bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized open-label phase II study evaluating antitumor activity of the survivin antisense oligonucleotide LY2181308 (LY) in combination with docetaxel (DO) for second-line treatment of patients with non-small cell lung cancer (NSCLC) using change in tumor size (CTS).
Authors: Talbot Denis Charles , Blackhall Fiona Helen , Kowalski Dariusz , Ramlau Rodryg , Bepler Gerold , Grossi Francesco , Lerchenmuller Christian A. , Pinder Mary Colleen , Mezger Jorg , Danson Sarah , Callies Sophie , Andre Valerie , Das Mayukh , Lahn Michael M. F. , Natale Ronald B. 
Published: March 2020

8051^ Background: Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO+LY compared with DO alone. Methods: Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N=180) 2:1 to receive DO+LY (LY 750 mg IV loading ×3, Q1W maintenance) or DO alone (75 mg/m2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. Results: 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY+DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84–3.65) with LY+DO and 3.35 mo (95% CI, 2.69–4.57) with DO (log-rank p=0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30–0.68, p=0.0001). Median OS was 7.9 mo (90% CI, 6.6–9.7) with LY+DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p=0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY+DO as was the PK profile. Conclusions: Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.
Prospective observational cohort study of second-line chemotherapy administration after first-line platinum-based chemotherapy for patients with advanced NSCLC in Japan (SAPPHIRE study).
Authors: Yoh Kiyotaka , Goto Yasushi , Naito Yoichi , Kishi Kazuma , Ohashi Yasuo , Kunitoh Hideo 
Published: March 2020

8058 Background: Maintenance therapy after first-line platinum-based chemotherapy (first-CT) is reported to be beneficial to patients with advanced non-small cell lung cancer (NSCLC). However, its impact on overall survival appears to be marginal or negligible, if those without maintenance receive active second-line chemotherapy (second-CT), which is initiated at disease progression. The purpose of this study is to investigate the proportion of second-CT administration after first-CT for patients with advanced NSCLC. Methods: From April 2010 to September 2011, 865 patients with advanced NSCLC who were initiated on first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to first-CT, whether or not they received second-CT, and if not, reasons for non-administration were recorded. This report describes from patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR. Results: A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of first-CT. Of all patients, 70% had adenocarcinoma, 20% had squamous cell carcinoma, and 10% were positive for the EGFR mutation. At this data cut off, 225 patients were excluded from the analysis due to disease progression and loss of follow-up during first-CT, and 194 (22%) patients received maintenance therapy after first-CT. Among the 508 patients who were followed up for at least 6 months, 131 patients (26%) could not receive second-CT; the reasons were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); others, 18 (14%). Conclusions: Preliminary results of this large observational study in Japan suggested that around 20% of patients missed an opportunity to receive appropriate second-CT despite the follow-up of advanced NSCLC patients after first-CT. Further investigation is needed to elucidate the selection criteria of patients that may benefit the most from maintenance therapy, not second-CT at disease progression.
A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts).
Authors: Rizvi Naiyer A. , Antonia Scott J. , Chow Laura Quan Man , Brahmer Julie R. , Juergens Rosalyn A. , Borghaei Hossein , Shepherd Frances A. , Laurie Scott Andrew , Gerber David E. , Goldman Jonathan Wade , Shen Yun , Harbison Christopher , Alaparthy Suresh , Chen Allen C. , Gettinger Scott N. 
Published: March 2020

8072 Background: A phase I study ofnivolumab (a PD-1 receptor blocking Ab) demonstrated durable responses and a tolerable safety profile in NSCLC pts who failed ≥1 chemotherapy regimen. We report an interim analysis of a phase I study with nivolumab + PT-doublets in chemotherapy-naive advanced NSCLC pts. Methods: Stage IIIB/IV NSCLC pts were randomized by histology ≥9 wk prior to data lock (Dec 2012) to: A) nivolumab/gemcitabine/cisplatin; B) nivolumab/pemetrexed/cisplatin; or C) nivolumab/carboplatin/paclitaxel according to a phase I dose de-escalation design to assess the toxicities and incidence of DLTs in the first 6 wk of dosing. Nivolumab doses were started at 10 mg/kg IV Q3W and given until progression. PT-doublet was given for 4 cycles at standard dosing. At a tolerable dose, cohorts were expanded up to 20 pts. Results: 43 pts were treated with nivolumab + PT-doublet: Arm A, n=12 squamous (sq); Arm B, n=15 (non-sq); and Arm C, n=16 (3 sq + 13 non-sq). No DLTs were seen across arms. Gr 3-4 regimen-related AEs were 49% across arms, and 25%, 47%, and 69% for Arms A, B, and C, respectively. Select Gr 3-4 toxicities reported included: pneumonitis, rash, nephritis, and colitis (Table). 3 pts had Gr 3 pneumonitis and were addressed with management algorithms (dose discontinuation and immune-modulating therapies). 2 pts fully resolved, however 1 resolved pt subsequently died from Aspergillus pneumonia. 1 pt died of disease progression with unresolved pneumonitis (autopsy confirmed). Total/Confirmed ORRs (RECIST 1.1) were 43/33%, 40/33%, and 31/31% in Arms A, B, and C, respectively. Conclusions: No DLTs were seen with 10 mg/kg nivolumab combined with PT-doublets; maintenance treatment is ongoing. Similar to monotherapy, select nivolumab related toxicities can be addressed with management algorithms. Safety, durability, and confirmation of responses will be updated based on a 2013 data analysis, including a 5 mg/kg nivolumab dose cohort. Clinical trial information: NCT01454102. [Table: see text]
Phase I study of ridaforolimus with cetuximab for patients with advanced non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck cancer.
Authors: Taber Angela Marie , Khurshid Humera , Perez Kimberly , Birnbaum Ariel E. , Olszewski Adam J. , Luppe Denise , Jean Maureen , Rosati Kayla , Safran Howard 
Published: March 2020

8075 Background: mTOR inhibition may overcome PI3K/AKT pathway mediated resistance to anti-EGFR therapy. We performed a phase I study to determine the dose-limiting toxicity (DLT) of ridaforolimus, an investigational oral mTOR inhibitor, in combination with the anti-EGFR antibody cetuximab. Methods: Patients with advanced NSCLC, colorectal cancer, and head and neck cancer that progressed after at least 1 prior regimen for metastatic disease were eligible. ECOG performance status 0-1. Patients with previously treated brain metastases that were stable for >3 months were eligible. Wild-type K-RAS was required in colon cancer. All patients received cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weekly. Three dose levels of ridaforolimus were planned: 20mg, 30mg, and 40mg daily, 5 days each week, on a 28-day cycle. Results: 12 patients were entered with NSCLC (n=7), colon cancer (n=4), and head and neck cancer (n=1). The median age was 58 (42-69). The median number of prior regimens for metastatic disease, by disease type, was NSCLC (n=3), colorectal (n=4), head & neck (n=4). Three patients completed the first dose level without DLT. Two of 3 patients at dose level 2 had dose-limiting mucositis. The first dose level was then expanded with six additional patients with NSCLC without any further dose-limiting toxicities. The recommended phase II dose of ridaforolimus is 20 mg daily, 5 days a week, in combination with cetuximab. Response and prolonged stable disease was demonstrated in NSCLC. Conclusions: The DLT of the combination of ridaforolimus and cetuximab is mucositis. The activity observed in heavily pretreated patients with NSCLC suggests that the combination of an mTOR inhibitor with an EGFR antibody merits further investigation in NSCLC. Clinical trial information: NCT01212627.
Progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation.
Authors: Yoshida Tatsuya , Yoh Kiyotaka , Goto Koichi , Matsumoto Shingo , Umemura Shigeki , Niho Seiji , Ohmatsu Hironobu , Ohe Yuichiro 
Published: March 2020

8078 Background: The progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation are clinically heterogeneous. The aim of this study is to evaluate progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation. Methods: From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring EGFR mutation were treated with EGFR-TKIs (erlotinib or gefitinib) at our institution. Among these patients, 104 patients who experienced RECIST PD assessed by radiologic findings were retrospectively evaluated for initial response on EGFR-TKIs, progression sites, focus of progression (solitary lesion or multiple lesions), patients status at RECIST PD, and post progression survival (PPS) from RECIST PD. Results: In 104 patients, 96 (92%) patients had EGFR major mutation (Exon 19 deletion and L858R), and 49 (47%) received EGFR-TKIs as first-line. The overall response rate and median progression free survival on EGFR-TKIs was 69 % and 8.2 months. At the time of RECIST PD, 44 (42%) patients had symptomatic, and 60 (58%) had asymptomatic. The progression sites were isolated CNS in 17 (16%) patients, isolated bone in 7 (7%), isolated pulmonary in 13 (12%), systemic in 67 (65%) patients. In the focus of progression, 24 (23%) patients have solitary lesion, and 80 (77%) have multiple lesions. After RECIST PD, 40 (38%) patients continued EGFR-TKIs, 25 (24%) were switched to cytotoxic agents, and 39 (38%) had best supportive care. 10 (10%) patients received local radiotherapy for isolated progression site (brain 6; bone 3; lung 1) and 8 of these patients continued EGFR-TKIs. The median PPS from RECIST PD was 10.6 months. Multivariate analysis identified that asymptomatic or solitary progression lesion at RECIST PD were associated with significantly longer PPS (asymptomatic: HR 0.34, 95% CI 0.19-0.58, P<0.001; solitary progression lesion: HR 0.39, 95% CI 0.16-83, P=0.013). Conclusions: The progression patterns at RECIST PD during EGFR-TKIs in advanced NSCLC patients harboring EGFR mutation have widely diversity. Further investigation for association between progression patterns at RECIST PD and clinical outcome after RECIST PD is warranted.
Phase I study of peptide vaccine targeting indeolamine 2,3 dioxygenase in metastatic lung cancer patients.
Authors: Iversen Trine Zeeberg , Engell-Noerregaard Lotte , Ellebaek Eva , Andersen Rikke , Larsen Stine Kiaer , Bjoern Jon , Jonassen Merete , Kalbacher Hubert , Zeyher Claus , Gouttefangeas Cecile , Thomsen Inger Birthe Moerk , Holm Bente , Mellemgaard Anders , Straten Per thor , Andersen Mads Hald , Svane Inge Marie 
Published: March 2020

8084 Background: To investigate the targeting of indeolamine 2,3 dioxygenase (IDO) enzyme by a synthetic peptide vaccine for patients with metastatic non small-cell lung cancer (NSCLC). Methods: We treated15 HLA-A2 positive patients with stage III-IV NSCLC and disease stabilization (SD) after standard chemotherapy. Patients were treated every second week (induction) for three months, and thereafter monthly until progression (maintenance) with imiquimod ointment and vaccine (100 µg IDO5 peptide sequence ALLEIASCL mixed with 900 µL montanide) administered subcutaneously. Primary end point was toxicity. Clinical benefit and immune monitoring were assessed. Results: Patient characteristics: mean age (63, range 51-71), sex (F=8,M=7), PS(0=9,1=6), histology (adenocarcinoma=93%), previously anti-neoplastic treatments (1st line=100%, 2nd =40% and 3rd=27% of patients). No grade 3-4 CTCAE toxicity was observed. Median PFS was 5.2 months and median OS 2.1 years. Long-lasting disease stabilization (SD≥8.5 months) was demonstrated in 7 patients (47%). Patients demonstrated significant improved OS (P=0.02) when compared to the untreated group of excluded HLA-A2 negative NSCLC patients. IDO expression was frequently detected in tumour biopsies by immune-histochemistry staining. Immune induction of IDO specific CD8 T-cells were demonstrated by IFN-y Elispot and Tetramer staining. Immune correlates of T-lymphocyte subsets were performed by flow cytometry. HPLC analyses of Trp/Kyn ratio suggested stabilization or decrease of IDO activity in 11/15 (73%) of the patients. Conclusions: The vaccine was safe and well-tolerated with no grade 3/4 toxicity occurring. Long-lasting SD was seen in 47% of the patients demonstrating a median OS of 2.1 year. IHC demonstrated frequent IDO activity in NSCLC tumour biopsies, and blocking of IDO activity was indicated by Kyn/Trp ratio measurements. Clinical trial information: NCT01219348.
Overcoming barriers in incorporating evaluation of quality of life (QL) and symptoms by using the ePRO version of the LCSS (eLCSS-QL) in a large-scale multinational NSCLC trial (AP-QL Trial).
Authors: Thongprasert Sumitra , Gralla Richard J. , Hollen Patricia J , Kim Hoon-Kyo , Hsia Te-Chun , Yuankai Shi , Alexis Karenza M. , Kohn Nina , Lesser Martin 
Published: March 2020

8092 Background: Survival and QL improvements are primary treatment goals in advanced NSCLC. Few trials evaluate both of these major endpoints well: typically only a minority of patients (pts) have QL followed over time, preventing such data from assisting in key decisions concerning the effectiveness and value of treatment. To overcome barriers, we used a computer-assisted version of the validated LCSS measure and tested this prospectively in a large study. Prior trials indicated that the eLCSS-QL requires only 2 minutes to complete the pt version and is highly acceptable. Methods: 622 pts received initial docetaxel (D)-based chemo, at 65 sites in 9 Asian countries. 70% male; 65% adenocarcinoma; median: KPS = 90; ECOG = 1 (27% ECOG 0). Stages: IV (72%), IIIB (28%). 84% had > two major symptoms. 80% had combination chemo with cisplatin (52%) or carboplatin (28%). Computer skills were low in 73%. eLCSS-QL was completed every 3 weeks at the clinic. We also surveyed 98 physicians (MD) and nurses (RN) treating these pts regarding communication, usefulness and acceptability of the eLCSS-QL. Results: 97% of pts completed the eLCSS-QL at baseline; 90% completed follow-up evaluations. Over 90% found the eLCSS-QL easy to use, acceptable to complete at each visit; >80% reported increased awareness of symptoms; making it easier to speak with MDs / RNs. 1% refused eLCSS-QL completion. Of MDs/RNs: >90% found the eLCSS-QL easy to use and increased symptom awareness; >80% reported improved communication, enhanced satisfaction with the pt visit, and recommend its use. Nearly 90% of MDs reported they could identify benefit from chemo earlier; 76% would order fewer imaging tests and 80% said the eLCSS-QL could save time. Major response rate 37%; median survivals: 13.9 months (D + cisplatin), 12.7 months (D + carboplatin). Conclusions: Patients, MDs, RNs all found the eLCSS-QL to be highly acceptable and easy to use with 90% of pts doing repeated QL measures. This large prospective trial demonstrates the potential for QL / symptom evaluation to aid in decision making and to guide appropriate use of chemotherapy and imaging while enhancing staff and pt satisfaction.
Differential activity of afatinib (AFAT), cetuximab (CET), and erlotinib (E) in a patient-derived xenograft (PDX) model of acquired E resistance.
Authors: Mack Philip C. , Goodwin Neal , Holland William S. , Kelly Karen , Lara Primo , Gandara David R. 
Published: March 2020

8110 Background: The UC Davis - Jackson Labs Consortium has established a PDX resource of over 50 NSCLC models (12 EGFR mutant) for experimental therapeutics and personalized medicine, using the NSG mouse. Here we report on a unique PDX model, LG703, derived from a patient at time of acquired E resistance. This tumor harbors EGFR L858R with no T790M mutation, high MET and very high EGFR protein expression. The patient is in remission following treatment with AFAT-CET. In this model, we investigated the respective contribution of CET and AFAT relative to E on tumor growth and signal transduction. Methods: Individual mice implanted with LG703 tumor fragments were randomized to E (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. Changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting. Results: AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period; whereas E resulted in temporary growth delay. After cessation of treatment, E-treated mice progressed rapidly and AFAT-treated mice progressed within 2 weeks. Mice treated with CET or AFAT-CET remained in complete remission. At 6h, E and AFAT significantly (>70%) reduced EGFR phosphorylation as well as that of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K. At 24h, E-treated tumors had returned to baseline-like states for all factors, AFAT showed an intermediate response, and CET, alone or with AFAT, achieved the greatest inhibition of pEGFR with sustained inhibition of all downstream effectors. Conclusions: In the LG703 PDX model, CET and AFAT+CET resulted in CRs, mirroring the patient's response to similar therapy, associated with sustained inhibition of pEGFR and multiple downstream signaling factors. In contrast, E exhibited only temporary growth delay associated with transient inhibition of EGFR pathway factors. These experiments demonstrate the potential of this PDX resource to assess new therapeutic strategies in models representing individual patients. Supported by BJALCF.
Biomarker prediction of chemotherapy-related amenorrhea.
Authors: Ruddy Kathryn Jean , O'Neill Anne M. , Miller Kathy , Schneider Bryan P. , Baker Emily , Sparano Joseph A. , Dang Chau T. , Northfelt Donald W. , Sledge George W. 
Published: March 2020

9508 Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period <12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients </= 45 (43/63) and 97% of patients >45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p<0.01), were >45 (p<0.01), and had AMH </=0.11 (p<0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p=0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients </= 45 (33/52) and 100% (48/48) of patients >45. 18-month CRA was more likely in women >45 (p<0.01) and with AMH </=0.11 (p<0.01) pre-treatment. Bevacizumab (p=0.15) and hormonal tx (p=0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.