bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).
Authors: Lee Chee Khoon , Scott Clare L. , Lindeman Geoffrey John , Gibbs Emma , Badger Heath D. , Paterson Robin John , Macnab Lauren , Kwan Edmond Michael , Boyle Frances M. , Friedlander Michael ,   On Behalf of the Australia and New Zealand Breast Cancer Trials Group
Published: September 2018

1104 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.
Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas.
Authors: Eilber Frederick C. , Sankhala Kamalesh Kumar , Chawla Sant P. , Chua-Alcala Victoria S. , Gordon Erlinda Maria , Quon Doris , Kim Katherine , Chawla Shanta , Wu Nancy , Wieland Scott , Levitt Daniel J. 
Published: September 2018

11051 Background: Aldoxorubicin (A) has demonstrated superior anti-tumor efficacy and lack of cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a linker which rapidly binds in vivo to albumin after iv. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/Mesna (I-M) days 1-14, as first line therapy or second line therapy in patients with soft tissue sarcomas (STS) to evaluate efficacy and toxicity. Methods: 27 patients have entered the study at 250 mg/m2 ( 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 of each per day) was given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles were repeated at 28 day interval. I-M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued per investigator decision in responding or SD patients for clinical benefit. Subjects were followed for tumor response (RECIST 1.1) by CT scans and echocardiogram/ECG for cardiac toxicity every 8 weeks along with standard labs. Enrollment continues up to 50 patients. Results: Demographics: Leiomyosarc. = 20%, liposarc. = 20%, synovial sarc. = 20%, rhabdosarc. = 8%, others = 32%. Caucasian, 11% Asian, 4% Black; 67% no prior tx, 26% 1 prior tx, 7% > 1 prior tx; Median cum. A = 1000 mg/m2 (740 mg/m2 D eq.; 185-4070 mg/m2 D eq.); I = 6.9 g/m2 (2.1-12.6 g/m2). Best response: 42% PR, 58% SD. Median PFS not reached. 10 subjects with either PR or SD had surgery to remove accesible tumors. Range of tumor necrosis = 70 to > 95%. Grade 3/4 AEs: neutropenia = 78%, febrile neutropenia = 9%, thrombocytopenia = 22%, anemia = 65%, nausea = 4%. Related SAEs = 4 (febrile neutropenia (2), pyrexia, stomatitis). No tx related deaths. No clinically significant cardiac AEs, no decrease in LVEF > 20% Conclusions: A can be administered for prolonged periods and safely with CI ifosfamide/mesna and achieves high ORR and SD with substantial tumor necrosis. Clinical trial information: NCT02235701.
Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with INI1 negative epithelioid sarcoma (NCT02601950).
Authors: Gounder Mrinal M. , Stacchiotti Silvia , Schöffski Patrick , Attia Steven , Italiano Antoine , Jones Robin , Demetri George D. , Blakemore Stephen , Clawson Alicia , Daigle Scott , Ribich Scott , Roche Maria , Rodstrom Jill , Ho Peter T.C. , Cote Gregory Michael 
Published: September 2018

11058 Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS) typically seen in young adults accounting for < 1% of all STS. While local disease may be indolent, ES can rapidly spread and patients (pts) with distant metastasis are often resistant to systemic treatment with 1 year survival of < 50%. The defining molecular feature of ES is the absence of tumor expression of INI1, a SWI/SNF subunit member involved in chromatin remodeling. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1 negative preclinical malignant rhabdoid tumors (MRT) models and phase 1 clinical activity in MRT and ES pts. The proposed mechanism of tazemetostat sensitivity is INI1 loss inducing compromised SWI/SNF activity and tumor dependence on PRC2 activity (of which EZH2 is the catalytic subunit). Preliminary phase 2 safety and efficacy of tazemetostat in ES pts is reported here. Methods: This is a phase 2 multicenter open-label single arm study of tazemetostat (800 mg po BID) in adult pts with ES whose tumors harbor evidence of INI1 loss. Pts enroll into 1 of 5 cohorts of different tumor types with INI1 loss/reduction, up to 30 pts each, using a 2-stage Green-Dahlberg design. For the ES cohort, primary endpoint is disease control rate (DCR) defined as objective response of any duration or stable disease (SD) lasting ≥32 wks. Success at stage 2 required DCR in ≥5/30 treated pts. Key secondary endpoints include safety/tolerability, ORR, PFS, OS, PK and response biomarkers e.g. H3K27me3. Results: In 31 ES pts with a median of 1 prior systemic therapy, stage 2 DCR criteria was surpassed with a RECIST confirmed PR (4 pts) and SD ≥32 wks (2 pts) observed to date. 13 pts are still on treatment therefore DCR and ORR will be updated. Tazemetostat was well tolerated with grade 1/2 fatigue (39%), nausea (26%) and vomiting (19%) as the most frequently reported AEs regardless of attribution. Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat monotherapy shows promising antitumor activity, including confirmed responses and long-term SD, with favorable safety/tolerability in ES. Enrollment has been expanded to 60 ES pts given the clinical activity described here. Clinical trial information: NCT02601950.
Discordance of histo-pathological diagnosis of patients with soft tissue sarcoma referred to tertiary care center.
Authors: Rastogi Sameer , Aggarwal Aditi , Soti Kamal Raj , Vanidassane Ilavarasi , Sharma Mehar C , Yadav Ajay , Sharma Aparna , Kataria Babita , Deo S. V. S. 
Published: September 2018

11064 Background: Reaching to the correct histo-pathological diagnosis of soft tissue sarcomas (STS) is a great challenge and is cornerstone for treatment planning. Need of expertise for diagnosis is limited by lack of expert pathologists and dedicated sarcoma oncologists in India. Through this study we highlight the pattern of pathological diagnosis and accuracy outside specialist centre. Methods: We did retrospective analysis of all patients referred to us with diagnosis of STS in the last 12 months (January 2016 to 2017). According to protocol, all patients had pathology review from our institute. If blocks were available then they were reviewed and if necessary, fresh biopsy was performed. Besides, pathological diagnosis was reviewed in joint clinic, giving clinico-radiological inputs to sarcoma pathologists. For patients diagnosed outside and had discordant report, we divided them into major discrepancy (including change of diagnosis of sarcoma to benign or other histological entity that could potentially change the treatment plan) or minor discrepancy (like mild change in grade or histopathological diagnosis not affecting the treatment plan). Results: There were 149 patients registered with median age of 36 years (14-77 years) and 93 patients (62.4%) were males. 85(57%) patients had localized disease. Most common subtypes were synovial sarcoma 16%, liposarcoma 9%, soft tissue ewings sarcoma 9%, MPNST 9%, leiomyosarcoma 8%, pleomorphic undifferentiated sarcoma 8% etc. Of 149 patients, 42 had not been worked up outside and thus comparison was not possible while 4 patients couldn’t retrieve blocks and repeat biopsy could not be performed. Of 97 patients (biopsy = 84, FNAC = 13) who had diagnosis from outside, 37% had major discrepancy and 24% had minor discrepancy compared with our biopsy review. Major discrepancy was more in non extremity than extremity STS (p = 0.003). Conclusions: Pathological diagnosis of more than half of patients referred from outside was discordant with respect to diagnosis of our centre with major implications on 37%. We believe this is due to lack of sarcoma pathology experts and virtually non-existent multidisciplinary clinics in set up outside tertiary care centres.
Correlation between a new growth modulation index (GMI)-based Geistra score and efficacy outcomes in patients (PTS) with advanced soft tissue sarcomas (ASTS) treated with trabectedin (T): A Spanish group for research on sarcomas (GEIS-38 study).
Authors: Martinez-Trufero Javier , Hindi Nadia , Cruz Josefina , Alvarez Alvarez Rosa Maria , Diaz Beveridge Roberto Pedro , Valverde Morales Claudia Maria , Gutierrez Antonio , Bernad Isabel Pajares , Lopez-Pousa Antonio , Vaz Salgado María Ángeles , Lavernia Javier , Cano Juana Maria , Sevilla Isabel , Rubió-Casadevall Jordi , De Juan Ana , Carrasco Juan Antonio , Hernandez Leon Nieves , Agra Pujol Carolina , Ferrando Lamana Lucia , Martin Broto Javier 
Published: September 2018

11070 Background: The GMI is a marker of drug activity and represents an intra-patient comparison of successive time to progression (TTP), defined as the TTP ratio between the second (or later) line (TTPn) of therapy divided by the prior line (TTPn−1). Defining a clinical profile of pts with GMI >1.33 could help to identify pts who can gain greater benefit from T. Methods: We retrospectively evaluated the concordance between the GMI and the efficacy outcomes and clinical profiles of 198 pts with ASTS treated with trabectedin 1.5 mg/m² (24-h infusion q3w) as a 2nd or further-line treatment from Jan 2007 to Jun 2016. Results: After a median follow-up of 58 months (m; range: 18-172) median overall survival from ASTS diagnosis (MOS) and from T (MT-OS) were 27.5 m (23-32.1) and 10.8 m (8.9-12.7), respectively, while median TTP from T (MT-TTP) and T-1 were 3.4 m (2.8-4) and 3.5 m (2.8-4.2). Overall, 106 pts (53%) had a GMI <1; 22 (11%) a GMI=1-1.33 and 70 pts (35%) a GMI >1.33. A high GMI (<1.33 vs >1.33) correlated with favorable efficacy outcomes: MT-OS: 23 vs 36 m (p<0.001), MT-TTP 2.3 vs 8.2 m (p<0.001) and clinical benefit (objective response + stable disease) 23% vs 68% (p=0.001). The multivariate analysis identified L-type sarcoma (Odds ratio: 1.99, 95% CI 1.06-3.71), metastatic free interval (MFI) from initial diagnosis > 8.1 m (2.24, 95%CI 1.19-4.18) and Karnofsky >80 (2.3, 95%CI 1.00-5.28) as factors independently associated to GMI> 1.33. Based on these 3 variables we defined a new GEISTRA score assigning 1 point for each adversely affected variable: non L-Sarcoma, MFI<8.1m or Karnofsky <80. This score showed a strong correlation with MT-TTP (p<0.001) and MT-OS (p<0.001). Conclusions: Based on the high GMI we defined a new GEISTRA score, which is strongly associated with favorable efficacy outcomes in pts with ASTS treated with T. Thus, GEISTRA score could be a potentially useful predictable clinical tool for T benefit. [Table: see text]
Prognostic value of microscopic evaluation of organ infiltration and visceral resection margins (VRM) in patients with retroperitoneal sarcomas (RPS).
Authors: Renne Salvatore Lorenzo , Tagliabue Marta , Pasquali Sandro , Collini Paola , Barisella Marta , Callegaro Dario , Colombo Chiara , Gronchi Alessandro , Fiore Marco 
Published: September 2018

11074 Background: Surgery with gross margin clearance (R0 and R1) is the standard treatment for RPS and visceral resection has been proposed even in the absence of macroscopic visceral infiltration. Formal definition and margin sampling procedures for pathological evaluation are lacking for RPS. This study investigated VRM as well as viscera infiltration and their association with patient survival. Methods: Consecutive patients operated on for primary RPS (2009-2014) were extracted from a prospectively maintained database. VRM were sampled for each resected organ and classified as negative and positive. Also, tumor infiltration of resected organs was classified as follow: absence of infiltration, infiltration of perivisceral fat, early infiltration (i.e., renal/adrenal capsule, muscular fascia, contact with muscular tunica of hollow viscera), and infiltration of the viscera. Results: In 207 patients VRM were negative in 182 (88%) and positive 25 (12%). Organ infiltration was absent, perivisceral, early, and visceral in 37 (18%), 13 (6%), 17 (8%), and 140 (68%), respectively. Overall survival analysis showed that patients with negative VRM plus organ infiltration (HR = 3.56; 95%CI 1.15-11.00, P = 0.028) and those with positive VRM irrespective of organ infiltration (HR = 7.76; 95%CI 2.18-27.65, P = 0.002) did worse that patients with negative VRM plus no organ infiltration, after adjustment from known prognostic features. Conclusions: After liberal multivisceral resection for primary RPS, up to 80% of patients have infiltrated organs at some extent, while VRM are positive in up to 10% of cases. Visceral resection is justified even in the absence of macroscopic infiltration. Systematic evaluation of microscopic involvement of adjacent viscera may stratify prognosis.
A phase I/II dose escalation and expansion study of cabiralizumab (cabira; FPA-008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS).
Authors: Sankhala Kamalesh Kumar , Blay Jean-Yves , Ganjoo Kristen N. , Italiano Antoine , Hassan Andrew Bassim , Kim Tae Min , Ravi Vinod , Cassier Philippe Alexandre , Rutkowski Piotr , Sankar Neil , Qazi Ibrahim , Sikorski Robert S. , Collins Helen , Zhang Charlie , Shocron Ellyn , Gelderblom Hans 
Published: September 2018

11078 Background: TGCTis a proliferative, neoplastic joint disease that presents as single nodule (local) or multiple nodules (diffuse D-TGCT). Localized overexpression of colony stimulating factor 1 (CSF1) leads to recruitment of cells expressing the CSF1 receptor (CSF1R), formation of a tumor and inflammation of joints and tendons. Cabira is a monoclonal antibody that inhibits the interaction of the CSF1 and IL-34 ligands with their shared receptor CSF1R. Methods: This Ph 1/2 study is evaluating the safety and efficacy of cabira monotherapy administered IV Q 2wk for 6 mo in patients (pts) with D-TGCT. Eligible pts have inoperable D-TGCT or tumor for which resection would cause unacceptable morbidity. Response is evaluated by MRI, pt reported outcomes, and Ogilvie-Harris (O-H) score (which combines pain, synovitis, range of motion and functional capacity on a scale of 0-12). Results: As of 15 Dec 2016, 22 pts received ≥ 1 dose of cabira at 1, 2 or 4mg/kg. Dose-related exposure increase and significant reduction in target peripheral monocytes were observed. No dose limiting toxicity was identified. 4 mg/kg was chosen for Ph2 based on efficacy, tolerability, and PK. AEs ≥ Gr 2 ( > 10%) were CK elevation 46%, rash and other skin disorders 36%, fatigue 23%, and periorbital/peripheral/face edema 18% each. Gr 3 AEs in ≥ 2 pt were CK elevation (n = 8) and periorbital edema (n = 2). Four drug-related SAEs were reported in 3 pts; hypertension, fever, CRP elevation, and myocarditis. AEs of CK elevation were asymptomatic, improved to < 2X ULN after protocol mandated drug discontinuation and are a known on-target effect of CSF1R inhibition. An amendment was made during Phase 2 to allow dosing with higher CK levels Activity at 4 mg/kg was: 1PR and 1 CK discontinuation in 3 pts in Ph1; 4 PRs in 7 evaluable pts with 6 additional ongoing in Ph2. Positive functional status improvements by O-H score were noted in objective responders (from 2 to 7). Conclusions: The initial demonstration of objective and functional activity supports further development of cabiralizumab in pts with D-TGCT. Updated data from the ongoing Ph2 will be presented. NCT02471716 . Clinical trial information: NCT02471716.
Interferon-gamma (INFG), an important marker of response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) and melanoma patients.
Authors: Karachaliou Niki , Crespo Guillermo , Aldeguer Erika , Drozdowskyj Ana , Gimenez Capitan Ana , Teixido Cristina , Molina-Vila Miguel Angel , Viteri Ramirez Santiago , Morales-Espinosa Daniela , Gil Maria de los Llanos , Gonzalez-Cao Maria , Martin Algarra Salvador , Pérez-Ruiz Elisabeth , Marquez Rodas Ivan , Rodriguez-Abreu Delvys , Blanco Remei , Puertolas Teresa , Royo Maria Angeles , Rosell Rafael 
Published: September 2018

11504 Background: PD-L1 can be induced by oncogenic signals or up-regulated via INFG in a STAT1- and NFκB-dependent manner. STAT3 opposes STAT1-mediated anti-tumor immune responses. I kappa B kinase epsilon (IKBKE) is an interferon signaling inducer. We explored whether INFG expression in pre-treatment tumors is associated with to the efficacy of ICB in NSCLC and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE and STAT1 was also examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1 and PD-L1 mRNA were examined. PD-L1 protein expression in tumor and immune cells was evaluated (Ventana SP142 assay). Progression free survival (PFS) and overall survival (OS) were estimated. Results: 17 previously treated NSCLC patients received nivolumab; 71% lung adenocarcinoma, 71% male, 53% smokers, 35% KRAS mutant, 88% EGFR wild-type (wt). 21 previously treated melanoma patients received pembrolizumab; 67% male, 67% BRAF wt. PFS to nivolumab was significantly longer in NSCLC patients with high vs. low INFG expression (5.12 vs. 2mo, p = 0.0124). PFS to pembrolizumab was significantly longer in melanoma patients with high vs. low INFG expression (4.99 vs. 1.86mo, p = 0.0099). Significantly longer OS was observed for melanoma patients with high vs. low INFG expression (not reached vs. 3.10mo p = 0.0183). There was a trend for longer OS for NSCLC patients with high vs. low INFG expression (10.15 vs. 4.86mo, p = 0.0687). The other gene levels and PD-L1 protein levels in tumor and immune cells did not affect the outcome to ICB. IKBKE was positively correlated with INFG and PD-L1 expression (NSCLC Spearman’s ρ = 0.58 and 0.65; melanoma Spearman’s ρ = 0.61 and 0.59), and STAT3 expression was loosely anticorrelated with PD-L1 expression (NSCLC Spearman’s ρ = −0.21; melanoma Pearson’s ρ = −0.01). Conclusions: INFG is an important marker for qRT-PCR mediated prediction of response to ICB in NSCLC and melanoma patients. Further research is warranted in order to validate that INFG is more accurate than PD-L1.
SHIVA: Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer—Overall survival (OS) analysis.
Authors: Dureau Sylvain , Ricci Francesco , Alt Marie , Loirat Delphine , Sablin Marie-Paule , Kamal Maud , Bieche Ivan , Armanet Sebastien , Delord Jean-Pierre , Goncalves Anthony , Gavoille Celine , Dubot Coraline , Isambert Nicolas , Campone Mario , Tredan Olivier , Marous Miguelle , Latouche Aurelien , Belin Lisa , Le Tourneau Christophe 
Published: September 2018

11515 Background: The SHIVA trial is a multicentric randomized phase II trial comparing molecularly targeted therapy among 11 drugs based on tumor molecular profiling versus conventional therapy in patients with any type of cancer that is refractory to standard of care (NCT01771458). Only patients who had a druggable molecular alteration (DMA) identified on a mandatory tumor sample from a metastatic site using targeted sequencing, CGH and IHC were randomized. Cross-over was allowed at disease progression. The trial did not show any difference for its primary endpoint (PFS) [Le Tourneau et al., Lancet Oncol 2015]. We report here the OS of randomized and non-randomized patients. Methods: OS was estimated in the 4 following groups: 1) randomized patients, 2) patients for whom a DMA was identified but who were not subsequently randomized because they did not meet the randomization criteria (PS of 0 or 1, adequate organ function), 3) non-randomized patients because of the absence of DMA, and 4) non-randomized patients because no genomic analyses were performed. Since 70% of patients randomized into the standard arm eventually crossed over to the targeted therapy arm, all randomized patients were analyzed in group 1. The groups were compared in terms of patient characteristics using student and χ2 tests. OS was estimated using the Kaplan Meier method. Results: Among 741 patients included in SHIVA, 8 patients were included twice. Follow-up data were available for 680 out of the 733 patients. 197, 78, 222 and 183 patients belonged to groups 1 to 4, respectively. Median OS of the whole cohort was 7.9 months [95% CI: 7.0–9.1].As compared to non-randomized patients due to the absence of identified DMA, non-randomized patients with a DMA had a significantly worse prognosis: HR = 2.3 [95% CI: 1.7–3.0] (p > 0.0001) whereas randomized patients had a non-significant trend toward a better prognosis: HR = 0.85 [95% CI: 0.7–1.1] (p = 0.18). Conclusions: A statistically significant difference in OS was only observed in patients with a DMA who were not randomized. However, our analysis does not allow showing an intrinsic prognostic value of the DMA on OS.