pts have died. Estimated median time to PSA progression and OS are 3.9 (95% C.I. 1.84-4.82) and 11.0 months (95% C.I. 7.5-16.4), respectively. Pts with normal baseline hemoglobin levels and those who received concomitant AA tended to have better PSA progression-free and OS (p<.06). Conclusions: Treatment with Ra-223 in combination with AA or ENZ in chemo-naïve mCRPC pts is feasible with no new safety signals of concern. Further evaluation of the combination of AA or ENZ with Ra-223 in this setting is warranted.
Clinical activity, safety, and biomarkers of MPDL3280A in metastatic urothelial bladder cancer: Additional analysis from phase IA study.
Authors: Kim Joseph W. , Bellmunt Joaquim , Powles Thomas , Loriot Yohann , Vogelzang Nicholas J. , Cruz Zambrano Cristina , Burris Howard A. , Teng Siew-leng Melinda , Shen Xiaodong , Bruey Jean-Marie , Boyd Zachary , Hegde Priti S. , Petrylak Daniel Peter 
Published: February 2017

297 Background: Metastatic urothelial bladder cancer (UBC) is a mutationally-complex disease in which PD-L1 expression in the tumor microenvironment may inhibit immune-mediated antitumor responses. MPDL3280A is a PD-L1-targeting antibody with an engineered Fc domain that disrupts PD-L1/PD-1 and PD-L1/B7.1 signaling. Methods: MPDL3280A was studied in a phase Ia metastatic UBC expansion cohort. UBC pts received MPDL3280A 15 mg/kg IV q3w for ≤16 cycles. Efficacy-evaluable pts were dosed by January 27, 2014 (≥12 week follow-up) with a data cutoff of April 21, 2014. RECIST v1.1 was used to assess ORR. PD-L1 expression (by immune cell IHC) was centrally evaluated from archival biopsies. In-tumor gene expression and peripheral biomarker analyses were done on pts dosed by Nov 20, 2013, with a cutoff of January 1, 2014. Results: In the UBC cohort, 33 IHC 2/3 pts, 36 IHC 0/1 pts, and 1 PD-L1 pt with unknown IHC were efficacy-evaluable. Median pt age was 65 y (36-89), and 73% were male. Visceral and liver metastases were present in 74% and 33% of pts, respectively. 73% had ≥2 prior therapies, and 91% had prior platinum. The unconfirmed ORR was 52% (95% CI, 34-69; 3 CRs, 14 PRs) in IHC 2/3 pts and 14% (95% CI, 6-28; 5 PRs) in IHC 0/1 pts. The median DOR was not yet reached (0.1+ to 42+ w in IHC 2/3 pts, n=17; 6+ to 19+ w in IHC 0/1 pts, n=5). 19/22 responding pts had ongoing responses. Median PFS was 24 w in IHC 2/3 pts (5 to 50+ w, n=33) and 8 w in IHC 0/1 pts (0.1+ to 30+ w, n=36). Of 74 pts evaluable for safety, all grade treatment-related AEs occurred in 65%, most often fatigue, decreased appetite and nausea. 5% had treatment-related G3-4 AEs. No treatment-related deaths were seen. The median follow-up was 5.4 mos (1+ to 12 mos, n=70). IHC 2/3 tumors had low expression of a baseline myeloid marker gene signature, including IL8 and IL1B, which was associated with MPLD3280A response. Additionally, circulating inflammatory markers (e.g., CRP) and tumor burden markers (e.g., HCG) decreased in responders by cycle 2. Updated data will be presented. Conclusions: MPDL3280A was well tolerated in UBC pts. Rapid and durable responses were seen and correlated with PD-L1 IHC status on immune cells. Biomarkers suggest a potential role for myeloid biology in primary resistance to MPDL3280A. Clinical trial information: NCT01375842.
A randomized trial of 79.2Gy versus 70.2Gy radiation therapy (RT) for localized prostate cancer.
Authors: Michalski Jeff M. , Moughan Jennifer , Purdy James , Bosch Walter , Bahary Jean-Paul , Lau Harold Y. , Duclos Marie , Parliament Matthew , Morton Gerard , Hamstra Daniel A. , Seider Michael J. , Lock Michael , Patel Malti , Gay Hiram Alberto , Vigneault Eric , Dignam James , Sandler Howard Mark 
Published: February 2017

4 Background: RTOG 0126 is a phase III trial for localized prostate cancer (PC) testing whether dose escalation to 79.2Gy with 3DCRT or IMRT will improve overall survival (OS). Methods: Stage cT1b-T2b with Gleason Score (GS) 2-6 and PSA ≥ 10 and <20 or GS 7 and PSA <15 were eligible and randomized to receive 79.2Gy or 70.2Gy. No androgen withdrawal was used. Treatment was 3DCRT or IMRT to 79.2Gy in 44 fractions or 70.2Gy in 39 fractions. The objective was to detect a 23% reduction in mortality hazard (HR=0.77) for 79.2Gy. ASTRO and Phoenix definition was used for biochemical failure (BF). Time to local progression (LP), distant metastases (DM), PC death, and late GI/GU toxicity was calculated from date of registration. OS was estimated by Kaplan Meier and arms compared with log rank test. BF, LP, DM, time to late GI/GU, and PC death were estimated by cumulative incidence method and arms compared with Gray’s test. Results: 1,532 men were randomized, 763 to 79.2Gy and 769 to 70.2Gy. 1,499 were eligible, 751 and 748 in the 79.2Gy and 70.2Gy arms respectively. Median age was 69, 70% had PSA < 10 ng/ml, 84% with GS 7, 57% had T1 disease, and 66% used 3D-CRT. With a median of 7.0 years follow up, the 5 and 10-yr rates of OS are 88% and 67% with 79.2Gy and 89% and 66% with 70.2Gy (p=0.87; HR (95%CI)=0.98 (0.79,1.21)). The ASTRO (Phoenix) BF rates at 5 and 10 yr are 25% (16%) and 30% (26%) with 79.2Gy and 40% (21%) and 45% (43%) with 70.2Gy (both p<0.0001). The 5 and 10-yr rates of LP are 1% and 4% with 79.2Gy and 2% and 8% with 70.2Gy (p=0.0059; HR (95%CI)=0.46 (0.27,0.81)). The 5 and 10 yr rates of DM are 2% and 5% with 79.2Gy and 3% and 8% with 70.2Gy (p=0.026; HR (95%CI)=0.57 (0.35,0.94)). The high dose arm had lower rate of salvage therapy, 13.5% vs 21%, p=0.0002. The 10 yr rates for time to late grade ≥ 2 GI/GU are 22%/15% with 79.2Gy and 16%/10% with 70.2Gy (p=0.0063/p=0.001). Time to late grade ≥ 3 GI was higher for the 79.2Gy arm (p=0.035) but time to late grade ≥ 3 GU toxicity was not (p=0.14). Conclusions: Despite significant improvement in BF, DM, and LP rates, dose escalation did not improve OS. Patients receiving high dose radiation experience more late toxicity. Clinical trial information: NCT00033631.
Comparison of simultaneous high dose stereotactic radiotherapy with normofractionated radiotherapy in patients with metastatic renal cell carcinoma under systemic therapy.
Authors: Staehler Michael D. , Lisa Behr , Nuhn Philipp , Schlenker Boris , Wilkowski Ralf 
Published: February 2017

467 Background: Conventional radiation therapy (RT) is considered ineffective in metastatic renal cell carcinoma (mRCC). There are data suggesting that this might be related to low doses per fraction and that higher doses could be more effective. We introduced hypofracationated high-dose radiation therapy in patients with an indication for radiotherapy an retrospectively compared the results to patients with a conventional radiation therapy. Methods: We identified 97 pts with mRCC and an indication for radiotherapy of metastatic lesions between 2007 and 2013. All pts underwent simultaneous systemic therapy based on targeted agents and systemic therapy. 83 pts had a hypofractionated high dose stereotactic radiation (HDRT) (5 Gy per fraction, 3 fractions per week, total 45 Gy) while 14 pts underwent conventional normo-fractionated radiotherapy (NDR) (1.8 Gy per fraction) as described elsewhere. Results: Median age was 64.1 years (27-86). 189 metastatic lesions were irradiated. 64% of the pts had clear cell histology, with 14% harboring papillary RCC type II and 11% other subentities. Median overall survival was significantly longer for pts after HDRT was 9.4 months (+/-9.4 months) and 4.5 months (+/- 3.4 months) after NDR (p=0.01). The multivariate cox regression analysis revealed the MSKCC risk score, HDR therapy and the disease free survival as positive predictors for survival. No grade III toxicities were found, with 24% of the patients experiencing grade 1 or 2 side effects, mainly diarrhea and fatigue. Conclusions: In mRCC HDRT with simultaneous systemic therapy is related to a better overall survival than NRT. HDRT in combination with targeted therapy should be regarded the standard of care if RT is indicated.
cMet: Results in papillary renal cell carcinoma of a phase I study of AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Gan Hui Kong , Lickliter Jason , Millward Michael , Gu Yi , Weiguo SU , Qi Chuan , MU Hua , Frigault Melanie , Morgan Shethah , Gardner Humphrey Athelstan , Albiges Laurence , Pal Sumanta Kumar , Burris Howard A. , Choueiri Toni K. 
Published: February 2017

487 Background: Met is a receptor tyrosine kinase that is deregulated across multiple cancer types, leading to uncontrolled tumor cell growth, invasion and survival. MET is frequently dysregulated in PRCC. Activating Met mutations are present in hereditary and a subset of sporadic PRCC cases (up to 21% of type I PRCC, Albiges et al, 2014). Trisomy of chromosome 7 (containing both MET and HGF genes) has been reported in 45-75% of sporadic PRCC cases; 81% of type I and 46% of type II PRCC have copy number alterations of MET (Albiges et al, 2014). Methods: AZD6094 (HMPL-504/volitinib) is a potent, selective Met inhibitor. Preclinically, AZD6094 inhibits in vitro growth of MET-amplified gastric and lung cell lines. In vivo AZD6094 induces regressions in PRCC explant models. Results: In phase I, AZD6094 was well tolerated, with good exposure and low accumulation (Gan et al, 2014). Two PRCC pts in the 600 mg QD cohort (one with ongoing treatment at 19 months) and 1 PRCC in the 1,000 mg QD cohort (ongoing treatment at 13 months) achieved PR. A fourth patient, on 300 mg BD, showed a best tumor response of 25% decrease from baseline. Analysis of tumor samples showed that all the responders had MET copy number increase. Conclusions: These encouraging findings have triggered a phase II trial. This is an open label non-randomised multi-centre study to assess the efficacy of AZD6094 monotherapy in treatment naive and previously treated PRCC patients. Eligibility includes PRCC histopathology, ECOG status 0 or 1, ability to comply with the collection of tumor samples, adequate haematological, liver, and kidney function, and measurable disease (RECIST 1.1). The study is ongoing in collaboration with Sarah Cannon Research Institute in the United States, Canadian, EU centres. This study is sponsored by AstraZeneca, clinical trial information: NCT02127710. Clinical trial information: NCT01773018.
High concordance of BAP1 and PBRM1 expression in patient-matched primary and metastatic ccRCC tumors.
Authors: Shreders Amanda , Joseph Richard Wayne , Serie Daniel , Kapur Payal , Ho Thai Huu , Eckel-Passow Jeanette , Brugarolas James , Parker Alexander S. 
Published: February 2017

507 Background: Clear cell renal cell carcinoma (ccRCC) is a well-described molecularly heterogeneous tumor. Herein, we assessed the concordance of two of the most commonly mutated genes in ccRCC, PBRM1 (~50%), and BAP1 (~15%), in patient-matched primary and metastatic tumors. Methods: One pathologist (PK) assessed PBRM1 and BAP1 protein expression using immunohistochemistry (IHC) in 99 patients with a primary and at least one metastatic ccRCC tumor available for analysis. All available metastatic tumors were analyzed. Results: A total of 99 patients (48 M0 and 51 M1) had both a primary tumor and at least one metastatic tumor available for analysis. There were a total of 158 metastases with one patient having up to 7 metastases available for analysis. The concordance between primary and patient-matched metastasis was 87% for PBRM1 and 99% for BAP1. We observed a similar concordance between patients with M0 versus M1 disease. Conclusions: While ccRCC is molecularly heterogeneous, PRBM1, and BAP1 are largely concordant between primary and metastatic lesions suggesting that PBRM1 and BAP1 are genetically truncal events in the molecular pathogenesis of ccRCC.
Effectiveness of massage therapy (MT) as a treatment strategy and preventive modality for chemotherapy-induced peripheral neuropathy (CIPN) symptoms.
Authors: Menendez Alvaro G. , Cobb Regina , Carvajal Alejandro Ramon , Healey Kathi , D'Ambra Diane , Espat N. Joseph 
Published: February 2017

193 Background: CIPN has a known negative impact on quality of life (QoL) and can be a dose-limiting side effect of cytotoxic drugs with no generally agreed upon therapeutic intervention. In this study MT was assessed as a primary and secondary preventive modality of CIPN symptoms under the hypothesis that it can be used as an effective prophylactic and therapeutic option. Methods: A single arm 10-week prospective study (n = 62) with pre/post intervention assessment using a validated survey instrument adapted from “Peripheral neuropathy associated with novel therapies […]”. (Clin J Onc Nur. 2008; (12)3:9-12) Results: 97% (60/62) had at least 2 CIPN-related symptoms. (Table 1) After a single MT session, at least 50% of pts (range 52-100%) reported improvement in all CIPN-related symptom categories. These observations were maintained until 2nd MT session except for vestibulocochlear related symptoms. Initially, 25/60 were on analgesics. Of these, 14 (56%) had no progression of symptoms after 1st MT session. 13/25 presented for 2nd session. 5/13 (38%) reported no progression, 4/13 (31%) reported complete resolution of symptoms and 4/13 (31%) had progression. Conclusions: With the exception of vestibulocochlear symptoms associated with CIPN, study participants reported 50% or greater improvement, which was maintained after 1st MT session. The data suggests that pts on analgesics may also benefit from MT as at least 66% (17/25) reported lack of progression or resolution of symptoms after MT intervention. Consideration for an MT-inclusive treatment strategy is supported by this study. [Table: see text]