bluuebunny/crossref_metadata_2025_split huggingface dataset:
C-met, a new prognostic biomarker in glioblastoma multiforme.
Authors: Dahlrot Rikke Hedegaard , Petterson Stine Asferg , Hermansen Simon Kjaer , Kristensen Bjarne Winther , Hansen Steinbjorn 
Published: March 2020

2088 Background: C-met is a tyrosine kinase receptor involved in growth, invasiveness and malignant progression in glioblastoma multiforme (GBM). Activation of the C-met pathway increases resistance towards DNA damage in glioma cell lines and it has been shown that an orally administrated C-met kinase inhibitor inhibits intracranial glioma growth in immunodeficient mice, suggesting that C-met is a potential target in glioma treatment. The purpose of the present study was to investigate the prognostic value of C-met in GBMs and subsequently correlate the prognostic value to known clinical variables, identified in a population-based cohort. Methods: Tissue samples from 186 GBM patients were analyzed using immunohistochemical staining and advanced quantitative image analysis. This provided continuous measurements based on staining intensity. Results: Median intensity was 70.8 (range 15.5-200.1). When divided at the median C-met was not prognostic. Further exploration showed that dichotomizing at an intensity of 75 (60% vs. 40%), high levels of C-met were associated with poor survival. However; C-met is a time-dependent factor and no prognostic effect was observed within the first 8.5 months after diagnosis (HR 0.97, 95% CI 0.62-1.51, p = 0.892). After 8.5 months, patients with high levels of C-met had a significantly poorer survival as compared to patients with low levels (HR 2.06, 95% CI 1.33-3.18, p = 0.001). This was significant in multivariate analysis adjusted for clinical variables; C-met (HR 1.89, 95% CI 1.22-2.93, p = 0.004), age (HR 1.02, 95% CI 1.00-1.03, p = 0.037), performance status (HR1.55, 95% CI 1.38-1.74, p = 0.004), and tumor crossing midline (HR 1.72, 955 CI 0.75-3.92, p = 0.201). Interestingly; C-met was only prognostic in patients who received post-surgical treatment, whereas no effect was observed in the 31 patients who underwent surgery only (HR 0.54, 95% CI 0.26-1.15, p = 0.113). Conclusions: Using advanced quantitative image analysis, we found that C-met was an independent prognostic factor of poor survival in GBMs. The effect did not appear within the first 8.5 months after the diagnosis and it was only seen in patients who received post-surgical treatment.
Effect of metformin and statins in high-grade brain tumors.
Authors: Lee Guek Eng , Tan Iain B. , Tham Chee Kian 
Published: March 2020

2091 Background: Metformin and statins are thought to have anti-cancer properties. Metformin induces AMPK activation and may be implicated in potentiating the therapeutic outcome of temazolamide. Statins at low dose are thought to have anti-cancer properties by inhibiting pro-angiogenic factors with resultant inhibition of tumor growth, but statins at high dose are thought to have counter-productive effects. Hyperglycaemia was shown to be associated with a poorer outcome in patients with newly diagnosed glioblastoma. Hence we investigate the effect of metformin and statins in high grade brain tumours. Methods: Among 249 patients with brain tumour, we identified 142 patients with high grade gliomas. 116 patients did not receive metformin or statins and 26 patients received metformin or statins. Patients’ demographics, clinical and histopathological characteristics were recorded. Overall survival was evaluated. Results: Among 142 patients with high grade gliomas, there were 86 patients with glioblastoma multiforme, and 56 patients with anaplastic astrocytoma or anaplastic oligodendroma. Median age was 60 years old. The average value of HbA1c value for patients on metformin was 7.2%. The average dose of simvastatin used was 20 mg and average total cholesterol was 5.1mmol/l. For patients who did not receive metformin or statins, the median survival was 72.9 months (95% confidence interval, 47.8 – 98.1); patients who received metformin or statins, the median survival was 39.1 months (95% confidence interval, 21.7 – 56.4) p = 0.24. Conclusions: There is a trend towards shorter overall survival of patients who received metformin and statins. Despite the anti-cancer properties of metformin and statins, patients with diabetes mellitus and hyperlipidaemia still fare worse. The effect of diabetes mellitus, hyperlipidaemia, as well as sugar and cholesterol control deserves a larger cohort study in patients with high grade brain tumours.
Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma or progressive secondary brain tumor.
Authors: Peyton James D. , Burris Howard A. , Bacha Jeffrey A. , Brown Dennis , Garner William J. , Schwartz Richard Stephen , Shih Kent C. 
Published: March 2020

2093 Background: Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat, and median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme (GBM). The front-line therapy for GBM - temozolomide (TMZ) - is subject to resistance by DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), leading to poor prognoses for patients with recurrent GBM. Dianhydrogalactitol (VAL-083)is a first-in-class bi-functional N7 DNA alkylating agent shown to cross the blood-brain barrier, accumulate in brain tissue, and have activity against GBM. Studies suggest that VAL-083 overcomes MGMT-driven drug resistance in vitro and targets cancer stem cells. The purpose of this study is to determine the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent GBM or progressive secondary brain tumor, and explore the safety, pharmacokinetics and tumor responses to treatment. Methods: Open-label phase I/II dose-escalation study of VAL-083 in patients with histologically confirmed primary WHO grade 4 malignant GBM, now recurrent, previously treated for GBM with surgery and/or radiation, if appropriate, and have failed both bevacizumab and temozolomide; or progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. The study uses a 3 + 3 dose escalation design, until reaching the MTD or maximum specified dose. Patients receive IV VAL-083 on days 1, 2, and 3 of each 21-day treatment cycle. In phase II, additional patients are treated at the MTD (or selected optimum dose) to measure tumor responses. Results: Cohort 1 (3 patients) and cohort 2 (4 patients) were completed without any DLT’s. Adverse events (AEs) have all been grade 1/2, with only 1 grade 3 AE, unrelated to treatment. Cohort 3 currently has 4 patient enrolled, without reaching the MTD. 1/7 (14.3%) patients in cohorts 1and 2 has prolonged stable disease (15+ cycles) on VAL-083 treatment. Conclusions: VAL-083 up to the 2nd dose level was well tolerated without any safety signals. Dose escalation is continuing. Clinical trial information: NCT01478178.
Phase I trial of temsirolimus (TEM) and perifosine (PER) for recurrent or progressive malignant glioma (MG).
Authors: Kaley Thomas Joseph , Pentsova Elena , Omuro Antonio Marcilio Padula , Mellinghoff Ingo K. , Nolan Craig , Gavrilovic Igor T. , DeAngelis Lisa Marie , Lacouture Mario E. , Holland Eric C. , Lassman Andrew B. 
Published: March 2020

2095 Background: PI3K/AKT/mTOR signaling is important in MG biology, and therefore a potential therapeutic target. The mTOR inhibitor TEM and the AKT inhibitor PER are well tolerated as single agents but have limited activity. Preclinical data demonstrate synergistic anti-tumor effects during combined therapy including extensive tumor apoptosis, cell-cycle arrest among surviving cells, and inhibition of both AKT and mTOR. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs. Methods: Adults with recurrent MG, KPS≥60, and not taking enzyme inducing AEDs were enrolled. There was no limitation on prior therapies except prior RT and temozolomide were mandatory. The dose of TEM was escalated in each cohort using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. The dose of PER was fixed as a 600 mg load on day 1 followed by 100 mg nightly (the single dose MTD) until dose level 7 when the load increased to 900mg. Results: Thirty-four patients (24 men) with median age 52 (range, 21-71) and median KPS 80 (range, 60-100) participated. Diagnoses included GBM (18), AA (7), AO (7) or transformed LGG (2). Twenty-one received bevacizumab previously. There were a total of 5 DLTs: 1 at dose level 3 (50mg TEM), then 2 at dose level 7 expansion (170mg TEM), and then 2 at dose level 6 expansion (170mg TEM). DLTs included thrombocytopenia (n=3), intracerebral hemorrhage (n=1) and lung infection (n=1). Two uPR were seen at 170mg TEM. Grade 3 non-dose limiting toxicities per patient included lymphopenia (7), hyperglycemia (4), anemia (2), neutropenia (1), transaminitis (3), hypophosphatemia (3), hypercholesterolemia (3), thrombocytopenia (2), and mucositis (2). The MTD is defined as 115mg TEM (dose level 5). Conclusions: Combination therapy with TEM 115 mg weekly and PER 100 mg daily (following 600 mg load) is tolerable in heavily pre-treated adults with recurrent MGs. Clinical trial information: NCT01051557.
Graded prognostic assessment index for breast cancer patients with brain metastases (BCBM).
Authors: Alva Venur Vyshak , Dahiya Saurabh , Du Lingling , Garje Rohan , Osei-Boateng Kwabena , Elson Paul , Suh John H. , Chao Samuel T. , Ahluwalia Manmeet Singh 
Published: March 2020

2096 Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index based on RTOG protocols in patients with brain metastases (BM). The purpose of this study was to evaluate prognostic factors to predict for overall survival (OS) in breast cancer BM (BCBM) treated at a single tertiary care center. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify BCBM who were treated in the recent years (2000-12). A proportional hazards model was used to assess OS, which was measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 161 BCBM (160 females) median age 52 years (range 27-84) were included for analysis. 48% of patients were ER positive, 31% were PR positive, 50% were HER2 positive while 31% of patients were triple negative. The median number of BM was 2 (range, 1-15). Karnofsky Performance Scale (KPS) of the patient was 90-100 in 50%, 70-80 in 47%) and <70 in 43%. Extracranial Metastases was present in 85% of patients. Overall 85% of patients had died at the time of analysis; median OS was 19.0 months (95% C.I. 15.7-23.2). Breast GPA that includes age, KPS and subtype was 0-1.0 in 5%, 1.5-2 in 31%, 2.5-3 in 35% and 3.5-4 in 29% of patients. Although GPA was statistically significant (p=0.002), some but not all of the factors used to derive it were significant (KPS [p=0.05],subtype [p=0.003] age [p=0.50]). Factors noted to be independently prognostic for OS (multivariable Cox proportional hazards model) included location of BM, number of extracranial metastases and uncontrolled primary tumor (Table). Conclusions: New GPA based on a set of independent prognostic factors is proposed. [Table: see text]
Post-bevacizumab treatment and clinical outcomes in recurrent malignant glioma.
Authors: Cha Yongjun , Kim Yu Jung , Kim Tae Min , Choi Seung Hong , Lee Se-Hoon , Kim Dong-Wan , Park Chul-Kee , Kim Il Han , Kim Jee Hyun , Kim Eunhee , Choi Byung Se , Kim Chae-yong , Kim In Ah , Heo Dae Seog 
Published: March 2020

2098 Background: Bevacizumab (Bev) and irinotecan combination therapy is effective against recurrent malignant glioma. However, post-Bev treatment and its clinical outcomes are not well investigated. Methods: We identified 103 consecutive recurrent malignant glioma patients who received Bev plus irinotecan at our institutions.Clinical records and magnetic resonance images were reviewed. Response and progression were assessed by RANO criteria. Results: Bev and irinotecan treatment produced response rate of 37.9% (95% CI, 29.1-47.5%). At a median follow-up time of 41 weeks, the median progression-free survival (PFS) was 17.1 weeks (95% CI, 14.3-20.0), and 6-month PFS (6M-PFS) was 27.8% (95% CI, 18.4-37.2). The median overall survival (OS) was 33.4 weeks (95% CI, 27.8-39.1). Response predicted for superior PFS (25.0 weeks vs. 11.0 weeks, p < .001) and OS (45.9 weeks vs. 26.7 weeks, p < .001). A total of 93 patients discontinued Bev treatment and the reasons for discontinuation were: disease progression in 59 (63.4%), toxicities in 4 (4.3%), physician’s decision in 5 (5.4%), patient’s refusal to further treatment in 25 (26.9%). The median OS was 26.7 weeks in 59 patients who discontinued Bev due to disease progression, and 45.7 weeks in 34 patients who discontinued Bev for reasons other than disease progression (p < .001). Among 85 patients who progressed after Bev, 42 (49.4%) received further therapy: chemotherapy in 32 (37.6%), radiotherapy in 9 (10.6%), and surgery in 1 (1.2%). Further chemotherapy regimens included temozolomide (31.2%), ACNU/CDDP (25.0%), Bev reintroduction (18.8%), erlotinib (12.5%), PCV (9.4%), and intrathecal methotrexate (3.1%). The median survival time after Bev failure was 15.6 weeks (95% CI, 13.3-17.8). Patients who received further therapy showed longer median OS (18.6 weeks vs. 12.9 weeks, p < .001). In patients who received chemotherapy, the median PFS and OS was 6.6 weeks and 20.6 weeks, respectively. Conclusions: Prognosis after Bev failure was poor. Proper selection of patients who may benefit from further treatment is warranted.
Vorinostat as a radiosensitizer for CNS malignancies: Preclinical results and phase I trial in brain metastasis.
Authors: Shi Wenyin , Lawrence Yaacov Richard , Choy Hak , Wachsberger Phyllis R. , Andrews David W. , Werner-Wasik Maria , Dicker Adam 
Published: March 2020

2100 Background: To evaluate the effect of vorinostat as radiosensitizer in human Glioblastoma cell lines in preclinical study, as well as a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) for patients with brain metastasis. Methods: Preclinical studies evaluated the effect of vorinostat on DNA repair enzyme expression, repair of radiation induced DNA damage, and cell survival to radiation treatment as a proof of concept. Further phase I clinical trial included patients with histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 mg to 400 mg daily using a 3+3 trial design. Results: Preclinical studies showed with increasing doses of vorinostat more profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. It enhanced the radiation effect in vitro. In the phase I trial, 17 patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n=1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 mg and 300 mg dose levels. In the 400mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Although both events were most likely related to disease progression rather than treatment. However, to be more conservative, we defined the death as a dose limiting toxicity. Conclusions: Preclinical studies demonostrated that vorinostat profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. Vorinostat administered orally once daily with concurrent whole brain radiation treatment is well tolerated to the dose of 300 mg. This is the recommended dose for phase II study. Clinical trial information: NCT00838929.
Characterization of the exposure-response relationship leading to recommendations for dosing optimization in a new drug application review.
Authors: Yang Jun , Mehrotra Nitin , Zhao Hong , Giusti Ruthann Marie , Demko Suzanne , Keegan Patricia , Booth Brian , Rahman Nam Atiqur 
Published: March 2020

2510 Background: On November 29 2012, the U. S. FDA approved cabozantinib (COMETRIQ) for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Drug-related toxicity was common at a dose of 140 mg once daily across Phase 1 to Phase 3 trials submitted in this NDA. During the review of this application, these safety findings raised the question whether the optimal cabozantinib dose was selected for the treatment of MTC. Exposure-response (E-R) analyses were performed to assess the appropriateness of the cabozantinib dose. Methods: The data were obtained from an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. To account for variable exposure levels due to dose modification and inter-individual pharmacokinetic variability, average exposure (Starting Dose*Dose intensity/individual CL/F) was used as the exposure metric in the E-R analyses. The relationships between cabozantinib exposure and progression free survival (PFS), and selected safety endpoints including diarrhea, palmar-plantar erythrodysesthesia (PPE) syndrome and time to dose modification (TTDM) were evaluated. Results: Kaplan-Meier analyses of PFS for each quartile of average cabozantinib exposure suggest that patients with lower exposure and those with higher exposure may have equivalent PFS, comparatively. The multivariate Cox proportional analysis identified individual patient’s clearance as a significant covariate for prediction of TTDM with a hazard ratio of 1.95 (95% CI [1.47-2.59]), suggesting that patients with higher exposures required dose modification earlier than patients with lower exposures. The results of the E-R analyses may be difficult to interpret due to the high rate of dose modification. Nevertheless, these results indicate that a lower dose may be as effective with improved tolerability. Conclusions: The E-R analyses along with the observed safety and efficacy data in the clinical trials led to an FDA requirement to conduct a post marketing clinical trial to evaluate the safety and efficacy of a lower cabozantinib dose.
Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop).
Authors: Balasubramaniam Sanjeeve , Bryla Christina , Redon Christophe E. , Lee Min-Jung , Peer Cody , Trepel Jane B. , Rajan Arun , Bonner William , Figg William Douglas , Fojo Antonio Tito , Piekarz Richard , Giaccone Giuseppe , Bates Susan Elaine 
Published: March 2020

2527 Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m2/24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and γH2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m2 and 80 mg/m2, respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m2/24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m2/24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m2/24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed γH2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring γH2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m2/24h, in combination with Cis 60 mg/m2 on day 1 and Etop 80 mg/m2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.
Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.
Authors: Milojkovic Kerklaan Bojana , Lolkema Martijn P. J. K. , Devriese Lot A. , Voest Emile E. , Nol-Boekel A. , Mergui-Roelvink M. , Mykulowycz Kristine , Stoebenau Joseph E , Fang Lei , Legenne Philippe , Wissel Paul Stephen , Smith Deborah A. , Giantonio Bruce J. , Schellens Jan HM , Witteveen Petronella 
Published: March 2020

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.