tbuckley/cabot-search huggingface dataset:
TBCRC028: A phase Ib/II trial of GDC-0941 (a PI3K inhibitor) in combination with cisplatin in metastatic androgen receptor-negative triple-negative breast cancer (TNBC).
Authors: Vandana Gupta Abramson, Brian Lehmann, Ingrid A. Mayer, Carlos L. Arteaga, Jennifer A. Pietenpol
Journal: Journal of Clinical Oncology (2014)

TPS1148 Background: We recently reported six distinct molecular subtypes of TNBC, including two basal-like subtypes with cell cycle and DNA damage response (DDR) gene expression (GE) signatures (BL1 and BL2) and a luminal androgen receptor (LAR) subtype which expresses AR by immunohistochemistry. BL1 and BL2 cell lines respond to DNA damaging agents, including cisplatin. Consistent with the frequent alterations in DDR and PI3K pathways in TNBC, the combination of cisplatin and the pan-PI3K inhibitor GDC0941 was very active against AR-negative TNBC cell lines in preclinical studies. This trial will evaluate the benefit of the addition of GDC-0941 to cisplatin in patients with metastatic AR-TNBC. Methods: This is an open-label phase Ib/II multiple institution trial in which patients with metastatic AR-TNBC will be randomized to: a) cisplatin 25 mg/m2 on days 1, 8, and 15 of a 28 day cycle, or b) cisplatin with GDC-0941. Biopsy of a metastatic lesion at baseline, at day 5-10, and at progression is required. Staging scans will be performed at baseline and every 2 cycles thereafter. Upon progression, patients on the cisplatin arm have the option to crossover to the combination arm with GDC-0941. The primary objectives are: to determine the safety and tolerability of cisplatin + GDC-0941 in patients with AR-TNBC (phase Ib) and efficacy, as measured by the overall response rate (phase II). Secondary objectives are to determine the clinical benefit rate and time to disease progression of both study arms. Correlative analyses will evaluate mechanisms of inherent and acquired resistance. Gene expression profiling to assign a TNBC subtype and whole exome analysis will be performed; the predictive effects of PI3K pathway mutations (PIK3CA, AKT, PTEN) will also be examined. Approximately 125 patients will be enrolled (80% power to detect a 20% improvement in the ORR with a type 1 error of 0.05). Clinical trial information: NCT01918306.
Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis
Authors: Katerina Chatzidionysiou, Sharzad Emamikia, Jackie Nam, Sofia Ramiro, Josef Smolen, Désirée van der Heijde, Maxime Dougados, Johannes Bijlsma, Gerd Burmester, Marieke Scholte, Ronald van Vollenhoven, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2017)

Objectives To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA). Methods An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials. Results For GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated. For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations. Conclusions Addition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease.
Evaluation ofthe clinical relevance of <i>Adjuvant! Online</i>: Did we forget ethics?
Authors: Emmanuelle Kempf, Luis Teixeira, Sandra Malak, Aude Kempf
Journal: Journal of Clinical Oncology (2014)

e17667 Background: Improved Early Stage Breast Cancer (ESBC) screening, subtype classification and treatment lead to increased clinical complexity. Risk prediction models (RPM), such as Adjuvant! Online (AO), have been created to help oncologists to select ESBC patients who might benefit from adjuvant therapy. Evaluating clinical relevance of AO is necessary to provide patients with the best treatment. The objective of the study is to determine, first, how AO clinical relevance is currently assessed; secondly, if there might be other ethically relevant evaluation criteria. Methods: First, we analyzed the literature dealing with AO to assess the most common evaluation methods of its clinical relevance. We determined the arguments underlying AO use guidelines. Secondly, we compared AO-based medical decision process to Evidence-Based Medicine (EBM) decision-making characteristics. We determined the changes induced by AO use on the medical decision reference process. We described the inherent and specific characteristics of AO software which could underlie such an ethical impact. Finally, we suggested other evaluation criteria. Results: So far, 20 international studies deal with AO clinical relevance. Both external validity, evaluated from patients´prognostic comparison in 14 studies, and internal validity, defined by the exhaustivity of AO prognostic factors in 17 studies, are the main methods for assessing AO clinical relevance. Oncology societies base their guidelines on these two arguments. Yet, using AO induces a qualitative gap with the EBM decision reference process. Specific characteristics, inherent to the software nature of AO, could lead to ethical imbalance in medical responsibility. Indeed, AO using provokes changes in decision temporality as well as EBM studies´ presentation. New ethical evaluation criteria might include medical attitude regarding both scientific knowledge and patients. Conclusions: Evaluating clinical relevance of a computer aid-decision tool such as AO is mainly based on external and internal validities. To improve this process, other new ethical evaluation criteria are required.
Renal carcinoma following therapy for cancer in childhood: A report from the Childhood Cancer Survivor Study.
Authors: Carmen Louise Wilson, Kirsten K. Ness, Joseph Philip Neglia, Sue Hammond, Wendy M. Leisenring, Marilyn Stovall, Leslie L. Robison, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2012)

9528 Background: Limited data exists describing the incidence of and risk factors for subsequent renal carcinoma among long-term survivors of childhood cancer. Methods: The study included 14,351 five-year survivors of childhood cancer diagnosed between 1970 and 1986 who participated in the Childhood Cancer Survivor Study. Chemotherapy and radiotherapy exposures were abstracted from medical records; total dose of radiation to the renal beds was estimated by a radiation physicist. Standardized incidence ratios (SIRs) were calculated using age-, sex-, and calendar-specific incidence data from the Surveillance, Epidemiology and End Results (SEER) program. Cumulative incidence was calculated treating death as a competing risk. Poisson regression analyses were used to assess associations between diagnosis and treatment characteristics and the risk of subsequent renal carcinoma while adjusting for changes in risk due to age. Results: Twenty-six survivors were diagnosed with a renal carcinoma at a median follow-up of 19.3 years (range: 1 month to 34.3 years) from study entry at 5 years post diagnosis. Eight patients received ≥5Gy radiotherapy to a renal bed, 16 received chemotherapy, seven of whom seven received both radiotherapy ≥5Gy and chemotherapy. Cumulative incidence of renal carcinoma at 20 years was 0.16% (95% CI 0.12-0.20). The SIR was 8.1 (95% CI 5.3-11.8) comparing survivors to the general population. Highest risk for renal carcinoma was observed among survivors of neuroblastoma (SIR 87.1, 95% CI 38.4-175.2), non-Hodgkin lymphoma (SIR 9.3, 95% CI 1.9-27.4), and bone tumors (SIR 7.0, 95% CI 1.4-20.4). In multivariable analyses, the risk of subsequent renal carcinoma was elevated among survivors exposed to platinum-based chemotherapy (Rate Ratio 3.1, 95% CI 0.9-10.6) or renal bed radiotherapy ≥5Gy (RR 3.6, 95% CI 1.5-8.4). Conclusions: While cumulative incidence is low, survivors of childhood cancer are at an eight-fold increased risk for subsequent renal carcinoma compared to the general population. In addition to a primary diagnosis of neuroblastoma, radiotherapy directed to the renal bed increased the risk for renal carcinoma.
Phase I safety and immunogenicity study of NY-ESO-1b peptide and Montanide ISA-51 vaccination of patients with ovarian cancer (OC) in high risk first remission
Authors: C. S. Magid Diefenbach, P. Sabbatini, C. Aghajanian, D. Spriggs, H. Lee, S. Pezzulli, A. A. Jungbluth, L. J. Old, S. Gnjatic, J. Dupont
Journal: Journal of Clinical Oncology (2006)

5078 Background: The Cancer Testis (CT) antigen NY-ESO-1 is expressed in over 60% of advanced OC. NY-ESO-1 demonstrates strong immunogenicity and expression is restricted to gonadal tissues, making it an appealing immunologic target. Patients with high risk OC (suboptimal debulking, incomplete CA125 response at 3 cycles, or positive second look surgery) have a high recurrence rate, with median time to progression (TTP) of 10–12mos. Strategies to prolong remission are needed. Methods: After primary surgery and platinum based chemotherapy high risk HLA-A*0201 OC patients in first clinical remission received HLA-restricted NY-ESO-1b peptide (100 μg) and Montanide adjuvant (0.5mL) every 3 weeks for a total of 5 vaccinations. NY-ESO1 tumor expression was evaluated by immunohistochemistry (IHC). Toxicity using NCI-CTC v2 and immunogenicity: 1) NY-ESO-1 specific humoral immunity (ELISA); 2) NY-ESO-1 specific T-cell immunity (tetramer and ELISPOT); and 3) delayed type hypersensitivity (DTH) were assessed on weeks 0, 1, 4, 7, 10, 13, 16. Patients were monitored for progression of disease (POD). Results: Seventeen out of 46 (37%) screened patients were HLA-A*0201+. Eight of 10 enrolled patients have completed therapy, one patient is receiving treatment, and one patient was removed before initiation for POD. Treatment related adverse events (AEs) included: Grade 1 fatigue, anemia, pruritus, myalgias and hyperthyroidism and Grade 2 hypothyroidism. No Grade 3/4 AEs were seen. Five patients (50%) had NY-ESO-1+ tumor; 3 of 3 treated patients with NY-ESO1+ tumor demonstrated T cell immunity by positive tetramer (0.65%–9%) and ELISPOT (35–250 spots). Four of 5 (80%) treated patients with NY-ESO-1- tumor demonstrated T cell immunity by tetramer (1–12%) and/or ELISPOT (250–400 spots). There was no evidence of DTH reaction. With long-term followup 4 of 8 patients have recurred with median TTP of 8.5mos; 4 patients remain in complete remission at intervals of 9, 16, 22, and 37mos to date. Conclusion: Vaccination of high risk HLA A*0201+ OC patients with NY-ESO-1b and Montanide has manageable toxicity, and induces specific T cell immunity in patients with both NY-ESO-1 positive and negative tumors. Additional testing is warranted. No significant financial relationships to disclose.
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Jorge A. Garcia, Robert Dreicer, Allan J. Pantuck, Naomi B. Haas, Ulka N. Vaishampayan, Drew W. Rasco, Allison Janine Tyler, Niranjan Sathyanarayana Rao, Penelope J. Bristow, Sanjeeva Reddy, Louis J. Denis, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2017)

240 Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase. It selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction supporting its use in future combination trials. Methods: This Phase 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Endpoints included maximum dose (MTD) and dose limiting toxicities, recommended Phase 2 dose, pharmacokinetics, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 23 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, nausea and dizziness. At 400mg, two pts experienced asymptomatic, reversible Gr 3 elevation of ALT/AST, but no recurrence when retreated at a lower dose (300mg). Testosterone decreased to below quantifiable limits and DHEA decrease of up to 80% was observed in ABI/ENZA naïve patients. Systemic exposure was high (C max , AUC and T 1/2 at 300 mg QD was 6.7 µm, 80 µm.h and 21.5h, respectively). RECIST defined Stable Disease up to 15+ months has been observed at the 100mg cohort despite prior ABI and ENZA exposure. PSA decline of &gt; 50% (51%-70%) was observed in 3 of 3 ABI/ENZA naïve patients at doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
Predictive biomarkers in a phase II trial of weekly carboplatin (CBDCA), paclitaxel (P), and cetuximab (C) induction and chemoradiation (CRT) in patients (pts) with resectable stage III/IVa,b head and neck squamous cell carcinoma (HNSCC): Eastern Cooperative Oncology Group E2303.
Authors: Amanda Psyrri, Ju-Whei Lee, Maria Vasilakopoulou, Eirini Pectasides, Barbara Burtness, David Rimm, Harold J. Wanebo, Arlene A. Forastiere
Journal: Journal of Clinical Oncology (2013)

6081 Background: We studied the addition of C to a sequential regimen of weekly CBDCA and P followed by CBDCA-P-radiation in pts with locally advanced resectable HNSCC. Tissue-based biomarkers may aid in pt selection for such approaches. Methods: Sixty-three eligible pts withoperablestage III/IV HNSCC participated in E2303, an Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly C, P and CBDCA x 6 followed by CRT with concurrent weekly C, paclitaxel, carboplatin. A tissue microarray was constructed and b-catenin, E-cadherin, Epidermal Growth Factor Receptor Variant III (EGFRVIII), insulin-like growth factor-1 receptor (IGF1R), NF-kappa b, p53, PI3Kp85, PI3Kp110a, PTEN, ΝRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each marker, time-to-event distributions (OS, PFS, and EFS) were estimated by Kaplan-Meier estimates and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate hazard ratios and test for significance, with primary site (oropharynx vs. non-oropharynx), disease stage (III vs. IV), and other important markers adjusted in the model. All p-values are two-sided. A level of p &lt; 0.05 is considered statistically significant. Results: Based on the continuous scale, pRb tended to association with EFS (p=0.05). On multivariable analysis, low pRb level was a significant predictor for improved EFS (p=0.048). Our pRb data analysis was based on 32 pts with marker data available. Conclusions: pRb level is a potential predictive biomarker for response to cetuximab. HPV E7 oncoprotein binds and degrades pRb; therefore, low pRb protein level might be a surrogate marker for HPV association.Large prospective studies will be required to determine the association between pRb, HPV status and response to cetuximab in HNSCC.
Cost-utility analysis of maintenance therapy with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502-eco phase III study.
Authors: Isabelle Borget, Maurice Perol, David Perol, Armelle Lavole, Laurent Greillier, Acya Bizieux-Thaminy, Virginie Westeel, Henri Berard, Jean Baptiste Auliac, Gerard Zalcman, Cecile Dujon, Gilles Robinet, Pierre Fournel, Pascal Thomas, Jacques Margery, Jean-Philippe Oster, Sylvie Chabaud, Alain Vergnenegre, Christos Chouaid
Journal: Journal of Clinical Oncology (2012)

e16560 Background: The IFCT–GFPC 0502 phase III study reported a prolongation of progression-free survival with maintenance with either gemcitabine or erlotinib versus observation after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC. The aim of this analysis is to assess the incremental cost-effectiveness ratio (ICER) of these strategies in the global population and in pre specified sub-groups. Methods: A cost-utility analysis was performed to evaluate ICER of maintenance therapy with either gemcitabine or erlotinib, compared to observation, from randomization until end of follow up. Direct medical costs (including drugs costs, hospitalization, follow-up examinations, second-line treatment and palliative costs) were prospectively collected per patient alongside the trial, until death, from the third party payer perspective. Utility data were extracted from literature. Sensitivity analyses were performed. Results: The ICER for maintenance therapy with gemcitabine and erlotinib were respectively 84,011 and 183,261 euros per quality-adjusted life years (QALY). Gemcitabine maintenance therapy had a favourable ICER in patients with PS = 0 (51,168 €/Qaly), in responders to induction chemotherapy (65,554€/Qaly) and in patients with squamous cell carcinoma (44,884€/Qaly); erlotinib had a favourable ICER in patients with PS = 0 (162,371 €/Qaly) and objective response to induction (101,569 €/Qaly ). Conclusions: Gemcitabine and erlotinib maintenance therapy have acceptable ICER but with a wide variation function of histology, PS and response to the first line chemotherapy.
Second malignant neoplasms (SMN) in childhood acute lymphoblastic leukemia (ALL): Primitive neuroectodermal tumor of bone (PNET) with p53 mutation
Authors: C. R. Suarez, A. B. Raj, S. J. Bertolone
Journal: Journal of Clinical Oncology (2004)

8173 Background: About 80% of children treated for ALL will be long term survivors. The estimated cumulative risk of a SMN is 2% to 3.3% 15 yrs after diagnosis. Methods: A review of the literature of 25,907 children treated for ALL revealed 274 SMN (1.07%). Results: The most frequently observed SMN are shown below: Others included CML(3), breast cancer (4), malignant histiocytosis (2), ovarian cancer (2), one case each of nephroblastoma, mucoepidermoid CA, bladder CA, malignant teratoma, leimyosarcoma of lung, and 22 unknown cases. In the lymphoma group there was an equal number of NHL and Hodgkins (10). In the AML/MDS group most were AML(26). Of all cases of SMN 62% recieved RT and the risk of a SMN appears to be dose related. Of significance is the fact that the overall survival rate for those patients with reported long term follow is 57.3% (101/176). The Ewings Family tumors and in particular PNET of bone are rare SMN. Of these 25,901 children treated for ALL there is only one case report of a PNET of bone. Our case of a chest wall PNET developing in an 8-yr-old boy one yr after completing therapy for standard risk ALL is the second case reported and the first one associated with germline and tumor cell p53 mutation. . Our patient did not receive RT and therefore can be excluded as a contributing factor. Exposure to anthracyclines and alkylating agents was minimal (75mg/m2 and 1gm/m2 of adriamycin and cytoxan respectively). Conclusions: We conclude that germline p53 mutation played a major role in the development of this rarely observed SMN and that cases of SMN in pediatric patients should be evaluated for p53 mutation. Overall long term survival for patients with SMN after treatment for ALL is encouraging at 57% and determination of p53 may influence therapeutic and prognostic considerations. One percent of children treated for ALL will develop SMN, the decrease use of RT in children with ALL should result in even a lower number of SMN. No significant financial relationships to disclose.
Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma.
Authors: Joseph J Sacco, Paul D. Nathan, Sarah Danson, Paul Lorigan, Steve Nicholson, Christian Ottensmeier, Philippa Corrie, Neil Steven, Andrew Goodman, James M. G. Larkin, T. R. Jeffry Evans, Satish Kumar, Sarah E Coupland, Paul Silcocks, Ernie Marshall
Journal: Journal of Clinical Oncology (2013)

9031 Background: Uveal melanoma (UM) is a rare cancer with a propensity for metastasis. There are no effective systemic therapies for metastatic UM, although dacarbazine is commonly used in practice. Sunitinib is a tyrosine kinase inhibitor with activity against several targets including c-Kit and VEGF receptors, both of which have been implicated in the pathogenesis of UM. Methods: In this randomized multicentre, phase II study (SUAVE), patients (pts) with metastatic UM, ECOG PS 0-2, and no prior systemic therapy for advanced disease, were randomized 1:1 to sunitinib (50mg daily for 28 days, followed by a 14 day break), or dacarbazine (1000 mg/m 2 once every 21 days). Crossover was permitted on progression. The primary endpoint was PFS; secondary endpoints included response rate and OS. A sample size of 124 was planned, with a power of 0.9 to detect an increase in 3 month PFS from 0.2 to 0.4 (HR: 0.563) and a one-sided alpha of 0.05. A preplanned futility analysis was performed after 50% of events, and recruitment stopped early, due to low conditional power (0.17% under current trend). Presentation of results was approved by DMC. Results: 74 pts from 12 centres were randomized over 24 months. Overall response rates of 0% and 8% were observed in the sunitinib and dacarbazine arms; while stable disease was observed in 24% of pts on sunitinib, and 11% on dacarbazine. PFS and OS were not improved with sunitinib (see Table). 11 pts in the sunitinib arm and 23 in the dacarbazine arm underwent crossover on progression. No unexpected AEs were observed, and no deaths due to toxicity occurred. Conclusions: In these preliminary results sunitinib did not have significant clinical activity in metastatic UM. This trial is one of the largest undertaken in metastatic UM and demonstrates that timely recruitment to collaborative multicentre randomized trials is achievable in this rare disease. Clinical trial information: 75033520. [Table: see text]