bluuebunny/crossref_metadata_2025 huggingface dataset:
CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab (Ipi) versus placebo in asymptomatic or minimally symptomatic patients (pts) with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).
Authors: Beer Tomasz M. , Logothetis Christopher , Sharma Padmanee , Loriot Yohann , Fizazi Karim , Bossi Alberto , Kwon Eugene D. , McHenry Brent , Gagnier Paul , Gerritsen Winald R.
Published: March 2020

TPS5093

Background: Globally, docetaxel remains the standard of care for metastatic CRPC; however, its use may be delayed until pts develop symptoms. The presence of infiltrating leukocytes in CRPC tumors suggests a natural antitumor immune response is occurring. This is supported by an overall survival (OS) benefit reported in men with asymptomatic or minimally symptomatic metastatic CRPC who received sipuleucel-T. Ipi, a monoclonal antibody that binds CTLA-4, augments antitumoral activity of cytotoxic immune cells. Ipi demonstrated OS benefit in two phase III trials for advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In phase I/II trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with a similar toxicity profile to that observed in melanoma. This global (149 sites in 24 countries) phase III study (ClinicalTrials.gov identifier: NCT01057810) evaluates Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The study is designed to detect a 9.3-month median difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo as induction therapy. Eligible pts will receive maintenance therapy of blinded study drug every 12 weeks. The accrual goal is 600 pts randomized. Clinical trial information: NCT01057810. [Table: see text] [Table: see text]
Randomized double-blind, comparative study of abiraterone acetate (AA) plus low-dose prednisone (P) plus androgen deprivation therapy (ADT) versus ADT alone in newly diagnosed, high-risk, metastatic hormone-naive prostate cancer (mHNPC).
Authors: Fizazi Karim , Larsen Julie S. , Matheny Shannon , Molina Arturo , Li Jinhui , Todd Mary Beth , Yu Margaret K. , Kheoh Thian San , Tran Namphuong
Published: March 2020

TPS5097

Background: Patients (pts) who initially present with metastatic prostate cancer (MPC) (up to 30% of men in Europe; 4% in US) typically progress to metastatic castration-resistant prostate cancer (mCRPC) with a poor prognosis. Prognostic factors impacting survival include high PSA concentration, high Gleason score, high volume of metastatic disease, and bone symptoms. AA decreases testosterone via CYP17 inhibition and is approved for treatment of mCRPC before and after docetaxel-based chemotherapy. Two recent reports (J Clin Oncol. 2012: 30 [suppl. abstr 4521 and 4556]) showed that AA + P in addition to ADT (LHRH agonist) in the neoadjuvant setting led to higher rates of undetectable PSA and complete pathologic response (cPR) or near-cPR in pts undergoing prostatectomy for high risk-localized prostate cancer than with ADT alone, suggesting a potential role for inhibiting extragonadal androgen synthesis prior to emergence of castration-resistance. Because of its benefit in mCRPC, as well as early activity in high risk-localized prostate cancer, AA is being evaluated in high risk mHNPC. Methods: Approximately 1,270 men with newly diagnosed (within 3 months of randomization) high risk mHNPC with at least 2 of 3 high risk factors (≥ 3 bone lesions, presence of visceral metastases or Gleason score ≥ 8) are being randomized to AA 1000 mg + P 5 mg daily + ADT or ADT alone. Pts are stratified by presence of visceral disease and ECOG PS (0-1 vs 2). Distant metastatic disease must be documented by positive bone scan or CT/MRI. ADT or orchiectomy within 3 mos of randomization is allowed. Continued use of anti-androgens after randomization is not allowed on study. The primary endpoint is overall survival. Secondary endpoints include radiographic PFS, time to next skeletal-related event, PSA progression, and subsequent therapy. Two interim analyses and a final analysis are planned. 300 sites from 36 countries will participate. As of February 4, 2013, one patient has entered screening. Clinical trial information: NCT01715285.
The Pacific trial: A randomized phase II study of OGX-427 in men with metastatic castration-resistant prostate cancer (mCRPC) and PSA progression while receiving abiraterone acetate (AA).
Authors: Chi Kim N. , Sweeney Christopher , Jacobs Cindy , Stewart Patricia S. , Hahn Noah M.
Published: March 2020

TPS5101

Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression and over-expressed in many cancers including prostate, bladder, lung, and breast. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a second-generation antisense oligonucleotide designed to inhibit Hsp27 expression with in vitro and in vivo efficacy that increases apoptosis, inhibits tumor growth, sensitizes cells to chemotherapy and inhibits AR activity (Cancer Res 2007;67(21):10455). A phase 2 study of OGX-427 in patients with mCRPC reported preliminary activity with 50% of patients having a ≥50% PSA decline during treatment (J Clin Oncol 30, 2012 (suppl; abstr 4514)). The purpose of this study was to evaluate the clinical activity of OGX-427 in patients with mCRPC progressing on AA. Methods: In this randomized, phase 2 study, 74 evaluable patients with mCRPC who are currently receiving AA and have PSA progression despite a prior response are randomized 1:1 to receive either OGX-427 (600 mg IV x 3 loading doses in week 1 followed by 1000 mg IV weekly) with AA or continuing AA alone. Additional eligibility criteria include: ECOG performance status ≤1, no evidence of radiographic progression, adequate liver/kidney/bone marrow function, and ≤1 prior chemotherapy for CRPC. Protocol therapy is continued until disease progression, unacceptable toxicity, or patient withdrawal. Eligible control arm patients may cross over to receive OGX-427 following disease progression. The primary objective of the study is to evaluate the proportion of patients progression-free at Day 60 post randomization. Secondary objectives include comparisons between arms of PSA and disease response, progression free survival, time to disease progression, serial serum levels of Hsp27, and circulating tumor cell enumeration. The study is designed to detect a 25% improvement in the primary endpoint (α = 0.2, β = 0.1). The study was initiated December, 2012. Clinical trial information: NCT01681433.
A phase I/II study of the vascular disrupting agent BNC105P in combination with gemcitabine-carboplatin in partially platinum-sensitive ovarian cancer patients in first or second relapse: An international collaborative group trial of ANZGOG and HOG.
Authors: Rischin Danny , Matei Daniela , Goh Jeffrey C. , Vaughan Michelle Margaret , Beale Philip James , Tenney Meaghan Elizabeth , Martyn Julie , Sommeijer Dirkje Willemien , Iglesias Jose Luis , Bibby David C. , Simpson Jeremy , Doolin Elizabeth E. , Williams Corinne E. , Stockler Martin R. ,   Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Published: March 2020

TPS5612

Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (<6 months vs 6 months or more), and first relapse vs. second relapse. Biomarker (tissue and blood-borne) sampling and PK analysis will also be undertaken. Clinical trial information: NCT01624493.
PARAGON: Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynecologic neoplasms: ANZGOG 0903.
Authors: Friedlander Michael , Sjoquist Katrin Marie , Sommeijer Dirkje Willemien , Bailey Lisa , Martyn Julie , Gillies Kim , Mileshkin Linda R. , O'Connel Rachel , Gebski Val , Vaughan Michelle Margaret , Blomfield Penny , Beale Philip James , Quinn Michael , Stockler Martin R. , Lombard Janine Margaret , Hadley Alison Maree , Amant Frederic , Edmondson Richard J ,   Australia New Zealand Gynaecological Oncology Group
Published: March 2020

TPS5614

Background: Many gynaecological cancers of different pathological type express estrogen and/or progesterone hormone receptors (ER/PR). Reports of tumour response and clinical benefit with hormonal therapies show variable rates of activity. There is a need to prospectively study the role of aromatase inhibitors in women with potentially hormone responsive recurrent gynaecological cancers to establish response rates, clinical benefit, quality of life (QoL) and identify predictors of response. Methods: PARAGON is phase II Gynecologic Cancer InterGroup trial lead by the Australia New Zealand Gynaecological Oncology Group, Cancer Research UK and the Belgian Gynaecological Oncology Group. The study is designed to facilitate research in rare tumours. The protocol allows postmenopausal women with recurrent gynaecological cancers to enrol into one of 7 subgroups; epithelial ovarian cancer (EOC) with only rising CA125 after first line chemotherapy, platinum resistant/refractory EOC, low grade EOC, endometrial carcinomas, endometrial stromal sarcomas, miscellaneous sarcomas and granulosa cell tumours and other sex cord stromal tumours. ER/PR positivity must be confirmed by immunohistochemistry. Each subgroup will enrol 25-50 patients with defined stopping rules based on response and reviewed by independent data monitoring committee (IDMC). Eligible patients receive 1 mg anastrozole daily until disease progression or unacceptable toxicity. Primary objective: clinical benefit (partial or complete response or stable disease). Secondary objectives: progression free survival, response duration, QoL, toxicity. Blood and tumour samples are being collected for translational studies and confirmation of ER/PR positivity. Recruitment commenced in 2011 in Australia, New Zealand and the United Kingdom. One hundred and fourteen of 350 planned patients have been enrolled to January 2013. In November 2012 IDMC recommended continuing recruitment to the EOC with rising Ca125 only and resistant/refractory subgroups based on review of activity outcomes for the first 25 patients. The trial will open in Belgium in April 2013. ACTRN12610000796088 Clinical trial information: 12610000796088.
Dovitinib as second-line therapy in patients with fibroblast growth factor receptor 2 (FGFR2)-mutated or non-mutated advanced and/or metastatic endometrial cancer (EC): A single-arm, multicenter, phase II study.
Authors: Konecny Gottfried E. , Finkler Neil , Garcia Agustin , Raspagliesi Francesco , Lopez Carolina Muriel , McCollum Michael , Rubio M Jesus , Squires Matthew , Pirotta Nicoletta , Upalawanna Allison , Yovine Alejandro Javier , Rocconi Rodney Paul
Published: March 2020

TPS5616

Background: Despite the use of combination chemotherapy and introduction of novel targeted agents, the prognosis for advanced and/or metastatic EC is challenging. The occurrence of somatic activating FGFR2 mutations in EC suggests an opportunity for testing FGFR inhibitors. Dovitnib (DOV) is a potent receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor and FGFR. The objective of the study is to investigate the efficacy and safety of DOV as second-line therapy in patients (pts) with advanced and/or metastatic EC. Methods: This multicenter, non-randomized, open label, single-arm, phase II study (NCT01379534) will enroll adult female pts (N~80) with either FGFR2 mutated (group 1) or non-mutated (group 2) histologically confirmed advanced and/or metastatic EC, who have documented radiological evidence of progressive disease (RECISTv1.1) after 1 prior line of chemotherapy, excluding adjuvant therapy. Eligible pts also need to have ≥1 measurable lesion (RECISTv1.1) and ECOG performance status ≤ 2. Pts will receive oral DOV of 500 mg/day, on a 5-days-on / 2-days-off dosing schedule until disease progression, unacceptable toxicity, death, or discontinuation due to any other reason. Primary endpoint is 18-week progression-free survival (PFS) rate (local review; RECIST v1.1) and secondary endpoints include overall response rate, disease control rate, duration of response, PFS, overall survival, safety, tolerability, pharmacokinetics, and pharmacodynamic effect of DOV on soluble plasma biomarker expression level. A 2-stage design with Bayesian interim monitoring (interim for futility analyses) will be used in each group. For stage 1, 20 pts will be enrolled into each group. If ≥ 8 of the first 20 pts with measurable disease at baseline in either group are progression-free after 18 weeks of treatment, 20 additional pts will be enrolled into that group in stage 2. Preliminary results for each group will be evaluated in the interim analysis. As of 20 January 2013, 43 pts have been enrolled (12 with and 31 without FGFR2 mutations). Clinical trial information: NCT01379534.
Pharmacodynamic study of neoadjuvant vemurafenib (VEM) in patients (pts) with BRAF mutated, locally advanced papillary thyroid cancer (PTC).
Authors: Cabanillas Maria E. , Holsinger F. Christopher , Sturgis Erich M. , Habra Mouhammed Amir , Davies Michael A. , Munsell Mark F. , French Jena , Busaidy Naifa , Hu Mimi I-Nan , Sherman Steven I.
Published: March 2020

TPS6100

Background: BRAF mutations are found in 40% of pts with newly diagnosed PTC but much more prevalent in recurrent PTC, ranging from 78-86%, suggesting they play an active role in tumor progression. Activating mutations in BRAF result in constitutive activation of MEK and subsequently ERK. ERK mediates activation of nuclear transcription factors coordinating expression of genes involved in proliferation and survival of malignant cells. PTC usually has an excellent prognosis, especially in younger pts and in pts who respond to the only effective treatment: surgery followed by radioactive iodine (RAI). However, more advanced stage disease at diagnosis, older age, and lack of RAI avidity are associated with a high rate of recurrence and distant metastasis, imparting a worse overall survival. Long-term outcomes depend highly on initial surgery outcome. Pts at highest risk of recurrence and death are those with gross residual disease after surgery and macroscopic tumor invasion. VEM is an inhibitor of the activated form of the BRAF serine-threonine kinase enzyme. The drug is FDA approved for the treatment of advanced melanoma and is currently being studied in a phase 2 trial in metastatic BRAF-mutated PTC. This is a neoadjuvant trial to determine if pharmacodynamic changes in the tumor correlate with response to drug. Methods: Pts with primary or recurrent BRAF mutated PTC who are planned for surgical resection are eligible. Pts will undergo baseline core biopsy prior to starting VEM 960mg bid. After 56 days of treatment they will undergo surgery and post-treatment specimen will be collected. Pts with widely metastatic PTC may continue VEM. The primary endpoint is to determine whether changes in ERK phosphorylation responses after treatment with VEM correlate with clinical response at day 56 in pts with locally advanced, BRAF mutated PTC. Secondary endpoints include assessments of safety of neoadjuvant VEM, response by RECIST, rate of surgical complications, persistent disease at the surgical site at 1 year, and mechanisms of resistance to VEM. The trial began enrolling pts in December 2012, with a total of 22 pts planned. This trial has no sponsor. Clinical trial information: NCT01709292.
ADAPT: Adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer.
Authors: Harbeck Nadia , Hofmann Daniel , Gluz Oleg , Kates Ronald E. , Kümmel Sherko , Nuding Benno , Rezai Mahdi , Kusche Manfred , Schumacher Claudia , Nitz Ulrike
Published: March 2020

TPS655^

Background: Indication of (neo-)adjuvant therapy is based on risk profile, hormone receptor and HER2 status at time of primary diagnosis. Data indicate dynamic proliferation changes after short-term induction therapy are superior to static initial biopsy results in predicting outcome and tumor response following neoadjuvant CTx in distinct BC subtypes. First generation trials such as TAILORx, MINDACT, NNBC-3, WSG planB utilize information of new prognostic/predictive tests to reduce overtreatment by CTx. Results still pending. ADAPT is a second generation trial addressing individualization of adjuvant decision-making in early BC by utilizing optimized pre-therapeutic biomarker information and early biomarker changes in a second core biopsy after 3-week subtype specific induction therapy. It aims at reducing over-/undertreatment in luminal tumors and optimizing therapy in HER2+ (T-DM1, pertuzumab) / TNBC (nab-paclitaxel + platinum/gemcitabine). Methods: Design: ADAPT combines static prognosis assessment by conventional markers (nodal status) and Recurrence Score (HR+) with dynamic measurement of proliferation changes after a short 3-week induction therapy, using the baseline diagnostic and repeat core biopsy following induction. ADAPT is a prospective, multi-center, controlled, non-blinded, randomized phase II/III trial, comprising an umbrella trial and 4 sub-trials (HR+/HER2-, HR+/HER2+, HR-/HER2+, TNBC). Eligibility criteria: Pre-/postmenopausal women with histologically confirmed unilateral primary invasive BC. Pts requiring CTx/targeted therapy with no contraindications. Statistics: Assumption across sub-protocols: CTx spared in 1120 HR+/HER2-, pCR achieved in 170 HER2+/TNBC pts. Outcome of good-proliferation responders/pCR pts will be compared to reference group (n=640 HR+/HER2- pts: low RS, no CTx, 94% 5yr survival). One-sided test of non-inferiority (3.2% margin, 90.8%) with alpha=0.05 will have 80% power. Present/target accrual:By 01/2013: 16/35 sites initiated. ADAPT HR+/HER2-: 161/4000 pts recruited. ADAPT HER2+/HR+: 9/380 pts recruited. ADAPT HER2+/HR- or TNBC: start of recruitment planned for Q2 2013. Clinical trial information: NCT01781338.
A phase II, dose-optimization trial of autologous T cells genetically engineered to express anti-CD19 chimeric antigen receptor (CART-19) in patients with relapsed or refractory (r/r) CD19+ chronic lymphocytic leukemia (CLL).
Authors: Porter David L. , Frey Noelle V. , Loren Alison W. , Levine Bruce , Kalos Michael , McConville Holly , Gilmore Joan , Chew Anne , Shen Angela , So Charlene , Sharr Michele , Wood Patricia Ann , June Carl H.
Published: March 2020

TPS7132

Background: The poor prognosis and lack of effective treatment options for patients with r/r CLL highlight the need for novel therapies in this setting. CD19 is a promising anticancer target because it is broadly expressed on normal and malignant B cells through several stages of maturation but absent on pluripotent stem cells. CART-19 (CTL019) therapy involves adoptive transfer of autologous T cells genetically modified via lentiviral transduction to express chimeric antigen receptors (CAR) designed to target CD19+ cells. CART-19 cells express a CD19 antigen recognition domain combined with intracellular signaling domains, CD137 (4-1BB) and CD3-zeta, which mediate cytolytic T-cell activity. In patients with r/r CLL, CART-19 therapy showed potent antileukemic activity with long-term persistence of transduced cells at doses from 1.4 × 107 to 1.1 × 109 CART-19 cells. As of August 2012, 3 of 8 evaluable CLL patients achieved CR (two > 24 months and one > 5 months) and remain in CR with detectable CART-19 cells. Two patients had PR lasting 3 and 5 months, and 3 patients did not respond (Porter et al. NEJM. 2011; Kalos et al. Sci Transl Med. 2011; Porter et al. ASH 2012). Here, we describe a study to determine the optimal dose of CART-19 cells (NCT01747486). Methods: Adults with relapsed or persistent CLL or SLL after ≥ 2 previous therapies will undergo leukapheresis to obtain T cells, which will be stimulated, expanded, and lentivirus transduced ex vivo to express the CD19/4-1BB/CD3-zeta CAR. Patients will undergo lymphodepletion chemotherapy prior to infusion of CART-19 cells. In stage I of the II-stage trial, 30 patients will be randomized 1:1 and receive either 1-5 × 108 or 1-5 × 107 CART-19 T cells. The optimal dose in stage I will be selected based on clinical responses, feasibility, and tolerability. In stage II, 8 additional patients will be enrolled into the selected dose cohort. Study objectives are to determine the efficacy (CR rate within 3 months) and safety (CTCAE v 4.0) of each dose, in vivo CART-19 expansion, and manufacturing feasibility. Three patients have been enrolled as of January 2013. Clinical trial information: NCT01747486.
A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia (CLL).
Authors: Eradat Herbert Aaron , Coutre Steven E. , Barrientos Jacqueline Claudia , Rai Kanti Roop , Farber Charles Michael , Hillmen Peter , Sharman Jeff Porter , Ghia Paolo , Coiffier Bertrand , Walewski Jan Andrzej , Berneman Zwi N. , O'Brien Susan Mary , Brown Jennifer R. , Peterman Sissy , Dansey Roger D. , Jahn Thomas Michael , Cramer Paula , Hallek Michael J.
Published: March 2020

TPS7133

Background: PI3K-delta is critical for the activation, proliferation and survival of B cells and plays a role in homing and retention of B cells in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and alters trafficking of malignant B cells in lymphoid tissues (Lannutti, 2011). Phase 1 trials demonstrated that idelalisib is highly active in heavily pretreated pts with CLL as a single agent or in combination with rituximab (R), bendamustine (B), or BR: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Coutre et al, 2012; Sharman et al, 2011). Methods: Study will enroll 390 pts with previously treated CLL who have measurable lymphadenopathy, have received prior therapy containing a purine analog or B and an anti-CD20 monoclonal antibody, are not refractory to B, have experienced CLL progression within 36 months from the completion of the last prior therapy, and are currently sufficiently fit to receive cytotoxic therapy. Pts are randomized in a 1:1 ratio to Arm A or B. On Arm A, subjects receive idelalisib continuously at 150 mg BID + R at 375 mg/m2 (1st dose) and then 500 mg/m2 every 4 weeks for 6 cycles + B at 70 mg/m2 on Days 1 and 2 of each 4-week cycle for 6 cycles. On Arm B, subjects receive placebo instead of idelalisib. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set. The study was initiated in June 2012 and a data monitoring committee has begun regular review of data. Clinical trial information: NCT01569295.
A phase II single-arm study of LDK378 in patients with ALK-activated (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ).
Authors: Shaw Alice Tsang , Mok Tony , Spigel David R. , Nishio Makoto , Felip Enriqueta , Tan Daniel Shao-Weng , Garcia-Campelo M. Rosario , Groen Harry J.M. , Dakhil Shaker R. , Schaefer Eric Scott , Farrell Nicholas John , Blakesley Rick E. , Weir Alexander , Ristic Mirta , Selvaggi Giovanni , Scagliotti Giorgio
Published: March 2020

TPS8119

Background: NSCLC harboring anaplastic lymphoma kinase (ALK) gene rearrangements (2–8% of cases) are sensitive to CRZ, the only approved ALK inhibitor, but invariably develop resistance. There are currently no standard ALK-targeted treatments for CRZ-resistant ALK+ NSCLC. LDK378 is a novel, oral ALK inhibitor with 20-fold greater potency than CRZ in enzymatic assays. In an ongoing phase I trial, LDK378 has demonstrated substantial clinical activity in patients (pts) with ALK+ NSCLC whose disease has failed CRZ. At a dose ≥400 mg (45 pts), the overall response rate (ORR) was 80%, with 47% confirmed responses (data cutoff August 31, 2012). Nausea, vomiting, diarrhea and fatigue were the main toxicities. The recommended phase II dose is 750 mg daily. Methods: This phase II multicenter, open label, single-arm study (CLDK378A2201) is designed to evaluate the efficacy and safety of oral LDK378 750 mg once-daily in pts with ALK+ (by FDA-approved FISH test) advanced NSCLC. Pts must have received cytotoxic chemotherapy (1–3 lines, including 1 platinum doublet) and progressed on CRZ as the last therapy prior to study entry. Pts with ECOG PS 0–2 and stable CNS metastases are eligible. LDK378 may be continued beyond RECIST-defined PD if there is evidence of clinical benefit. The primary objective is to assess the antitumor activity of LDK378 in terms of ORR by investigator assessment (using RECIST v1.1). Secondary/exploratory objectives include evaluating response endpoints (duration of response, time to response and ORR by independent radiological review), PFS, OS, safety, PK, and impact on patient-reported outcomes. The primary analysis will occur when all pts have completed 6 cycles or discontinued treatment earlier. The study design (137 pts) provides 90% power to test a null hypothesis of ORR ≤25% vs. a target ORR of ≥38%: if ≥45 responses are observed (estimated ORR 33%), the null hypothesis will be rejected at a one-sided significance level of 0.025. The study is recruiting in 67 sites from 14 countries across Europe, Asia and North America. As of February 5, 2013, 7 pts have been enrolled. ClinicalTrials.gov identifier NCT01685060. Clinical trial information: NCT01685060.
A phase III comparative study of nivolumab (anti-PD-1; BMS-963558; ONO-4538) versus docetaxel in patients (pts) with previously treated advanced/metastatic nonsquamous non-small-cell lung cancer (NSCLC).
Authors: Gettinger Scott N. , Brahmer Julie R. , Rizvi Naiyer A. , Ready Neal , Chow Laura Quan Man , Antonia Scott J. , Buyse Marc E. , Jassem Jacek , Finckenstein Friedrich Graf , Crinò Lucio , Lynch Thomas James
Published: March 2020

TPS8121

Background: Lung cancer is the leading cause of cancer mortality globally. Non-squamous NSCLC represents up to 75% of NSCLC cases with most pts diagnosed with advanced disease, which progresses rapidly following failure of 1st-line platinum-based doublet (Pt-doublet) chemotherapy. Benefit from current therapies has reached a plateau with median overall survival (OS) for late stage NSCLC pts of 10-12 months. Standard 2nd-line therapy (single-agent chemotherapy; eg. docetaxel) results in OS of 8 months. Expression of programmed death-1 (PD-1), an immune checkpoint receptor that negatively regulates T-cell activation, is associated with poor prognosis in NSCLC. Nivolumab, a PD-1 receptor blocking antibody, prevents activation of PD-1 by its known ligands, PD-L1 and PD-L2, and demonstrated durable antitumor activity in NSCLC pts in a phase 1 study (Topalian ST, et al. N Engl J Med 2012). We present a phase III study comparing OS benefit of nivolumab vs docetaxel in pts with metastatic/recurrent non-squamous NSCLC. Methods: In this study, 574 pts will be randomized 1:1 to receive nivolumab 3 mg/kg IV q 2 weeks (wks) or docetaxel 75 mg/m2 q 3 wks until disease progression or unacceptable toxicity. Pts will include those having progressed during/after Pt-doublet ± bevacizumab (bev) for advanced disease as well as pts with EGFR-mutant or ALK-rearranged NSCLC who have progressed following treatment with a tyrosine kinase inhibitor (TKI) and a Pt-doublet ± bev. Prior maintenance therapy with erlotinib, pemetrexed and/or bev is allowed. Pts will be stratified by prior use of maintenance therapy and receipt of 1 vs 2 (Pt doublet and TKI) prior lines of therapy. Response will be assessed (modified RECIST 1.1) at 9 wks following treatment initiation and every 6 wks thereafter until disease progression. The primary objective is to compare the OS of nivolumab vs docetaxel treated pts. Secondary objectives include comparison of objective response rates, progression-free survival and disease related symptom progression, and evaluation of clinical benefit of nivolumab vs docetaxel in PD-L1+ vs PD-L1- tumor subgroups. Clinical trial information: NCT01673867.
AHL 2011: A Lysa randomized phase III study of a treatment driven by early PET response compared to a standard treatment in patients with Ann Arbor stage III-IV or high-risk IIB Hodgkin lymphoma.
Authors: Casasnovas Rene-Olivier , Meignan Michel , Reman Oumedaly , Gaillard Isabelle , Stamatoullas Aspasia , Brice Pauline , Salles Gilles A. , Bouabdallah Reda , Bologna Serge , Nicolas-Virelizier Emmanuelle , Morschhauser Franck , Janvier Maud , Andre Marc , Berriolo-Riedinger Alina , Traverse-Glehen Alexandra , Edeline Veronique , Dartigues Peggy , Parrens Marie , Mounier Nicolas , Ferme Christophe
Published: March 2020

TPS8615

Background: ABVD is the most widely chemotherapy regimen used as standard treatment of advanced Hodgkin lymphoma (HL). The escalated BEACOPP (BEAesc) regimen which delivers more drugs at higher dose intensity was shown to improve patient’s PFS but not OS when compared to ABVD (Federico M, 2009; Viviani S, 2011; Carde P, 2012). The better efficiency of BEAesc is associated to a marked immediate hematologic toxicity and a higher risk of secondary myelodysplasia/leukemia. Also, the gonadal toxicity which is a real concern in young women, is quite higher when using BEAesc. So, to better manage HL treatment we need to identify early responding patients able to benefit from a strategy of dose intensity decrease after upfront BEAesc, without impairing the disease control. PET performed after 2 cycles of chemotherapy (PET2) might identify such a population suitable for receiving ABVD after 2 cycles of upfront BEAesc, and was implemented in the present study. Methods: The AHL 2011 trial (NCT01358747) was designed to test in 16 to 60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 cycles of BEACOPPesc, delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEAesc for PET2 positive patients, compared to a treatment not monitored by PET, delivering the best BEAesc schedule consisting in 6 cycles of this regimen (Engert A, 2012). A baseline PET is mandatory before treatment and PET2 are centrally reviewed within 48 hours and interpreted according to Deauville criteria. The allocation of treatment in the experimental arm is based on the PET2 central review result. PFS is the primary endpoint of the study with an hypothesis of non-inferiority of the experimental arm with a margin of 10% (85% 5y-PFS in the control arm vs >75% in the experimental arm). With a 6-year of accrual period, inclusion of 405 patients in each arm would have 80% power to detect a HR of 1.77 using a one-sided log rank test with significance level of 0.025. The trial started in May 2011 and to date, 385 patients have been enrolled. The DSMC reviewed the trial in November 2012 and suggested that the trial continue as planned. Clinical trial information: NCT01358747.
A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL).
Authors: Leonard John , Zinzani Pier Luigi , Jurczak Wojciech , Rummel Mathias J. , Salles Gilles A. , Kimby Eva , Arkenau Hendrik-Tobias , Davies Andrew John , Johnson David Michael , Evans Shelley , Dansey Roger D. , Godfrey Wayne R. , Kahl Brad S.
Published: March 2020

TPS8617

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase 1 trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with acceptable safety profile (de Vos et al, 2011). Methods: 375 pts with previously treated iNHL, who have measurable lymphadenopathy, have received prior anti-CD20-antibody-containing therapy, and who have iNHL that is not refractory to rituximab (R) are randomized in a 2:1 ratio into Arm A or Arm B. In Arm A, pts receive idelalisib at 150 mg BID continuously + R at 375 mg/m2 (weekly x 4 then every 8 weeks x 4). In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (<18 months vs ≥18 months). The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012 (NCT01732913). Clinical trial information: NCT01732913.
Apolipoprotein A-IV Enhances Fatty Acid Uptake by Adipose Tissues of Male Mice via Sympathetic Activation
Authors: Zhu Qi , Weng Jonathan , Shen Minqian , Fish Jace , Shen Zhujun , Coschigano Karen T , Davidson W Sean , Tso Patrick , Shi Haifei , Lo Chunmin C
Published: March 2020

Apolipoprotein A-IV (ApoA-IV) synthesized by the gut regulates lipid metabolism. Sympathetic innervation of adipose tissues also controls lipid metabolism. We hypothesized that ApoA-IV required sympathetic innervation to increase fatty acid (FA) uptake by adipose tissues and brown adipose tissue (BAT) thermogenesis. After 3 weeks feeding of either a standard chow diet or a high-fat diet (HFD), mice with unilateral denervation of adipose tissues received intraperitoneal administration of recombinant ApoA-IV protein and intravenous infusion of lipid mixture with radioactive triolein. In chow-fed mice, ApoA-IV administration increased FA uptake by intact BAT but not the contralateral denervated BAT or intact white adipose tissue (WAT). Immunoblots showed that, in chow-fed mice, ApoA-IV increased expression of lipoprotein lipase and tyrosine hydroxylase in both intact BAT and inguinal WAT (IWAT), while ApoA-IV enhanced protein levels of β3 adrenergic receptor, adipose triglyceride lipase, and uncoupling protein 1 in the intact BAT only. In HFD-fed mice, ApoA-IV elevated FA uptake by intact epididymal WAT (EWAT) but not intact BAT or IWAT. ApoA-IV increased sympathetic activity assessed by norepinephrine turnover (NETO) rate in BAT and EWAT of chow-fed mice, whereas it elevated NETO only in EWAT of HFD-fed mice. These observations suggest that, in chow-fed mice, ApoA-IV activates sympathetic activity of BAT and increases FA uptake by BAT via innervation, while in HFD-fed mice, ApoA-IV stimulates sympathetic activity of EWAT to shunt FAs into the EWAT.
When Measurements Matter: Poverty, Wealth, and the Politics of Inequality in the United States
Authors: O’Connor Alice
Published: March 2020

This essay explores two critical moments in the recent history of US inequality, when economic measures drew attention to gaping disparities in the American political economy: the early 1960s, when popularized social statistical reporting led to the “discovery” of, and declaration of “war” on, poverty; and the 2010s, when the “1 percent” became a potent symbol of the increasingly extreme concentration of wealth. Despite pronounced differences, both moments reveal how even the most dramatic of measurements could be, and were, used as much to minimize as to reveal the broader dimensions of inequality, in ways that help us to understand the limited political response.
The Origins of White Care
Authors: Seiler Cotten
Published: March 2020

This article explores the nineteenth-century conceptualization of racialized whiteness that foregrounded empathy as whites’ signal evolutionary achievement and the font of their potential. Neo-Lamarckian evolutionary science in the United States articulated whiteness as an acquired disposition to care, as both noun and verb. This deep context helps us account for the rise of a statist, ameliorative new liberalism at the turn of the century and the building of a midcentury apparatus of “white care”: a surround of institutions and infrastructure dedicated to the education, health, security, mobility, and comfort of the white citizenry. The care-oriented liberalism emplaced by the New Deal was rooted in a biopolitical imperative to “make live” the valorized white portion of the population.
Suspicion and/as Radical (Care)
Authors: Charles Nicole
Published: March 2020

Bourgeoning technological advances in biomedicine profoundly animate modern biopolitical understandings of risk and protection and related ways of knowing, offering, and seeking care. But what might it mean to embody protection by means of suspicion toward these very medicotechnological deployments of care? What can suspicion toward biomedical and technological forms of care teach us about histories of risk, medicine, and the imperative to care in the postcolonial world? This article wrestles with these questions. Drawing on ethnographic fieldwork in Barbados between 2015 and 2018, it embraces care’s historically antithetical meanings to examine the caring work of the human papillomavirus (HPV) vaccine and Afro-Barbadians’ hesitancy toward it. Looking closer at care, the impetus to care, and the consequences of refusing that care, it gestures toward the risks and potentialities of not-doing and the affective feelings of suspicion that exist for Afro-Barbadian parents who have refused the care of the HPV vaccine for their adolescent children amid an epidemic of cervical cancer in the developing world.
Skeletal stem cells: insights into maintaining and regenerating the skeleton
Authors: Serowoky Maxwell A. , Arata Claire E. , Crump J. Gage , Mariani Francesca V.
Published: March 2020

Skeletal stem cells (SSCs) generate the progenitors needed for growth, maintenance and repair of the skeleton. Historically, SSCs have been defined as bone marrow-derived cells with inconsistent characteristics. However, recent in vivo tracking experiments have revealed the presence of SSCs not only within the bone marrow but also within the periosteum and growth plate reserve zone. These studies show that SSCs are highly heterogeneous with regard to lineage potential. It has also been revealed that, during digit tip regeneration and in some non-mammalian vertebrates, the dedifferentiation of osteoblasts may contribute to skeletal regeneration. Here, we examine how these research findings have furthered our understanding of the diversity and plasticity of SSCs that mediate skeletal maintenance and repair.
Connecting brain to behaviour: a role for general purpose steering circuits in insect orientation?
Authors: Steinbeck Fabian , Adden Andrea , Graham Paul
Published: March 2020

The lateral accessory lobes (LALs), paired structures that are homologous among all insect species, have been well studied for their role in pheromone tracking in silkmoths and phonotaxis in crickets, where their outputs have been shown to correlate with observed motor activity. Further studies have shown more generally that the LALs are crucial both for an insect's ability to steer correctly and for organising the outputs of the descending pathways towards the motor centres. In this context, we propose a framework by which the LALs may be generally involved in generating steering commands across a variety of insects and behaviours. Across different behaviours, we see that the LAL is involved in generating two kinds of steering: (1) search behaviours and (2) targeted steering driven by direct sensory information. Search behaviours are generated when the current behaviourally relevant cues are not available, and a well-described LAL subnetwork produces activity which increases sampling of the environment. We propose that, when behaviourally relevant cues are available, the LALs may integrate orientation information from several sensory modalities, thus leading to a collective output for steering driven by those cues. These steering commands are then sent to the motor centres, and an additional efference copy is sent back to the orientation-computing areas. In summary, we have taken known aspects of the neurophysiology and function of the insect LALs and generated a speculative framework that suggests how LALs might be involved in steering control for a variety of complex real-world behaviours in insects.
Anharmonic Vibrational Analysis of Ethylene, Butadiene, and Longer Conjugated Alkenes by Double-Hybrid Density-Functional Theory Calculations
Authors: Furuya Kazuhiko , Sakamoto Akira , Tasumi Mitsuo
Published: March 2020

The anharmonic vibrational wavenumbers of ethylene, trans-1,3-butadiene, and conjugated all-trans alkenes (1,3,5-hexatriene, 1,3,5,7-octatetraene, and 1,3,5,7,9-decapentaene) were calculated by using the double-hybrid density-functional method. The coefficients of terms constituting the energy in the default double-hybrid density-functional (B2PLYP) were carefully optimized for ethylene. Calculations using this modified double-hybrid density-functional (B2ePLYP) gave anharmonic vibrational wavenumbers for the above-mentioned molecules in satisfactory agreement with the published data on fundamentals, overtones, and combinations. Isotope effects observed for deuterated species were mostly well reproduced.
Ο "χαρισματικός" μαθητής-επίδοξος συγγραφέας στα "Παιδιά της Νιόβης" του Τάσου Αθανασιάδη
Authors: Βλαχονικολέα Γεωργία
Published: March 2020

Οι σημαντικότερες σύγχρονες θεωρίες περί "χαρισματικότητας" στα ακαδημαϊκά κριτήρια δόμησης της συγκεκριμένης έννοιας εντάσσουν και τις αναπτυγμένες "γλωσσικές ικανότητες". Ο Τάσος Αθανασιάδης, "ο γνησιότερος, [ίσως], Έλληνας κλασικός μυθιστοριογράφος" (Τσούπρου, 2013: 136), εμβαθύνει στον εσωτερικό κόσμο των Χαρακτήρων, ενστερνιζόμενος τον "ψυχολογικό ρεαλισμό", με τον οποίο "απεικονίζεται και την ίδια στιγμή διερευνάται ο ψυχικός κόσμος του ανθρώπου, ακόμη και στις πιο ακραίες εκδηλώσεις του, [όπως εκείνη της υψηλής <γλωσσικής νοημοσύνης>]" (Παρίσης & Παρίσης, 2005: 160). Η παρούσα μελέτη σκοποθετείται στον τρόπο "αναπαράστασης" του "χαρισματικού" μαθητή – επίδοξου συγγραφέα στο "τελευταίο μείζον [μυθιστόρημα] του Αθανασιάδη" (Σταυροπούλου, 2014: 430). Ως μέθοδος έρευνας προκρίνεται η Ποιοτική Ανάλυση Περιεχομένου. Η μυθοπλαστική "εικόνα" του "χαρισματικού" μαθητή – επίδοξου συγγραφέα "αναγιγνώσκεται", βάσει του μοντέλου διαφοροποίησης "χαρισματικότητας - ταλέντου" του François Gagné (1998)˙ συμπληρωματικά, βάσει της "σύνθετης τυπολογίας Χαρακτήρων" του Βαγγέλη Αθανασόπουλου (2010). Τα λογοτεχνικά ευρήματα αναδεικνύουν τη συμβολή ενδογενών (κίνητρα, στοιχεία της προσωπικότητας) και εξωγενών (οικογένεια, σχολείο, συνομήλικοι, σημαντικά γεγονότα της ζωής) παραγόντων στη διαδικασία μετατροπής της έκδηλης φυσικής ικανότητας (γλωσσική) σε συστηματικά καλλιεργημένη δεξιότητα (συγγραφική). Τα ερευνητικά ευρήματα ερμηνεύονται, σύμφωνα με την "τοιχογραφία" (ιστορική - κοινωνική - ιδεολογική) της εποχής "αναφοράς" τους, το αδιάπτωτο ενδιαφέρον του Αθανασιάδη για τις εξελίξεις στον τομέα της Ψυχολογίας, όσο και τη "βιοθεωρία" του.
Το Διαπολιτισμικό Σχολείο στη Γαλλία
Authors: Γριβόπουλος Κωνσταντίνος
Published: March 2020

Η παρούσα μελέτη είναι βιβλιογραφική και σκοπό έχει να περιγράψει τις εκπαιδευτικές δομές μέσω των οποίων υλοποιείται η διαπολιτισμική εκπαίδευση στη Γαλλία. Αρχικά, παρατίθενται μερικές βασικές έννοιες που άπτονται της έννοιας της Διαπολιτισμικής Εκπαίδευσης και, στη συνέχεια, περιγράφονται οι βασικότερες συναφείς εκπαιδευτικές δομές που λειτουργούν στο γαλλικό εκπαιδευτικό σύστημα. Μεταξύ άλλων, αναφέρονται τα τμήματα ένταξης και προσαρμογής, τα δίκτυα εκπαιδευτικής προτεραιότητας, καθώς και νεότερες προσεγγίσεις. Παρατηρείται ότι η αντίληψη της εκπαιδευτικής πολιτικής για το ζήτημα αυτό διαφοροποιήθηκε σταδιακά από το αφομοιωτικό μοντέλο στο διαπολιτισμικό, σύμφωνα με το οποίο οι διαφορετικές πολιτισμικές καταβολές συνυπάρχουν αλληλεπιδραστικά και ισότιμα στα πλαίσια μιας συνεκτικής δημοκρατικής κοινωνίας, μακριά από πάσης φύσεως διακρίσεις και αποκλεισμούς.