bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of soluble programmed death-ligand 1 (soluble PDL1) during chemotherapy and its prognostic implication in cancer patients.
Authors: Ha Hyerim , Bang Ju-Hee , Nam Ah-Rong , Park Ji Eun , Kim Mei Hua , Bang Yung-Jue , Oh Do-Youn
Published: September 2018

11542

Background: The soluble form Programmed Death-Ligand 1(sPDL1) is suggested to have immunosuppressive activity and under investigation as candidate biomarker for immuno-oncology drug development. In this study, we measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in biliary tract cancer (BTC) patients. Methods: From 90 advanced BTC patients (training cohort 42 patients, validation cohort 48 patients) who were candidates for palliative 1st-line chemotherapy, blood was collected at pre-and post-chemotherapy. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were also obtained. Results: OS of all patients was 11.5 months (95% CI; 9.7-16.2). The best response was CR in 7 patients (7.8%), PR 20 patients (22.2%), SD 52 patients (57.8%) and PD 11 patients (12.2%). Median sPDL1 at pre-chemotherapy was 0.97 ng/mL (range 0.6-1.9). Patients with high pre-chemo sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low pre-chemo sPDL1 (9.1 vs. 12.5 months, p =0.003). In multivariate analysis, high pre-chemo sPDL1 (HR 1.96, 95% CI; 1.2-3.9, p = 0.011) and pre-chemo NLR (HR 1.82, 95% CI; 1.1-3.0, p = 0.020) were independent poor prognostic factors for OS. Post-chemotherapy sPDL1 and its changes compared with pre-chemotherapy were not significantly different across tumor response groups. However, at the time of disease progression, sPDL1 was increased significantly compared with pre-chemo sPDL1 (1.59 ng/mL vs 0.72 ng/mL, p = 0.003). In PR group, sPDL1 at pre-chemo, post-chemo, and PD was 1.19, 0.98, and 2.77 ng/mL, respectively. In SD group, sPDL1 at pre-chemo, post-chemo, and PD was 1.16, 1.19, and 1.83 ng/mL, respectively. In PD group, sPDL1 at pre-chemo and PD was 0.62, and 1.04 ng/mL. Conclusions: sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlates with disease progression.
Cell surface GRP78 expression on T and NK cell sub-populations of breast cancer patients.
Authors: Yerushalmi Rinat , Lubin Ido , Lipovettzky Julia , Hardy Britta , Raiter Annat
Published: September 2018

11561

Background: The targeting of unfolded protein response (UPR) in tumor cells has received much attention. However, data are sparse on the impact of UPR on T and NK cells. The master regulator of UPR is the glucose-regulated protein 78 (GRP78) that is expressed in some tumor cells or normal stressed cells. There are few studies concerning GRP78 expression on T and NK cells in cancer and its relationship to stress induction by chemotherapy. We aimed to reveal the effect of UPR activation on the peripheral T and NK cells of breast cancer patients by the evaluation of cell surface GRP78 expression on T and NK cells before and after neoadjuvant chemotherapy. Methods: Forty-seven patients with triple negative, ER positive/Her2 negative and Her2 positive breast cancer were included. FACS analysis of their blood specimens before and after neoadjuvant treatment was performed. For multicolor FACS analysis, anti-CD3, CD4, CD8, CD56, CD16, NKG2D, CD45RA, CD45RO, CCR7 CD62L and anti-GRP78 antibody (AF488) were added to one of the tubes. A second tube was incubated with IgG-AF488 as isotype control. Analysis of the different T and NK subpopulations that expressed cell surface GRP78 were analyzed with the Gallios Flow cytometer and Kaluza Flow Analysis Software (Beckman Coulter, Inc.). Results: The percentage of cell surface GRP78 baseline expression in CD3 (1.8±0.9), CD8 (2.9±1.5), NKG2D (4.8±2) and CD45RO/CD62L/CCR7 active T memory cells (2.1±0.5) in Her2 positive patients were significantly higher than in triple negative and ER positive/Her2 negative patients. GRP78 expression on CD56, CD16 and NKG2D cells measured after neoadjuvant treatment was significantly higher in patients with complete response (CR) compared to patients without CR. 89% of the CR patients presented with Her2+ subtype. The non-CR patients include triple negative and Her2 negative subtypes. Conclusions: GRP78 was found to be expressed in the different T and NK sub-populations. The level of expression changed with each breast cancer subtype and response to chemotherapy. These novel findings suggest that GRP78 may be used as a new predictive biomarker. It sets the stage for understanding the mechanism of UPR activation on the immune system in breast cancer.
SEER study of breast cancer specific mortality (BCSM) in patients with lobular tumors treated based on recurrence score results.
Authors: Baehner Frederick L. , Shak Steven , Miller Dave P. , Petkov Valentina I.
Published: September 2018

11568

Background: Linking the 21-gene assay RS result to the SEER Registries demonstrated very low 5-y BCSM with low RS and high 5-y BCSM with high RS across subgroups, such as nodal status, age, tumor size and grade (npj Breast Cancer 2016). Given the large sample size and interest in outcomes as a function of tumor characteristics, we characterized the relationship between RS results and BCSM in patients reported by SEER with lobular morphology. Methods: Patients with RS and lobular morphology based on the registry ICD-O-3 code 8520 were eligible if node negative (N0) or node positive up to 3 positive nodes (N+mic,1-3), HR+, HER2- negative, no prior malignancy, and diagnosed between Jan 2004 and Dec 2012. No information in SEER is available regarding lobulars, ie., trabecular, alveolar, solid and pleomorphic. 5-y BCSM was estimated using actuarial methods. Results: There were 6,075 eligible patients reported with lobular morphology (11% of cases). Median age was 59 years; 88%/12% were N0/N+; 31%/62%/7% grade 1/2/3; 61%/39% ≤2 cm/>2 cm. Median follow-up was 44 months. A minority (8%) had RS >25. Chemotherapy (CT) use and BCSM increased with increasing RS. In multivariable analysis in N0 disease, continuous RS result and tumor size predicted BCSM (p=0.003 and p=0.04, respectively), whereas age and tumor grade were non-significant. In multivariable analysis in N+ disease, continuous RS result alone predicted BCSM (p=0.002). Conclusions: In these analyses the prognosis of patients with lobular breast cancer treated based on RS results depends on both nodal status and the RS result. The 5-y BCSM for lobular breast cancer is excellent with RS of 25 or less, and increases for RS >25. [Table: see text]
Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.
Authors: Bae Jooeun , Nguyen Brandon , Tai Yu-Tzu , Hideshima Teru , Chauhan Dharminder , Munshi Nikhil C. , Anderson Kenneth Carl
Published: September 2018

11577

Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138+ tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138+ myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+). Treg cells (CD3+CD4+/CD25+FOXP3+) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3+CD4+ and CD3+CD8+T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( > 150%) or checkpoint inhibitor ( > 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.
Association of MLL2 mutation positive non-small cell lung cancer with prognosis.
Authors: Ardeshir-Larijani Fatemeh , Wildey Gary , Fu Pingfu , Bhateja Priyanka , Lipka Mary Beth , Dowlati Afshin
Published: September 2018

11598

Background: Myeloid/lymphoid or mixed-lineage leukemia protein 2 (MLL2) is an epigenetic regulator expressed in many tissues. Although MLL2 mutations are associated with poor prognosis in different types of cancer, the clinical impact of this gene in lung cancer remains unclear. Here, we evaluated the clinical and genomic characteristics of MLL2 alteration in non-small cell lung cancer (NSCLC) and compared it to small cell lung cancer (SCLC) Methods: Between 2014 and 2016 tumor samples of 194 Stage III and IV NSCLC patients and 50 SCLC patients underwent targeted-exome sequencing. The association of MLL2 mutation with survival outcomes was measured using KaplanMeier methods (PFS, OS). Coxs proportional hazards regression model was performed for multivariate survival analyses with known clinical prognostic features. All tests were two-sided and p-values = 0.05 were considered statistically significant. Results: The MLL2 mutation rate was 17.5% (N=34) in NSCLC. Patients with mutant MLL2 had significantly lower overall survival (OS) (9.97 vs. 30.2 months, p < 0.0001) and progression-free survival (PFS) (8.46 vs. 24.1 month, p = 0.0007) compared to those with wild type MLL2. The median overall survival in the entire NSCLC cohort was 23.3 months (95% CI: 16.5  34.4). Interestingly, MLL2 mutation was significantly more common in females (p = 0.017). There was no significant association of MLL2 mutation status with age, smoking history, race or histology . Using a multivariate Cox regression model with adjustments based on tumor stage, smoking histology and chemotherapy, MLL2 mutation remained the most remarkable prognostic factor in NSCLC: OS Hazard Ratio 2.79, p = 0.0001 and PFS Hazard Ratio 1.99, p < 0.001. By comparison, the MLL2 mutation rate in SCLC was 24% (N=12) and showed no gender bias (p=0.874). There was no significant decrease in survival associated with MLL2 mutation in SCLC (OS p = 0.966, PFS p = 0.641). Conclusions: This study demonstrates that MLL2 mutation specifically impacts survival outcome only in NSCLC but not SCLC.
Impact of PIK3CA tumor mutation on the association of aspirin or NSAID use and time to breast cancer recurrence.
Authors: McCarthy Anne Marie , He Wei , Regan Susan , Chan Andrew T. , Moy Beverly , Iafrate A. John , Bardia Aditya , Armstrong Katrina
Published: September 2018

1521

Background: Aspirin or NSAID (A/N) use post diagnosis is associated with lower risk of breast cancer recurrence and mortality in cohort studies. A potential mechanism is that A/Ns may suppress cell growth and induce apoptosis in tumors driven by phosphatidylinositol 3 kinase ( PIK3CA), the most common oncogene mutation in breast cancer. An interaction of A/Ns and PIK3CA mutation has been observed for colorectal cancer prognosis, but has not been studied in breast cancer. The objective was to assess time to breast cancer recurrence (TTR) with respect to A/N use and PIK3CAmutation. Methods: Patients with HR+/HER2- breast cancer treated at Massachusetts General Hospital in 2009-2014 who received tumor genotyping were included. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a high-throughput tumor genotyping assay using DNA from formalin-fixed, paraffin-embedded tumor tissue. A/N use beginning 6 months post diagnosis through metastasis was extracted from electronic medical records using coded data and natural language processing. Patients with de novo metastatic disease or progressive disease within 6 months of primary diagnosis were excluded. TTR was estimated using Cox proportional hazards models. Results: Among breast cancer patients (N=212), 60 (28%) used A/Ns and 69 (33%) had PIK3CA mutation (see Table). After adjusting for age, stage, adjuvant endocrine therapy, radiation, and chemotherapy, A/N users had significantly longer TTR (HR=0.65 p=0.01). The association was similar for wild type (HR=0.58 p=0.01) and PIK3CA mutated tumors (HR=0.60 p=0.06), with no significant interaction of A/N use and PIK3CA (p=0.34). Conclusions: Among HR+ breast cancer patients, those who used A/Ns following primary diagnosis had longer TTR than non-users, regardless of tumor PIK3CA mutation status. The study provides a model for how tumor genomics could be integrated into secondary chemoprevention studies. [Table: see text]
Awareness of cervical cancer and screening among rural Nepalese women.
Authors: Shrestha Anju
Published: September 2018

1553

Background: Cervical cancer is leading female cancer in Nepal. Despite the existence of effective screening using Pap smear, the uptake of screening is poor. Objectives of this study were to determine the baseline information about the knowledge of cervical cancer and explore attitude and practice of Pap smear screening among the women of rural community of Nepal. Methods: A cross sectional population based descriptive study of female attending free cervical cancer screening camp in different rural community of Nepal organized by Nepal cancer Support group and Nepal cancer Hospital, funded by Direct Relief was conducted from 1/06/2016 to 31/12/2016- using self- administered questionnaire to elicit information on demographic characteristics, knowledge, screening behaviors and determinants of cervical cancer. Results: A total of 2529 women participated in nine screening camp, out of which 55.95% (1416) were illiterate whereas only 4.95% (129) were graduate. Mean age of participates were 40.5±11.97 (17-83)yrs. 31.63% (800) of women married before age of 16 and 32.08% (811) women had their first childbirth before age of 18 years. Only 6.88% (174) women were working outside and rest were working in household work and farming. 76.24% (1928) women knew nothing about cervical cancer. Although 38.71% (979) women heard about Pap smear, only 10.36% (262) knew about eligibility of screening, 1.58% (40) knew about screening interval and 16.57% (419) know that Pap smear is used for detections of cancerous and precancerous lesions of cervix. However, knowledge of risk factors for cervical cancer was found in 5.9% (150). Of the female respondents, 78.09% (1975) did not feel susceptible to cervical cancer and 82.25% (2080) had never been screened before. The most common reason for not doing Pap test is they never heard about it (59.99%:1516). The other reason includes do not have any symptoms (17.79%:450); embarrassment (2.49%:62); do not know where to do (1.27%:32); fear of finding out cancer (0.51%:13) and never advised by doctor (0.4%:10). Conclusions: The study revealed very low cervical cancer knowledge and poor screening behavior among the women. This may be due to lack of awareness, education and low priority of women’s health issue.
The clinical impact of the Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score on breast cancer patients survival.
Authors: Yamashita Nami , Inoue Yuka , Tanaka Kimihiro , Saeki Hiroshi , Oki Eiji , Tokunaga Eriko , Maehara Yoshihiko
Published: September 2018

1560

Background: Recent reports show that the preoperative immunonutritional status correlate with the survival rate in cancer patients. The Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are used as screening tools for immunonutritional status and reported to be a predictor of postoperative recurrence in patients with various gastrointestinal cancers. However, the clinical importance of the PNI and CONUT in breast cancer has not been elucidated. The aim of this study is to investigate the clinical impact of preoperative PNI and CONUT on long-term survival of breast cancer patients. Methods: We retrospectively analyzed 653 consecutive stage I-III breast cancer patients who were treated from January 2002 to December 2013. The PNI score was calculated as 10 x serum albumin (g/dl) + 0.005 x total lymphocyte count (per mm3). The CONUT score is calculated from three parameters, serum albumin, cholesterol, and total lymphocytes count. The patients were divided into two groups according to the PNI and CONUT score. The uni- and multivariate Cox regression analyses were performed to evaluate the prognositic value of the PNI and CONUT in breast cancer. Results: The malnutritional status was observed in 170 (26%) and 131 (20%) patients as low-PNI and high-CONUT, respectively. The relapse-free survival (RFS) and overall survival (OS) rates were significantly lower in the low-PNI group (RFS: p < 0.0001, OS: p < 0.0001) and high-CONUT group (RFS: p = 0.0009, OS: p = 0.0018). In the multivariate analysis, low-PNI was independent prognostic factors for both RFS and OS (RFS: HR2.33, p = 0.032, OS: HR5.01, p = 0.0009). In the subset analysis, the low-PNI group showed poor prognosis especially in the postmenopausal, hormone receptor negative patients. The low-PNI also had poorer prognosis in post-recurrence survival. Conclusions: The preoperative PNI is a strong independent predictor of long-term survival among breast cancer patients.
Development and validation of a residual risk score to predict breast cancer risk in unaffected women negative for mutations on a multi-gene hereditary cancer panel.
Authors: Hughes Elisha , Judkins Thaddeus , Wagner Susanne , Wenstrup Richard J. , Lanchbury Jerry S. , Gutin Alexander
Published: September 2018

1579

Background: Women who are unaffected with cancer but have a significant family history of breast cancer (BC) are frequently referred for hereditary cancer testing with multi-gene panels; however, < 10% test positive for clinically actionable mutations. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms) that individually confer modest BC risk, but together may explain the genetic susceptibility for BC in many women without monogenic mutations. Here, we describe the development and validation of a polygenic residual risk score in a large, consecutive cohort of women who tested negative for mutations in known BC susceptibility genes. Methods: This IRB-approved study includes women of European ancestry tested with a multi-gene hereditary cancer panel who were negative for mutations in 11 genes associated with BC ( BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Clinical information was collected from provider-completed test request forms. The dataset was divided into a training (July – November 2016) and validation cohort (November 2016 – April 2017). Multivariable logistic regression models were used to evaluate 94 common variants and develop candidate residual risk scores as predictors of personal BC history (invasive ductal carcinoma, IDC) in the training cohort. Independent variables included age, personal/family cancer history, and ancestry. An optimal subset of the 94 common variants and a residual risk score will be selected through cross-validation followed by independent validation. Results: The training cohort includes 11,838 women (median age 47 years), 18% of whom reported a personal history of IDC and 36% of whom reported BC in a first-degree relative. Results from validation of the residual risk score in an independent cohort of approximately 12,000 women will be completed at the time of presentation. Conclusions: The validation and clinical implementation of a residual risk score for women at risk for hereditary BC may offer significant potential for the management of high-risk, unaffected women who test negative for monogenic BC mutations.
Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.
Authors: Bonneterre Jacques , Bertrand Nicolas , Tresch-Bruneel Emmanuelle , Dumont Aurelie , Preusser Matthias , Weller Michael , Revillion Francoise , Le Rhun Emilie
Published: September 2018

2007

Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p < 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, < 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.
Results of the OPARATIC trial: A phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM).
Authors: Halford Sarah E. R. , Cruickshank Garth , Dunn Laurence , Erridge Sara , Godfrey Lisa , Herbert Christopher , Jefferies Sarah , Lopez Juanita Suzanne , McBain Catherine , Pittman Marc , Sleigh Rebecca , Watts Colin , Webster-Smith Mark F , Chalmers Anthony J.
Published: September 2018

2022

Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. Results: 48 patients were recruited (median age 51(18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in 73 of 74 tumor core specimens from 27 patients; mean conc. 588nM (97-1374nM), and in 27 of 28 tumor margin specimens from 10 patients; mean conc. 500nM (97-1237nM). Margin: core ratios ranged from 0.2–3.9(mean 1.2); tumor: plasma ratios ranged from 0.01 to 0.9 (mean 0.25). Olaparib dosing on days 1-5 was hindered by myelosuppression. Expansion cohort dose was defined as TMZ 75 mg/m2daily plus olaparib 150 mg (OD) days 1-3 weekly. Of 13 evaluable patients receiving expansion dose-schedule, 9 completed cycle 1, 2 completed cycle 2 and 2 completed cycle 3. Currently 45% of the evaluable patients remain progression-free at 6 months, with 2 still on treatment (full data set May2017). Of 35 evaluable patients, 24 experienced AE Grade ≥3 (see Table). Conclusions: Olaparib penetrates both core and margins of recurrent GBM despite failing to penetrate the intact brain barrier in pre-clinical heathy rodent models. Combination with extended low dose TMZ is safe and well tolerated, yielding encouraging 6 month progression-free survival rates. Clinical trial information: NCT01390571. [Table: see text]
Comparison of 2-hydroxyglutarate (2HG) levels in tissue and serum of isocitrate dehydrogenase (IDH)-mutated (MUT) versus wild-type (WT) gliomas.
Authors: Sim Hao-Wen , Nejad Romina , Zhang Wenjiang , Mason Warren P. , Bernstein Mark , Aldape Ken , Zadeh Gelareh , Chen Eric Xueyu
Published: September 2018

2037

Background: IDH mutations are common in low-grade gliomas and confer significantly improved prognosis. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, and subsequently to the oncometabolite 2HG. Mutant IDH leads to preferential accumulation of the R relative to the S enantiomer of 2HG. We analyzed the ratio of R to S enantiomers (rRS) in glioma tissues and matched serum samples, and correlated findings with IDH status, 1p19q codeletion status and survival. Methods: Fresh frozen glioma tissues and matched serum samples were obtained from the University of Toronto Brain Tumor Bank. IDH status was determined by immunohistochemistry and confirmed by 450K methylation profile or direct sequencing. 1p19q codeletion status was determined by loss-of-heterozygosity PCR analysis. R-2HG and S-2HG levels were quantified using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC column. Results: Glioma tissues from 70 patients were analyzed – 52 with IDH MUT and 18 WT. 30 had matched serum samples. Using glioma tissues, rRS clearly distinguished MUT vs WT (median 574 vs 1.3, p < 1x10-9) with only three outliers. In contrast, rRS was not elevated in serum samples (median 1.5 vs 1.2, p = 0.13). Overall survival (OS) was significantly longer for MUT vs WT (median 178 vs 33 months, p < 1×10-7). Stratifying MUT by tissue rRS, median OS was 197, 178, 178 and 122 months for lowest to highest quartiles of rRS respectively. 1p19q codeletion status and tumor latency did not explain this trend, given rRS was similar in codeleted vs non-codeleted MUT, and similar in MUT operated < 3 vs ≥3 months from diagnosis. Progression-free survival results corresponded to OS. Conclusions: rRS from glioma tissues effectively differentiated MUT vs WT, whereas serum samples were unreliable. Unlike current methods, tissue rRS enables real-time determination of IDH status, and thus may guide clinical practice such as extent of surgical resection intraoperatively and upfront selection of adjuvant therapy. rRS potentially stratifies survival within MUT patients, providing detailed correlative information.
Expanded phase I study of intratumoral Ad-RTS-hIL-12 plus oral veledimex: Tolerability and survival in recurrent glioblastoma.
Authors: Chiocca E. Antonio , Yu John , Phuphanich Surasak , Lukas Rimas Vincas , Kumthekar Priya , Yang Yijun , Zhou Qiang (John) , Buck Jill Y. , Deary Alicia , Cai Hongliang , Barrett John A. , Cooper Laurence JN , Lebel Francois M.
Published: September 2018

2044

Background: Glioblastoma (GBM) is an aggressive brain tumor affecting ~74,000 people worldwide annually. Recurrent GBM patients have a median OS (mOS) of 6-7 months. OS in patients who have failed temozolomide, bevacizumab or equivalent salvage chemotherapy, is ~3-5 months. New therapies are urgently needed. Ad-RTS-hIL-12 (Ad) is a novel gene therapy expressing IL-12 under the control of an oral activator ligand, veledimex (V), through the RheoSwitch Therapeutic System. Intratumoral administration of Ad results in targeted tumor cytotoxicity and induction of systemic T cell memory. Ad + V is a treatment strategy to extend the IL-12 therapeutic window. Methods: In a multicenter Phase I dose escalation trial and expansion cohort, subjects with recurrent or progressive Grade III or IV glioma undergoing resection were injected intratumorally with Ad 2 x 1011 viral particles and daily oral V for 15 doses, beginning prior to surgery. The primary endpoint is safety and tolerability of Ad + V; secondary endpoints include OS. Results: 25 subjects were dosed in 3 dose escalation cohorts: 20 mg (n = 7), 30 mg (n = 4), and 40 mg (n = 6) and an expansion cohort of 20 mg (n = 8). Results show V crossed the blood brain-barrier with 35±5% of plasma levels detected in the brain tumor. The 20 mg dose (n = 15) had better drug compliance (86%) than the 30 mg (63%) or 40 mg (52%) cohorts and the 20 mg cohort shows better survival (mOS 12.7 months) compared to other cohorts. The frequency of related ≥Grade (G)3 AEs in the 20 mg cohort was significantly lower: 20% in 20mg, 50% in 30mg and 40 mg. In the 20 mg cohort, the most frequent AEs were transient mild flu-like symptoms seen in 12/15, G3 cytokine release syndrome in 2/15, G3 elevated ALT/AST in 1/15 and G3 lymphopenia in 3/15. All AEs reversed promptly upon discontinuing V. Conclusions: Overall, Ad + 20 mg V is well tolerated; toxicities were predictable and reversible upon discontinuing V. There is a correlation between V dose, BBB penetration and drug related AEs. The tolerability and encouraging survival observed to date warrant further investigation in a pivotal trial. A stereotactic arm and a pediatric trial in diffuse intrinsic pontine glioma patients are planned. Clinical trial information: NCT02026271.
An investigator-initiated phase I study of ONX-0801, a first-in-class alpha folate receptor targeted, small molecule thymidylate synthase inhibitor in solid tumors.
Authors: Banerji Udai , Ingles Garces Alvaro Henrique , Michalarea Vasiliki , Ruddle Ruth , Raynaud Florence I. , Riisnaes Ruth , Nava Rodrigues Daniel , Tunariu Nina , Porter Joanna C , Ward Sarah Emily , Parmar Mona , Turner Alison Joanne , Seeramreddi Satyanarayana , Hall Emma , Dean Emma Jane , Basu Bristi , George Angela , Kaye Stan B , Banerjee Susana N. , De Bono Johann S.
Published: September 2018

2503

Background: ONX-0801 is a first-in-class alpha folate receptor (AFR) targeted thymidylate synthase inhibitor, engineered to differentially accumulate 6000-fold in AFR overexpressing cancer cells. Methods: A 3+3 dose escalation design was used and two IV schedules were explored. Schedule A, weekly dosing (QW) and schedule B, once every 2 weeks dosing (Q2W). A cycle consisted of 4 weeks and treatment was stopped after 6 cycles in both schedules. An expansion cohort to evaluate clinical activity in patients with AFR overexpressing high grade serous ovarian cancer (HGSOC) was planned. Results: 21 patients each were treated in schedule A and B exploring doses ranging from 1-6 mg/m2 and 2-12 mg/m2, respectively. The dose limiting toxicity on schedule A was G3 cellulitis; no dose limiting toxicity was seen on schedule B. The most common toxicities were fatigue 15/42 (36%), nausea 9/42 (21%) and dysgeusia 5/42 (12%). Within schedule A at 4 mg/m2, 2 patients developed suspected drug-related changes on pulmonary function tests (drop in Dlco > 15%) at cycles 5 and 6, respectively. No cases of suspected drug-related drop in Dlco were noted in patients treated in schedule B. No grade 3-4 diarrhea, mucositis or neutropenia were seen in either cohort. The Cmax, AUC and half-life at 12 mg/m2 were 4952 ng/mL, 85170 h*ng/mL and 26 h, respectively. Pre-clinical PK-PD modelling aimed to achieve concentrations between 0.05-1 µM and this was achieved for periods of 48 h at doses of 4 mg/m2and above. Based on safety and PK, the recommended phase II dose (RP2D) of ONX-0801 was 12 mg/m2 Q2W and an expansion in patients with HGSOC is ongoing. 5 patients with HGSOC had partial responses (PRs) in the dose escalation cohort. In the current expansion cohort in patients with HGSOC, 5/11 patients had PRs. Archival samples have been analyzed from 8/11 patients in the expansion cohort. 4/4 AFR+ve and 4/4 AFR-ve patients did and did not have a PR following treatment with ONX-0801, respectively. Conclusions: The RP2D of ONX-0801 is 12 mg/m2 Q2W. At the RP2D, multiple patients with AFR overexpressing HGSOC have had PRs and further randomized biomarker prespecified phase II trials are warranted. Clinical trial information: NCT02360345.
Phase I study of ABBV-399, a c-Met antibody-drug conjugate (ADC), as monotherapy and in combination with erlotinib in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Angevin Eric , Strickler John H. , Weekes Colin D. , Heist Rebecca Suk , Morgensztern Daniel , Nemunaitis John J. , Fan Xiaolin , Beaulieu Juliette , Motwani Monica , Afar Daniel E. , Naumovski Louie , Kelly Karen
Published: September 2018

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Background: The c-Met receptor is overexpressed in ~50% of pts with NSCLC. ABBV-399 is a first-in-class ADC composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells. Methods: ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monoT; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met overexpression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA). Results: As of January 9, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monoT. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), and anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3, 4.5, and 10+ months. At week 12, 6 of 16 pts (37.5%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (30.8%), and acneiform rash, diarrhea, fatigue, nausea, and dry skin (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 1+, 2.7, 5.3+, and 11+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 8 of 13 pts (61.5%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology. Conclusions: ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Updated efficacy/safety data and MET gene status will be presented. Clinical trial information: NCT02099058.
Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy.
Authors: Bernatchez Chantale , Haymaker Cara L. , Hurwitz Michael E. , Kluger Harriet M. , Tetzlaff Michael T. , Jackson Natalie , Gergel Ivan , Tagliaferri Mary Ann , Zalevsky Jonathan , Hoch Ute , Fanton Christie , Iacucci Ernesto , Aung Sandra , Imperiale Michael , Liao Ej , Bentebibel Salah E , Tannir Nizar M. , Hwu Patrick , Sznol Mario , Diab Adi
Published: September 2018

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Background: NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand effector CD8+ T and NK cells over T regulatory cells in the tumor microenvironment. Immune changes in the tumor microenvironment after NKTR-214 treatment was assessed in patients with locally advanced or metastatic solid tumors. Methods: NKTR-214 was administered IV in an outpatient setting q2w or q3w. Serial blood and tumor tissue samples were collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression analyses. Results: 26 patients (pts) have been treated with NKTR-214 at q3w, 4@0.003, 9@0.006, 6@0.009 and 1@0.012 mg/kg. Six pts received 0.006 mg/kg q2w. 58% of pts had prior immunotherapy. The most common Gr1-2 TRAEs were fatigue (73%) and pruritus (65%), and decreased appetite (46%). One pt experienced Gr3 syncope and hypotension at the highest dose tested and continued treatment at a lower dose. No drug-related AEs led to study discontinuation. No immune-related AEs or capillary leak syndrome were observed. 6 pts (23%) experienced tumor shrinkage from 10-30%. Three immunotherapy naïve pts receiving sequential anti-PD1 therapy, after ending treatment with NKTR-214, experienced significant tumor regression at first scan. In all pts evaluated, blood samples showed increases in newly proliferating (Ki67+) T and NK cells 8 days post dose. Flow cytometry and/or IHC revealed an up to 10-fold increase from baseline in tumor CD8+T and NK cells in the tumor microenvironment, with minimal changes to Tregs. PD-1 expression increased 2-fold in TILs. Gene expression analysis of tumor tissue showed increases in several immune checkpoint genes, cytotoxic markers (IFNg, PRF1, and GZMB), as well as a dynamic change in T cell clonality. Conclusions: Based on a favorable safety profile and strong correlative biomarker data, a phase 1/2 trial combining NKTR-214 and nivolumab is currently enrolling. Clinical trial information: NCT02869295.
First-in-human phase I study of an oral HSP90 inhibitor, TAS-116, in advanced solid tumors.
Authors: Yanagitani Noriko , Horiike Atsushi , Kitazono Satoru , Ohyanagi Fumiyoshi , Kondo Shunsuke , Shimomura Akihiko , Fujiwara Yutaka , Doi Toshihiko , Kuboki Yasutoshi , Kawazoe Akihito , Shitara Kohei , Ohno Izumi , Banerji Udai , Sundar Raghav , Ohkubo Shuichi , Huang Jerry M. , Nishio Makoto , Yamamoto Noboru
Published: September 2018

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Background: TAS-116 is an oral non-ansamycin, non-purine, and non-resorcinol highly selective inhibitor of HSP90α/β. The objective of this FIH study was to determine the MTD and investigate the safety, tolerability, PK, PD (HSP70 protein levels in PBMCs), and antitumor activity of TAS-116. Methods: The study is being conducted in Japan and the UK. Patients with advanced solid tumors received escalating doses of TAS-116 once daily (QD) with an accelerated titration design. After the MTD was determined, safety and tolerability of 5 days on / 2 days off per week administration (QDx5) at the MTD in QD was explored. In parallel, the MTD with every other day administration (QOD) was evaluated by using a 3 + 3 design. Results: As of 20 September 2016, 52 patients were enrolled. TAS-116 was evaluated at doses of 4.8 to 150.5 mg/m2/day in the QD schedule and doses of 107.5 to 295.0 mg/m2/day in the QOD schedule. The MTD was 107.5 mg/m2/day with QD and 210.7 mg/m2/day with QOD. QDx5 at the MTD in QD using a flat dose of 160 mg was evaluated. The most common adverse events in all regimens were gastrointestinal disorders and increased creatinine. DLTs were observed in 4 patients in QD (night blindness, visual disorder, AST/ ALT/gamma-GTP elevations, and anorexia) and in 2 patients in QOD (platelet count decreased, febrile neutropenia, pneumonia, respiratory failure, and septic shock). Reversible eye disorders were observed in all schedules, but those observed in QDx5 were limited to grade 1. The PK level demonstrated dose proportionality without unexpected accumulation under repeated administration. Dose-related HSP70 induction of PBMCs was observed. As of 20 September 2016, three confirmed durable PRs by RECIST were observed (239 days in GIST and 173 days in NSCLC with QD; 293 + days in NSCLC with QOD). PR and SD ≥ 12 weeks were observed in 15 out of 47 patients. Conclusions: TAS-116 had an acceptable safety profile under all schedules, especially QDx5. Preliminary antitumor activity was demonstrated with evidence of target engagement. Dose expansion at the MTD in this phase 1 study and the phase 2 study in patients with GIST are ongoing. Parts of this study will be expanded to the US with an amended study protocol. Clinical trial information: NCT02965885.
Axitinib plus crizotinib in patients with advanced solid tumors and metastatic renal cell carcinoma (mRCC): Preliminary phase 1b results.
Authors: Michaelson M Dror , Gupta Shilpa , Agarwal Neeraj , Szmulewitz Russell Zelig , Powles Thomas , Pili Roberto , Bruce Justine Yang , Vaishampayan Ulka N. , Larkin James M. G. , Rosbrook Brad , Lechuga Mariajose , Valota Olga , Tarazi Jamal Christo , Shepard Dale Randall
Published: September 2018

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Background: Axitinib (AX) is a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) and a standard treatment for mRCC. Upregulation of mesenchymal-epithelial transition factor (c-MET) is implicated in resistance to VEGFR-directed therapy. An ongoing ph Ib study (NCT01999972) evaluated the safety and efficacy of AX + crizotinib (CZ), a TKI of c-MET, anaplastic lymphoma kinase (ALK), and ROS1. Methods: mRCC patients (pts) with advanced solid tumors were treated with AX + CZ in a dose escalation phase (DESC). After determining maximum tolerated dose (MTD) (modified toxicity probability interval), mRCC pts were enrolled into 2 cohorts in a dose expansion phase (DEXP). Cohort 1 (C1) was treatment-naïve and C2 had 1–2 prior therapies. The primary objectives were to assess the tolerability of AX + CZ, to obtain the MTD, and to select the recommended phase II dose. Results: As of Aug 5, 2016, 24 pts were screened and 22 pts treated in the DESC. Pts received AX 3 mg twice daily (BID) + CZ 200 mg BID (n = 5); AX 3 mg BID + CZ 250 mg BID (n = 3); AX 5 mg BID + CZ 200 mg BID (n = 4); or AX 5 mg BID + CZ 250 mg BID (n = 10) in a median 4 (range 1–23) cycles. There were no cycle 1 dose-limiting toxicities. One pt discontinued due to an AX-related alanine aminotransferase increase. Fifteen (68.2%) pts experienced Grade 3–4 adverse events (AEs), none in ≥2 pts; 1 pt had a Grade 5 AE (disease progression). AX 5 mg BID + CZ 250 mg BID was established as the MTD. Most frequent AEs in the MTD group were fatigue (70.0%), nausea (70.0%) and diarrhea (60.0%). In the ongoing DEXP, 15 pts have been treated at the MTD (n = 11 in C1, and 4 C2). Response evaluation (RECIST) is ongoing, with 1 complete response (CR), 3 partial responses (PR) and 4 stable disease (SD) in 10 pts in C1, and 1 PR and 2 SD in 4 pts in C2. Overall, 10 (66.7%) pts experienced Grade 3–4 AEs and 1 pt had a Grade 5 AE (disease progression). Most frequent AEs (≥60% pts) were nausea and diarrhea. Conclusions: We have identified AX 5 mg BID + CZ 250 mg BID as the MTD for combination therapy. This regimen has manageable toxicities and exhibits antitumor activity in treatment-naïve and pretreated mRCC. Further studies in VEGFR, c-MET, ALK and ROS1 tumor types are warranted. Clinical trial information: NCT01999972.
Phase I study of indenoisoquinolines LMP776 in adults with relapsed solid tumors and lymphomas.
Authors: O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Meehan Robert S. , Streicher Howard , Takebe Naoko , Sharon Elad , Conley Barbara A. , Harris Lyndsay , Collins Jerry M. , Moore Nancy , Juwara Lamin , Rubinstein Larry , Quinn Mary Flanagan , Pommier Yves , Cushman Mark , Doroshow James H. , Chen Alice P.
Published: September 2018

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Background: Indenoisoquinolines (ID) are non-camptothecin inhibitors of topoisomerase (TOP1) identified following a COMPARE analysis of the National Cancer Institute’s (NCI) in vitro anticancer drug discovery screen. IDs have improved characteristics over camptothecin top1 inhibitors, with better chemical stability (lacking the labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the trapped DNA-TOP1 cleavage complex and at different DNA sequence sites to camptothecins (Kohlhagen et al. Mol Pharmacol. 2005). IDs have shown more activity against camptothecin-resistant cell lines and mouse models, as well as in cells overexpressing the ATP-binding cassette (ABC) transporters, and multidrug resistance (MDR-1/ABCB1) genes. A parallel first-in-human Phase I study conducted at the NCI of LMP400 in patients with refractory solid tumors and lymphomas showed this molecule to be well tolerated (Kummar et al, Cancer Chemother Pharmacol. 2016). A trial of LMP776 (NSC725776), has completed accrual. Primary Objectives: define the maximum tolerated dose (MTD) of LMP776 and the dose-limiting toxicities (DLTs). Methods: Phase I trial using Design 4 of the Simon accelerated titration designs (Simon et al. JNCI, 1997), with doses escalated based on toxicity during cycle 1. LMP776 was administered via central line QD over 1 hour on days 1–5 q 28-days. Response is defined by RECIST 1.1 on CT. Results: 32 of 34 patients (pts) were evaluable for toxicity and response. Enrollment was expanded at dose level (DL) 2 to 6 pts due to a hypocalcemia DLT, with subsequent enrollment on a 3+3 design. MTD was established at DL7 (12mg/m2, DLT myelosuppression). Common Grade 3/4 adverse events by CTCAE v.4 included anemia (5 pts, 15%), thrombocytopenia (5), lymphopenia (5) and neutropenia (3 pts, 9%). 12 (37%) pts experienced stable disease (SD), with a median of 4 cycles of treatment (range 2-9). 10 (30%) pts with SD remained on study for ≥4 months, with 4 pts on study ≥6 months. Conclusions: LMP776 is overall well tolerated. Explorative correlatives and additional trials are being considered. Clinical trial information: NCT01051635.