bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experience of implementing a novel random sampling BICR audit for investigator (INV)-assessed progression-free survival (PFS) in the PALOMA-3 trial.
Authors: Huang Xin , Zhang Ke , Turner Nicholas C. , Bartlett Cynthia Huang , Giorgetti Carla , Cristofanilli Massimo 
Published: September 2018

1058 Background: PFS has frequently been used as a primary endpoint for evaluating efficacy of anticancer therapies in randomized clinical trials. Given high correlation between INV and independent (BICR) assessments with respect to the relative treatment effect, a pre-planned BICR audit of INV progression assessment in a random subgroup of patients (pts) instead of a BICR review of all progression assessments can be an acceptable approach to verify the INV assessments and to evaluate the potential bias in INV PFS results. Methods: PALOMA-3 was a randomized, double blind, placebo (PCB) controlled, Ph 3 study with the primary objective of demonstrating the superiority of palbociclib (PAL) + fulvestrant (F) over PCB + F in women with HR+, HER2- metastatic breast cancer (MBC). The primary endpoint was INV assessed PFS. BICR assessment of PFS was performed with the use of a novel audit approach involving a random sample–based BICR to verify if the INV assessed PFS was accurate. A third-party core imaging laboratory performed the blinded review for a randomly selected subgroup of pts (~40%). NIH and PhRMA methods were used to evaluate the potential for bias in the INV PFS results. Results: PAL + F improved PFS in patients with HR+, HER2- MBC. The observed INV HR was 0.46 (95% CI: 0.36, 0.59; stratified 1-sided p < 0.0001) in favor of PAL + F. The median PFS was 9.5 mo (95% CI: 9.2, 11.0) in the PAL + F arm and 4.6 mo (95% CI: 3.5, 5.6) in the PCB + F arm (Lancet Oncol. 2016; 17: 425–39). The estimated HR of the complete BICR data incorporating the information from the complete INV assessed PFS and the random sample audited BICR subgroup was 0.33 with the upper bound of the 1-sided 95% CI of 0.47. The results confirmed the INV assessed treatment effect and detected no INV bias in favor of PAL + F. Conclusions: PALOMA-3 is the first registrational trial to use a BICR audit and has received positive reviews from regulatory agencies. The experience of implementing the random sampling BICR audit in PALOMA-3 demonstrates that this approach can be used for randomized, double blind oncology trials with solid tumors where INV assessed PFS is the primary endpoint and a large treatment effect is targeted. Sponsor: Pfizer. Clinical trial information: NCT01942135.
RADICAL trial: A phase Ib/IIa study to assess the safety and efficacy of AZD4547 in combination with either anastrozole or letrozole in ER positive breast cancer patients progressing on these aromatase inhibitors (AIs).
Authors: Seckl Michael , Badman Philip David , Liu Xinxue , MacPherson Iain R. , Zubairi Ishtiaq Husain , Baird Richard D. , Garcia-Corbacho Javier , Cresti Nicola , Plummer Elizabeth R. , Armstrong Anne Caroline , Allerton Rozenn , Landers Donal , Nicholas Hanna , McLellan Lyndall , Lim Adrian K. , Coombes Charles 
Published: September 2018

1059 Background: Patients with metastatic ER positive breast cancer invariably experience disease progression whilst taking AIs. Fibroblast growth factor receptor inhibitors (FGFRI) such as AZD4547 can reverse endocrine resistance in breast cancer cells. Consequently, we designed the RADICAL trial to test the safety and efficacy of AZD4547 combined with letrozole (L) or anastrozole (A). Methods: Patients with prior disease progression on either AI were initially recruited to a Phase Ib study which showed that L 2.5mg or A 1mg daily continuously could be safely combined with AZD4547 80mg twice daily on a 1wk on/1 wk off schedule. Pharmacokinetic data showed no significant interactions. Subsequently, 52 patients progressing on these AIs were recruited, either continuing, or, if other therapies had subsequently been given, restarting their prior AI together with AZD4547. Primary endpoint was change in tumour size (RECIST v 1.1) at 12 weeks compared to baseline. Results: Enrolled patients had previously received a median of 4 (range: 1-11) systemic therapies, including endocrine treatments with a median of 2 (range: 1-6). The mean tumour size change at 12 and 28 weeks was 7% (95%CI: -4%, 17%) and 8% (95%CI: -4%, 20%), respectively. Clinical benefit assessed by partial response (PR) or stable disease (SD) occurred in 36.5% (1 PR and 18 SD) and 25% (2 PR and 11 SD) of patients at 12 and 28 weeks, respectively. The median progression free survival was 3.1 months (95%CI: 2.4-5.4). Most adverse events (AEs) were G1/2 (95.3%). 11 (21%) patients developed asymptomatic AZD4547-induced retinal pigment epithelial detachment, all resolved and 1 and 6 were able to continue on study medication at full and half dose, respectively. Among 34 G3/4 AEs, only 6 were probably/possibly related to AZD4547. Out of 13 unrelated serious AEs, 2 were fatal. Conclusions: Combined AZD4547 with L or A appears to be safe and shows anti-tumour activity in advanced ER+ patients resistant to these AIs. Development of a biomarker to select patients for this therapy will facilitate future studies. Clinical trial information: NCT01791985.
Analysis of everolimus starting dose as prognostic marker in HR+ mBC patients treated with everolimus (EVE) + exemestane (EXE): Results of the 3rd interim analysis of the non-interventional trial BRAWO.
Authors: Fasching Peter A. , Grischke Eva-Maria , Schuetz Florian , Decker Thomas , Uleer Christoph , Salat Christoph , Foerster Frank , Schmidt Marcus , Mundhenke Christoph , Tesch Hans , Jackisch Christian , Wimberger Pauline , Aktas Bahriye , Zahn Mark-Oliver , Tome Oliver , Bloch Wilhelm , Hanson Sven , Fischer Thomas , Schubert Joerg , Lueftner Diana 
Published: September 2018

1061 Background: BRAWO is a German non-interventional study, which enrolled more than 2400 patients (pts) with advanced/metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with EVE and EXE. Main objectives are a) the impact of physical activity on efficacy and quality of life, b) prophylaxis and management of stomatitis in clinical routine, and c) the sequence of therapy when EVE is used in daily clinical practice. Methods: In this update on the results of the 3rd interim analysis (data cut-off 18-Oct-2016) we analyzed under real world conditions the first 1.078 patients followed up until disease progression for their progression-free survival (PFS) events. A two-stage process based on a Cox regression model was used to check the relevance of the start dose on PFS. In the first step potentially relevant covariates defined by medical experts were evaluated for relevance. In the second step start dose and all covariates showing a p-value of at most 0.1 in first step including all two-interaction of start dose with these parameters were included into the model. Results: Our multivariate analysis support the evidence that predictive factors, such as body mass index (BMI, p-value: < 0.001), therapeutic line (1st vs. 2nd+3rd vs. ≥4th; p-value: 0.013), presence of visceral metastases (p-value: < 0.001) and ECOG (Eastern Cooperative Oncology Group, p-value: < 0.001) status at the beginning of the therapy correlated significantly with the PFS. 283 patients started with 5mg and 795 Patients started with 10 mg. Starting dose had no significant impact on the PFS (neither as main effect nor within interactions, p-value: 0.44-0.88). Conclusions: Even though the approved and recommended starting dose for treatment with EVE is 10 mg, physicians sometimes start EVE-treatment with a lower starting dose, trying subsequently to increase the dose to the recommended dose of 10mg to allow the patient’s organism to adapt to the therapeutic. As the study was not powered to detect possible differences in PFS by starting dose, the result of showing no detrimental effect of a lower start dose may be the result of limited power. Clinical trial information: EUPAS9462.
Fulvestrant as maintenance therapy after first-line chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer (FANCY), a prospective, multicenter, single arm phase 2 study.
Authors: Wang Shusen , Zheng Qiufan , Xu Fei , Xia Wen , Ouyang Quchang , Pang Danmei , Yuan Huimin , Shi Yanxia , Peng Roujun , Yuan Zhongyu 
Published: September 2018

1066 Background: Fulvestrant is potent for treatment of hormone receptor (HR)-positive advanced breast cancer (ABC); however, few data exist for this regimen as maintenance endocrine treatment after chemotherapy (CT). In our phase 2 trial, we aimed to assess efficacy and tolerability of fulvestrant 500mg as maintenance therapy in patients with disease control after first-line CT. Methods: Simon’s two-stage design was used. We enrolled postmenopausal women with histologically confirmed HR-positive, HER2-negative ABC, who achieved disease control after four to eight cycles of first-line CT. Fulvestrant 500 mg was intramuscularly injected on day 1, 15, 29, then every 28 (±3) days subsequently, until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR), secondary endpoint included progression-free survival (PFS) since maintenance treatment, PFS since first-line CT, objective response rate (ORR) and safety. Results: Between Dec 10, 2013, and Sept 30, 2015, 58 patients were enrolled. 25 (43%) patients were deemed as resistance to endocrine treatment, 36 (62%) patients had a visceral disease. Median follow-up was 21 months. After fulvestrant maintenance treatment, 36 patients remained disease stabilising for at least six months, and eight (14%, 95% CI 6-25) patients achieved a response, resulted in a CBR of 76% (95% CI 63-86), which met its primary endpoint. The median PFS since fulvestrant treatment was 16·1 months (95% CI 10·3 to not reached), and median PFS since first-line CT was 19·5 months (95% CI, 15·6 to not reached). 39 (67%) of 58 patients reported at least one adverse event (AE), of which predominantly were grade 1 or 2. The most common grade 3 AEs were increased alanine aminotransferase in two (3%) patients, increased aspartate aminotransferase in one (2%) patient, and arthralgia in one (2%) patient. No patient discontinued treatment due to AE. Conclusions: Fulvestrant 500mg is active in maintenance therapy in non-progrssion patients with HR-positive ABC after first-line CT. Further study is needed to assess long-term outcome of maintenance therapy. Clinical trial information: NCT02000193.
Evolution of overall survival according to year of diagnosis (2008-2014) and subtypes, among 16703 metastatic breast cancer (MBC) patients included in the real-life "ESME" cohort.
Authors: Delaloge Suzette , Ezzalfani Monia , Dieras Veronique , Bachelot Thomas Denis , Debled Marc , Jacot William , Brain Etienne , Mouret-Reynier Marie-Ange , Goncalves Anthony , Dalenc Florence , Patsouris Anne , Ferrero Jean-Marc , Levy Christelle , Vanlemmens Laurence , Lefeuvre Claudia , Mathoulin-Pélissier Simone , Petit Thierry , Courtinard Coralie , Cailliot Christian , Pérol David 
Published: September 2018

1078 Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p<0.0001). Conclusions: Although OS of MBC has slightly improved over the past decade, this remains mostly confined to HER2+ cases, highlighting the need for new strategies for the luminal and triple negative populations. [Table: see text]
A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results.
Authors: Attia Steven , Bolejack Vanessa , Ganjoo Kristen N. , George Suzanne , Agulnik Mark , Rushing Daniel A. , Loggers Elizabeth Trice , Livingston Michael B. , Wright Jennifer A. , Chawla Sant P. , Okuno Scott H. , Reinke Denise K. , Riedel Richard F. , Davis Lara Emily , Ryan Christopher W. , Maki Robert G. 
Published: September 2018

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.
Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study.
Authors: Raut Chandrajit P. , Espat N. Joseph , Maki Robert G. , Araujo Dejka M. , Williams Toni Faith , Wolff Johannes E. , DeMatteo Ronald P. 
Published: September 2018

11009 Background: Adjuvant IM reduces risk of recurrence and improves survival in pts with high-risk primary GIST. Joensuu et al 2016 demonstrated higher 5-yr overall survival (OS) rates of 91.9% vs 85.3% in pts treated with adjuvant IM for 3 vs 1 yr, respectively. It is unknown if further extension of treatment duration can improve outcome. Methods: PERSIST-5 is a single-arm, phase II trial that enrolled pts ≥18 yrs of age, who underwent macroscopically complete resection of primary KIT (+) GIST with high risk of recurrence within 12 wks prior to IM treatment. High risk was defined as primary GIST (any site) ≥2 cm with a mitotic count ≥ 5/50 HPF or non-gastric primary GIST ≥5 cm. Pts were treated with IM 400 mg/d for 5 yrs or until progression, relapse, or intolerance. Primary endpoint was recurrence-free survival (RFS, defined as time of treatment start to first recurrence or death). Results: IM was administered to 91 pts with a median age of 60 yrs (range 30-90). Median tumor size was 6.5 cm (range 2.3-30 cm; 55% gastric origin). Median treatment duration was 55.7 mos (range, 0.5-75). Forty-six (50.5%) pts completed study treatment. The 5- and 8-yr estimated RFS rates were 90% (95% CI, 80-95) and 81% (95% CI, 62-91), respectively. The 5- and 8 year OS rate was 95% (95% CI, 86-99). There were 7 recurrences; 1 pt recurred and died while on IM ( PDGFRA D842V mutation) and 6 pts recurred after IM discontinuation. Two pts died after IM discontinuation, unrelated to study treatment and without recurrence. Forty-five pts discontinued study treatment; common reasons included patient choice (20%), adverse events (AEs, 17%), protocol deviation (4%), and loss of follow-up (4%). The most common AEs of all grades (regardless of relationship to IM) were nausea (71%), diarrhea (63%), fatigue (50%), muscle spasm (41%), vomiting (39%), and periorbital edema (34%). Conclusions: Five yrs of IM treatment was effective in preventing recurrence in pts with sensitive mutations who underwent resection of primary GIST. Nearly half of the patients discontinued treatment early, and most recurrences occurred after IM discontinuation. Clinical trial information: NCT00867113.
Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST).
Authors: Heinrich Michael C. , Jones Robin Lewis , von Mehren Margaret , Schoffski Patrick , Bauer Sebastian , Mir Olivier , Cassier Philippe Alexandre , Eskens Ferry , Shi Hongliang , Alvarez-Diez Terri , Schmidt-Kittler Oleg , Healy Mary Ellen , Wolf Beni B. , George Suzanne 
Published: September 2018

11011 Background: Oncogenic mutations in KIT or PDGFRα drive > 85% of GIST. However, primary and acquired mutations in the activation loop of PDGFRα and KIT are not effectively treated by approved therapies. A phase 1 study (NCT02508532) was initiated in advanced GIST to assess the safety, PK and clinical activity of BLU-285, a potent, highly-selective oral inhibitor that targets KIT Exon 17 and PDGFRα D842 activation loop mutants. Methods: Adult patients (pts) with unresectable GIST, who had received ≥2 kinase inhibitors including imatinib or who had a primary PDGFRα D842 mutation regardless of prior therapy, were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design, which allowed additional accrual to dose levels demonstrated to be safe. Adverse events (AEs) per CTCAE v4.03, PK and plasma/tumor mutant DNA levels were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 01JAN17 cutoff, 40 pts (21 PDGFRa/19 KIT) have been treated with BLU-285 at doses of 30-600 mg. Median number of prior kinase inhibitor regimens was 4.5 (2-12) KIT/2.5 (0-4) PDGFRα. RECIST 1.1 responses were seen across all dose levels for PDGFRα GIST and at higher dose levels for KIT GIST. Of 17 PDGFRα D842V pts with ≥1 radiographic assessment, 7 had confirmed PR (ORR 41%) and 10 had SD. Of 11 evaluable KIT pts treated at doses ≥ 135 mg, 2 had PR (1 confirmed; ORR 18%) and 5 SD. BLU-285 is rapidly absorbed (Tmax 2-8 h), exposure increases linearly with dose, and half-life is > 24 h supporting QD dosing. Most AEs were grade 1 or 2, most commonly nausea (48%), fatigue (45%), peripheral edema, periorbital edema, vomiting (30% each), diarrhea (25%), anemia, dizziness, and lacrimation (23% each). There were no grade 4 or 5 BLU-285-related AEs, dose limiting toxicities, or discontinuations. 29 pts (all 21 PDGFRα pts) remain on treatment (duration 1-14 mo). Updated results including MTD, ct-DNA and central radiographic assessments will be presented. Conclusions: Precision targeted therapy with BLU-285 demonstrates important clinical activity in pts with both PDGFRα- and KIT-mutant GIST that is resistant to available therapies. Clinical trial information: NCT02508532.
Phase (Ph) 2 stage 1 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor, in women with advanced AR+ triple-negative breast cancer (TNBC) or estrogen receptor (ER)+ BC: CLARITY-01.
Authors: Gucalp Ayca , Danso Michael A. , Elias Anthony D. , Bardia Aditya , Ali Haythem Y. , Potter David , Gabrail Nashat Y. , Haley Barbara B. , Khong Hung T. , Riley Elizabeth Carloss , Ervin Leigh , Eisner Joel Robert , Baskin-Bey, M.D. Edwina , Moore William Richard , Traina Tiffany A. 
Published: September 2018

1102 Background: Seviteronel (Sevi), an oral selective CYP17-lyase and AR inhibitor that blocks testosterone and estradiol production and competitively antagonizes the AR, is in Ph 2 clinical development for BC and prostate cancer. The primary objective of this ongoing Ph 2 study (NCT02580448) is to estimate the activity of once daily Sevi in women with AR+ TNBC and ER+ BC as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wk), respectively. Methods: Patients (pts) with ER+/HER2-normal metastatic BC following progression of ≥1 prior line of endocrine therapy or TNBC were enrolled with no limit of prior therapies in either cohort. Evaluable pts had AR ≥10% via central IHC staining (TNBC only) and 1 post-baseline scan. Sevi was administered at 450 mg oral daily. Scans were performed every 8 wk. Circulating tumor cell (CTC) enumeration was performed by EPIC CTC analysis. A Simon’s 2-stage design was employed to determine activity (≥2 of 13 CBR16 in TNBC and ≥2 of 12 CBR24 in ER+ BC allow for accrual to Stage 2). Results: As of 4 Oct, 2016, 16 pts with AR+ TNBC (6 evaluable) and 14 pts with ER+ BC (11 evaluable) were enrolled. 67% had visceral metastases; 10% had stable brain metastases. 60% had ≥2 lines of prior therapy for advanced disease. 13 of 14 (93%) TNBC pts who underwent central AR testing had AR ≥10%. Four pts in the TNBC cohort and 8 pts in the ER+ cohort remain on therapy. CBR16 (TNBC) and CBR24 (ER+) was 2 of 6 (33%) and 2 of 11 (18%) allowing Stage 2 accrual in both cohorts. 7 of 10 evaluable pts with CTCs present at baseline had a CTC decline at C2D1, including all that met CBR (-94.3% [-27.5, -100] median [range]). The most common adverse events (≥ 25%) were fatigue (50%), nausea (43%) and decreased appetite (33%); all Grade 1/2. Updated CBR data will be presented at the time of presentation. Conclusions: Sevi Stage 1 activity is suggested by CBRs, along with associated CTC declines in heavily pre-treated pts with high disease burden. The observed safety profile is consistent with on-target pharmacology. Stage 2 enrollment is ongoing. Sevi may provide a novel treatment option for women with AR+ TNBC or ER+ BC. Clinical trial information: NCT02580448.