bluuebunny/crossref_metadata_2025_split huggingface dataset:
BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) after 30 months of follow-up.
Authors: Gambacorti-Passerini Carlo , Lipton Jeffrey Howard , Tee Goh Yeow , Casado Luis Felipe , Zaritskey Andrey , le Coutre Philipp D. , Duvillie Ladan , Pavlov Dmitri , Countouriotis Athena Maria , Byrne Jennifer 
Published: March 2020

6512 Background: The BELA study compared the efficacy and safety of BOS (dual Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n = 250) or IM 400 mg/d (n = 252) and stratified by Sokal risk group and geographic region. Efficacy analyses included all randomized pts (ITT); safety analyses included all treated pts (BOS, n = 248; IM, n = 251). Data described below are for ≥24 mo of follow-up; updated data for ≥30 mo of follow-up will be presented. Results: Median treatment duration was 27.5 mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving treatment. The primary reason for BOS discontinuation was a treatment-emergent adverse event (TEAE; 24% vs 7% with IM); the primary reason for IM discontinuation was disease progression (13% vs 4% with BOS). Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 79% for BOS and 80% for IM. Cumulative major molecular response (MMR) rates by 24 mo were 59% for BOS and 49% for IM (P = 0.019), including 16% and 12% of pts with complete molecular response (4.0-log sensitivity). On-treatment transformation to accelerated/blast phase occurred in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML progression); 24-mo Kaplan-Meier overall survival estimates were 97% (BOS) and 95% (IM). BOS was associated with higher incidences of gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs 16%]; primarily transient), but lower incidences of edema (13% vs 40%) and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs 10%]). Grade ≥3 TEAEs in ≥2% of BOS or IM pts were diarrhea (12% vs 1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade ≥3 lab abnormalities (≥15% of pts) with BOS and IM were neutropenia (10% vs 24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase (23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS was effective for newly diagnosed CP CML and had a distinct toxicity profile. With continued follow-up both on-treatment transformation to accelerated/blast phase and overall survival continue to favor BOS versus IM.
Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma.
Authors: Weber Jeffrey S. , Flaherty Keith T. , Infante Jeffrey R. , Falchook Gerald Steven , Kefford Richard , Daud Adil , Hamid Omid , Gonzalez Rene , Kudchadkar Ragini Reiney , Lawrence Donald P. , Burris Howard A. , Long Georgina V. , Algazi Alain Patrick , Lewis Karl D , Kim Kevin B. , Puzanov Igor , Sun Peng , Little Shonda M , Patel Kiran , Sosman Jeffrey Alan 
Published: March 2020

8510 Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.
Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations.
Authors: Ascierto Paolo Antonio , Berking Carola , Agarwala Sanjiv S , Schadendorf Dirk , Van Herpen Carla , Queirolo Paola , Blank Christian U. , Hauschild Axel , Beck J. Thaddeus , Zubel Angela , Niazi Faiz , Wandel Simon , Dummer Reinhard 
Published: March 2020

8511 Background: BRAF and NRAS mutations occur in 50-60% and 15-20% of cutaneous melanomas, respectively. MEK162, a selective inhibitor of the kinases MEK1 and MEK2, has shown pre-clinical activity in BRAF and NRAS mutant (mt) melanoma models. This open label, phase II study assessed the antitumor activity of MEK162 in patients (pts) with BRAFV600 and NRAS mt advanced cutaneous melanoma. Methods: MEK162 was administered orally at a starting dose of 45 mg twice daily. Treatment was until unacceptable toxicity, disease progression (PD) or investigator or patient refusal. Tumor response was assessed by CT imaging every 8 weeks (RECIST 1.0) until PD. Results: As of 16 Sept 2011, the full analysis and safety populations comprised 66 pts: 42 BRAF mt and 24 NRAS mt. Median age 58.0 years; 57.6% male; 72.7% WHO performance status 0. All NRAS pts and all but 2 BRAF (1 each stage IIIB and IIIC) pts had stage IV disease, and 87.5% of NRAS pts and 66.7% of BRAF pts had received prior therapy at study entry. Median time from 1st diagnosis to 1st dose of drug was 40.4 months. Median time on study was 10.4 and 8.5 weeks for the BRAF and NRAS arms. Relative dose intensities of 80–<100% were received by 71.4% and 70.8% of pts, respectively. Among 29 BRAF mt and 13 NRAS mt pts evaluable for efficacy, 1 confirmed and 6 unconfirmed partial responses (PRs) and 9 pts with stable disease (SD) were recorded in the BRAF arm and 2 confirmed PRs, 1 unconfirmed PR and 4 pts with SD recorded in the NRAS arm. Common treatment–related adverse events (AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%), acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation (25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts (6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in >1pt were diarrhea (4.5%) and CK elevation (15.2%). 5 pts discontinued due to toxicity. 34 pts are ongoing with more responses under current review. Conclusions: MEK162 showed clinical activity and good tolerability in pts with BRAF and NRAS mt advanced melanoma. This is the 1st targeted therapy to show activity in pts with NRAS mt melanoma.
A phase II single arm study of pazopanib and paclitaxel as first-line treatment for unresectable stage III and stage IV melanoma: Interim analysis.
Authors: Fruehauf John P. , Alger Beverly , Parmakhtiar Basmina , Jakowatz James G. , Bettis Claudette , Chuang Tony , Ein-Gal Shlomit Y. 
Published: March 2020

8524 Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.
Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial.
Authors: Khan Qamar J. , Kimler Bruce F. , Reddy Pavan S. , Sharma Priyanka , Klemp Jennifer R. , Fabian Carol J. 
Published: March 2020

9000 Background: Musculoskeletal (MS) pain and fatigue are common in women on adjuvant Aromatase Inhibitors (AIs) and lead to reduced compliance. Pilot studies suggest a positive impact of vit D on MS pain and disability from AIs. We conducted a bi-institutional, double blind, placebo controlled randomized trial to study the impact of 30,000 I.U of vit D3 in preventing worsening of MS pain and fatigue in women starting letrozole. Methods: Women with stage I-III breast cancer starting adjuvant AI and a 25(OH)D level of 40 ng/ml or less were eligible. Women with prior renal stones or hypercalcemia were excluded. All subjects received letrozole, plus standard dose vitD3 (600 IU) and calcium (1200 mg) daily, all provided by the study. Women were randomly assigned to 30,000 IU of oral vitD3 wkly (vitD arm) or matched placebos (PL arm) for 24 weeks. The following were assessed at baseline, 12 wks, and 24 wks (end of study): 1) 25OHD levels, 2) symptoms tools (BFI – Brief Fatigue Inventory, HAQII - Health Assessment Questionnaire II, Qualitative Joint Pain (none, mild, moderate, severe), BPI – Brief Pain Inventory) and 3) hand grip strength with a dynamometer. Results: 160 women (80/arm) were enrolled from 4/09 to 7/10. There were no differences between the two arms in demographics/tumor characteristics. Median age was 61, median BMI was 29.8 kg/m2. 43% had adjuvant chemotherapy. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 wks and 31 at 24 wks in the PL arm and 22, 53 and 57 in vitD arm. One patient in the PL arm developed mild hypercalcemia. There were no SAEs. 147 subjects were evaluable for efficacy. 3 subjects, all in the PL arm discontinued early due to a MS adverse event. At wk 24, a higher proportion of women in PL (51%) vs vitD arm (37%) had a protocol defined MS event (worsening of joint pain, disability from joint pain or discontinuation of Letrozole due to MS symptoms) (p=0.069). A significantly higher proportion of women in PL (72%) vs vitD arm (42%) had an adverse QOL event (worsening of pain, disability or fatigue) (p=<0.001). Conclusions: 30,000 IU/week of vitamin D3 is safe and results in decreased adverse QOL events from adjuvant aromatase inhibitors in women with breast cancer.
Evaluation of food effect on pharmacokinetics (PK) of GDC-0449 (G) in advanced solid tumor patients.
Authors: Sharma Manish , Kang Soonmo Peter , Karrison Theodore , Wu Kehua , Turcich Michelle , Geary David , Takebe Naoko , Graham Richard A. , Maitland Michael L. , Schilsky Richard L. , Ratain Mark J. , Cohen Ezra E. W. 
Published: March 2020

e13106 Background: GDC-0449 (Vismodegib, Genentech), an orally bioavailable small-molecule SMO (Smoothened) inhibitor, was recently approved for advanced basal cell carcinoma (BCC) and is being evaluated in other solid tumors. This study sought to determine whether there is a significant effect of food on the PK of G. Methods: In part I, patients (pts) were randomized 1:1 to fasting overnight (FO) or a high fat meal (HF) before a single dose of G 150 mg. The study was later amended to 1:1:2 randomization to FO, HF or a low fat meal (LF). Plasma concentrations of G were determined by a validated liquid chromatography-tandem mass spectrometry assay. PK endpoints were observed Cmax, observed Tmax, and AUC (0-24 and 0-168 hours). In part II, pts randomized to FO or HF in part I took G 150 mg/day in a fasting state, while pts randomized to LF took G 150 mg/day in a fed state. PK endpoints after two weeks were steady state (ss) Cmax, ss Tmax, and ss AUC (0-24 hours). 60 pts enrolled 10/09-11/11, of which 43 were evaluable for PK: 18 FO; 14 HF; 11 LF. Pt characteristics: Female 53%; median age 59; PS 0: 62%, 1: 38%. Tumor types: 43% colorectal; 17% pancreatic; 40% other. Results: PK data were log-transformed for analysis. AUC (0-168 hours) after a single dose was higher in HF than in FO pts (p = 0.049); ratio of geometric means = 1.46 (90% CI = 1.07-1.99). There was a trend toward higher Cmax after a single dose in HF than in FO pts (p = 0.071); ratio of geometric means = 1.39 (90% CI = 1.03-1.88). There were no significant differences between groups for single dose AUC (0-24 hours) and Tmax. There were no significant differences between fasting and fed groups for ss Cmax, ss Tmax, or ss AUC (0-24 hours). The frequencies of drug-related Grade ≥ 3 toxicities were similar in the fasting and fed groups. There were no objective responses; 11 pts (18%) had stable disease for a median duration of 16 weeks and a maximum of 104 weeks (BCC). Conclusions: A high fat meal increases plasma exposure to a single dose of G, but there are no significant PK or safety differences between fasting and fed groups at ss. GDC-0449 can be taken with or without food for daily dosing. This study design is an efficient way to evaluate the effect of food on oral anti-cancer drugs. Supported by NCI grant 5U01-CA69852-12.
Medical treatment consensus in unresectable midgut gastrointestinal neuroendocrine tumors.
Authors: Strosberg Jonathan R. , Fisher George A. , Benson Al B. , Malin Jennifer L. , Anthony Lowell Brian , Arslan Bulent , Gibbs John F. , Greeno Edward , Iyer Renuka V. , Kim M. K. , Maples W. , Philip Philip Agop , Wolin Edward M. , Cherepanov Dasha , Broder Michael S. 
Published: March 2020

e14610 Background: Neuroendocrine tumors (NETs) comprise mostly carcinoid or pancreatic NETs and are rare with symptoms that may be difficult to control. Current treatment guidelines lack some specificity. We summarize an expert panel consensus on medical treatment of well-differentiated unresectable midgut NETs. Methods: Consensus statements were developed via RAND/UCLA Delphi process, which involved a diverse group of physician experts (e.g., by specialty, geography, practice) developing comprehensive clinical patient scenarios and rating the scenarios on the appropriateness of various medical therapies before and after a face-to-face meeting. Experts and moderator were blinded to funding source. Scenarios were rated on a 1-9 scale and were labeled as appropriate, inappropriate, or uncertain. Scenarios with >2 ratings in 1-3 and >2 in 7-9 range were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists (age: 38-63 years) were from the northeast, midwest, south, and west regions. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean 15.5 years (range: 6-33). Panelists rated 202 scenarios. The proportion for which there was disagreement decreased from 11.7% (23 scenarios) before the meeting to 4.5% (9) after. Post-meeting, 49% (99 scenarios) were rated inappropriate, 29.7% (60) were uncertain, and 16.8% (34) were appropriate. Consensus statements from the scenarios included: 1) it is appropriate to use somatostatin analogs (SA) as 1st-line therapy in all patients, 2) it is appropriate to increase the dose/frequency of octreotide-LAR as 2nd-line therapy in patients with uncontrolled symptoms up to 60 mg every 4 weeks or up to 40 mg every 3 or 4 weeks for refractory carcinoid syndrome. Other treatment options may also be appropriate in 2nd-line. Conclusions: Treatment consensus obtained in this study is concordant with NCCN recommendations. The Delphi process allowed quantification of ratings in a systematic and reliable way while improving consensus in a group of physicians on the appropriateness of medical therapies in midgut NETs.
Gender as a factor associated with poor compliance in the treatment of metastatic renal cell carcinoma with VEGF-targeted therapy in Japanese patients.
Authors: Uemura Motohide , Tsujimura Akira , Kawashima Atsunari , Arai Yasuyuki , Tanigawa Go , Nin Mikio , Yasunaga Yutaka , Yoshioka Toshiaki , Nomura Hironori , Mukai Masatoshi , Fukuda Satoko , Oka Daizo , Nishimura Kenji , Yoshida Takahiro , Satou Mototaka , Hatano Koji , Nakai Yasutomo , Takayama Hitoshi , Nishimura Kazuo , Nonomura Norio 
Published: March 2020

e15065 Background: Sorafenib and Sunitinib are multikinase inhibitors used as first -or second-line treatment of metastaic renal cell carcinoma (mRCC). In a multi-institutional study with Japanese patients, we found that good compliance(one month relative dose intensity ≥50% in Sorafenib (Eur J Can 2011) and continuing therapy for more than one course in Sunitinib) was the most important factor in improving progression free survival (PFS) time. Because PFS has been reported to be a predictor of overall survival(OS) (Heng et al. Cancer 2011), we hypothesized that good compliance with these drugs was the most important factor contributing to positive outcomes. Here, we analyzed the clinical results in our series and determined the factors most closely associated with poor compliance of VEGF-targeted therapy. Methods: We retrospectively analyzed a database comprising 143 patients treated by Sorafenib and 69 patients by Sunitinib as both first- and second-line therapy for mRCC. Cohorts were defined by gender, eGFR, Eastern Cooperative Oncology Group Performance Status (ECOG PS), T stage, prior nephrectomy, lactate dehydrogenase level, anemia, hypercalcemia, initial oral dose, and compliance. We used the Cox regression model and logistic regression analysis to calculate the hazard ratio (HR) for univariate and multivariate analysis. Results: Median PFS and OS were 9.0 months and 30.3 months, respectively. Median PFS time of the patients with good compliance (9.1months, 95%CI; 7.1-11.0) was much better than that of the patients with poor compliance (3.0 months, 95%CI; 2.5-3.5) (p<0.001), although there was no significant difference in median OS time. In multivariate analysis, good compliance together with PS and anemia became the prognostic factor to predict superior PFS. In clinical items, female (HR; 3.513, 95%CI 1.567-7.871, p=0.002), poor ECOG PS (p=0.022) and renal impairment (p=0.026) were significantly associated with poor compliance in multivariate analysis. Conclusions: We need to improve drug compliance of femalepatients and patients with poor ECOG PS and renal impairment receiving sorafenib or sunitinib for the treatment of mRCC.
Severe zoledronic acid (ZOL)-associated hypophosphatemia and prognosis in patients with castration-resistant prostate cancer (CRPC).
Authors: Warr Julia , Yam David , VanDraanen Leah , Goodall Shannon , Giotis Angie , Pasetka Mark , Isogai Pierre K , Mamedov Alexandre , DeAngelis Carlo , Emmenegger Urban 
Published: March 2020

e15180 Background: ZOL therapy is associated with severe (i.e., grade ≥ 3) hypocalcemia and hypophosphatemia in a subset of patients with metastatic CRPC. However, as opposed to the distinct clinical picture of hypocalcemia, the symptoms of hypophosphatemia are less pathognomonic. Furthermore, serum phosphate abnormalities are not regularly reported. Methods: To characterize the rate and clinical impact of severe hypophosphatemia in CRPC patients undergoing ZOL therapy, we identified CRPC patients receiving at least 3 doses of ZOL at our Centre between 01/2004 and 03/2011. Patient demographics, disease characteristics and laboratory parameters were extracted using the Oncology Symptom Control and Information Resource database, and by means of manual chart review. Results: 12 of 90 evaluable patients developed grade ≥ 3 hypophosphatemia (nadir) after 364±299 days (mean±SD) following the first dose of ZOL. While only one patient presented with concomitant severe hypocalcemia, the hypophosphatemia nadir coincided with rising PSA readings in 9 out of 11 informative patients. Severe ZOL-associated hypophosphatemia identified patients with worse outcome (median overall survival from time of CRPC diagnosis to death 685 days) compared to patients without documented hypophosphatemia (907 days, HR 0.52, p=0.049; n=42), or patients with grade 1-2 hypophosphatemia (1035 days, HR 0.44, p=0.016; n=36). Otherwise, the prognostic nomogram developed by Armstrong et al appears not to capture the poor prognosis of patients with severe ZOL-associated hypophosphatemia. Conclusions: Grade 3-4 hypophosphatemia occurs in about 15% of CRPC patients undergoing ZOL therapy and is associated with worse prognosis when compared to patients with absent or mild hypophosphatemia. The latter is usually transient and likely related to increased parathyroid hormone levels due to calcium decreases as a consequence of bisphosphonate therapy. On the other hand, the distinct clinical behavior of CRPC presenting with ZOL-associated severe hypophosphatemia suggests that secreted tumor-associated factors such as fibroblast growth factor 23 may contribute to this phenomenon.